endothelin-1 and Inflammation

Aneurysmal subarachnoid hemorrhage (SAH) is an acute cerebrovascular emergency resulting from the rupture of a brain aneurysm. Despite only accounting for 5% of all strokes, SAH imposes a significant health burden on society due to its relatively young age at onset. Those who survive the initial bleed are often afflicted with severe disabilities thought to result from delayed cerebral ischemia (DCI). Consequently, elucidating the underlying mechanistic pathways implicated in DCI development following SAH remains a priority. Neuroinflammation has recently been implicated as a promising new theory for the development of SAH complications. However, despite this interest, clinical trials have failed to provide consistent evidence for the use of anti-inflammatory agents in SAH patients. This may be explained by the complexity of SAH as a plethora of inflammatory pathways have been shown to be activated in the disease. By determining how these pathways may overlap and interact, we hope to better understand the developmental processes of SAH complications and how to prevent them. The goal of this review is to provide insight into the available evidence regarding the molecular pathways involved in the development of inflammation following SAH and how SAH complications may arise as a result of these inflammatory pathways.

Topics: Brain Ischemia; Endothelin-1; Humans; Inflammation; Intracranial Aneurysm; Metabolic Networks and Pathways; Mitogen-Activated Protein Kinases; Oxyhemoglobins; Platelet Activating Factor; Reactive Oxygen Species; Serotonin; Subarachnoid Hemorrhage; Thrombin

The etiology of hypertension involves complex interactions among genetic, environmental, and pathophysiologic factors that influence many regulatory systems. Hypertension is characteristically associated with vascular dysfunction, cardiovascular remodelling, renal dysfunction, and stimulation of the sympathetic nervous system. Emerging evidence indicates that the immune system is also important and that activated immune cells migrate and accumulate in tissues promoting inflammation, fibrosis, and target-organ damage. Common to these processes is oxidative stress, defined as an imbalance between oxidants and antioxidants in favour of the oxidants that leads to a disruption of oxidation-reduction (redox) signalling and control and molecular damage. Physiologically, reactive oxygen species (ROS) act as signalling molecules and influence cell function through highly regulated redox-sensitive signal transduction. In hypertension, oxidative stress promotes posttranslational modification (oxidation and phosphorylation) of proteins and aberrant signalling with consequent cell and tissue damage. Many enzymatic systems generate ROS, but NADPH oxidases (Nox) are the major sources in cells of the heart, vessels, kidneys, and immune system. Expression and activity of Nox are increased in hypertension and are the major systems responsible for oxidative stress in cardiovascular disease. Here we provide a unifying concept where oxidative stress is a common mediator underlying pathophysiologic processes in hypertension. We focus on some novel concepts whereby ROS influence vascular function, aldosterone/mineralocorticoid actions, and immunoinflammation, all important processes contributing to the development of hypertension.

Topics: Aldosterone; Angiotensin II; Endothelin-1; Endothelium, Vascular; Humans; Hypertension; Inflammation; Intercellular Signaling Peptides and Proteins; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Sex Factors; Signal Transduction; Vascular Remodeling; Vascular Stiffness; Vasoconstriction

Endothelium guarantees vascular homeostasis by the opposite action of substances by vasodilating/antithrombogenic and vasoconstricting/prothrombotic activities. Obesity is characterized by endothelial dysfunction associated with a condition of vascular low-grade inflammation.. Analysis of available basic or clinical papers published in peer-reviewed international journals on microcirculation and obesity.. Vascular low-grade inflammation, which characterizes obesity, is secondary to abnormal production of proinflammatory cytokines, including TNF-α. TNF-α, generated either in small vessels or within the perivascular adipose tissue (PVAT) of patients with obesity, stimulates reactive oxygen species generation, mainly through NAD(P)H oxidase activation, which in turn reduces nitric oxide (NO) availability. These aspects are highlighted by the insulin resistance status and macronutrient intake that characterize the obesity condition. Oxidant excess has also been proposed as a mechanism whereby TNF-α interferes with the endothelin-1/NO system at the level of small vessels from patients with obesity.. In obesity, microvasculature from visceral fat is an important source of low-grade inflammation and oxidative stress that, together with the PVAT, directly contribute to vascular changes, favoring the development and acceleration of the vascular atherothrombotic process in this clinical condition.

Topics: Adipose Tissue; Endothelin-1; Endothelium, Vascular; Humans; Inflammation; Insulin; Insulin Resistance; Microvessels; Obesity; Oxidative Stress; Tumor Necrosis Factor-alpha

Preterm birth (PTB), defined as birth before 37 completed weeks of gestation, occurs in up to 18 percent of births worldwide and accounts for the majority of perinatal morbidity and mortality. While the single most common cause of PTB has been identified as inflammation, safe and effective pharmacotherapy to prevent PTB has yet to be developed.. Our group has used an in vivo model of inflammation-driven PTB, biochemical methods, pharmacological approaches, a novel endothelin receptor antagonist that we synthesized and RNA knockdown to help establish the role of endothelin-1 (ET-1) in inflammation-associated PTB. Further, we have used our in vivo model to test whether sphingosine kinase, which acts downstream of ET-1, plays a role in PTB.. We have shown that levels of endothelin converting enzyme-1 (ECE-1) and ET-1 are increased when PTB is induced in timed pregnant mice with lipopolysaccharide (LPS) and that blocking ET-1 action, pharmacologically or using ECE-1 RNA silencing, rescues LPS-induced mice from PTB. ET-1 activates the sphingosine kinase/sphingosine-1-phosphate (SphK/S1P) pathway. S1P, in turn, is an important signaling molecule in the proinflammatory response. Interestingly, we have shown that SphK inhibition also prevents LPS-induced PTB in timed pregnant mice. Further, we showed that SphK inhibition suppresses the ECE-1/ET-1 axis, implicating positive feedback regulation of the SphK/S1P/ECE-1/ET-1 axis.. The ET-1/SphK/SIP pathway is a potential pharmacotherapeutic target for the prevention of PTB.

Topics: Animals; Endothelin-1; Female; Humans; Inflammation; Lipopolysaccharides; Lysophospholipids; Mice; Phosphotransferases (Alcohol Group Acceptor); Pregnancy; Premature Birth; Sphingosine

Age-associated structural and functional remodeling of the arterial wall produces a productive environment for the initiation and progression of hypertension and atherosclerosis. Chronic aging stress induces low-grade proinflammatory signaling and causes cellular proinflammation in arterial walls, which triggers the structural phenotypic shifts characterized by endothelial dysfunction, diffuse intimal-medial thickening, and arterial stiffening. Microscopically, aged arteries exhibit an increase in arterial cell senescence, proliferation, invasion, matrix deposition, elastin fragmentation, calcification, and amyloidosis. These characteristic cellular and matrix alterations not only develop with aging but can also be induced in young animals under experimental proinflammatory stimulation. Interestingly, these changes can also be attenuated in old animals by reducing low-grade inflammatory signaling. Thus, mitigating age-associated proinflammation and arterial phenotype shifts is a potential approach to retard arterial aging and prevent the epidemic of hypertension and atherosclerosis in the elderly.

Topics: Aging; Animals; Arteries; Atherosclerosis; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Humans; Hypertension; Inflammation; Phenotype; Renin-Angiotensin System; Sympathetic Nervous System; Syndrome; Vascular Stiffness

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, mainly secreted by endothelial cells. It acts through two types of receptors: ETA and ETB. Apart from a vasoconstrictive action, ET-1 causes fibrosis of the vascular cells and stimulates production of reactive oxygen species. It is claimed that ET-1 induces proinflammatory mechanisms, increasing superoxide anion production and cytokine secretion. A recent study has shown that ET-1 is involved in the activation of transcription factors such as NF-κB and expression of proinflammatory cytokines including TNF-α, IL-1, and IL-6. It has been also indicated that during endotoxaemia, the plasma level of ET-1 is increased in various animal species. Some authors indicate a clear correlation between endothelin plasma level and morbidity/mortality rate in septic patients. These pathological effects of ET-1 may be abrogated at least partly by endothelin receptor blockade. ET-1 receptor antagonists may be useful for prevention of various vascular diseases. This review summarises the current knowledge regarding endothelin receptor antagonists and the role of ET-1 in sepsis and inflammation.

Topics: Animals; Bosentan; Cytokines; Endothelin Receptor Antagonists; Endothelin-1; Humans; Inflammation; Lipopolysaccharides; NF-kappa B; Oligopeptides; Peptides, Cyclic; Piperidines; Pyridines; Reactive Oxygen Species; Sepsis; Signal Transduction; Sulfonamides; Superoxides; Tetrazoles

The exact pathogenesis of multiple sclerosis (MS) is incompletely understood. Although auto-immune responses have an important role in the development of hallmark focal demyelinating lesions, the underlying mechanism of axonal degeneration, the other key player in MS pathology and main determinant of long-term disability, remains unclear and corresponds poorly with inflammatory disease activity. Perfusion-weighted imaging studies have demonstrated that there is a widespread cerebral hypoperfusion in patients with MS, which is present from the early beginning to more advanced disease stages. This reduced cerebral blood flow (CBF) does not seems to be secondary to loss of axonal integrity with decreased metabolic demands but appears to be mediated by elevated levels of the potent vasospastic peptide endothelin-1 in the cerebral circulation. Evidence is evolving that cerebral hypoperfusion in MS is associated with chronic hypoxia, focal lesion formation, diffuse axonal degeneration, cognitive dysfunction, and fatigue. Restoring CBF may therefore emerge as a new therapeutic target in MS.

Topics: Blood Flow Velocity; Brain Ischemia; Cerebrovascular Circulation; Cognition Disorders; Diffuse Axonal Injury; Endothelin-1; Humans; Inflammation; Multiple Sclerosis

Inflammation is one of the most important causes of the majority of cancer symptoms, including pain, fatigue, cachexia, and anorexia. Cancer pain affects 17 million people worldwide and can be caused by different mediators which act in primary efferent neurons directly or indirectly. Cytokines can be aberrantly produced by cancer and immune system cells and are of particular relevance in pain. Currently, there are very few strategies to control the release of cytokines that seems to be related to cancer pain. Nevertheless, in some cases, targeted drugs are available and in use for other diseases. In this paper, we aim to review the importance of cytokines in cancer pain and targeted strategies that can have an impact on controlling this symptom.

Topics: Adrenal Cortex Hormones; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemokines; Cyclooxygenase 2; Cytokines; Endothelin-1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Interferon-gamma; Interleukin-6; Neoplasms; Neurons, Efferent; Pain Management; Quality of Life

Arterial aging is the major contributing factor to increases in the incidence and prevalence of cardiovascular disease, due mainly to the presence of chronic, low-grade, 'sterile' arterial inflammation. Inflammatory signaling driven by the angiotensin II cascade perpetrates adverse age-associated arterial structural and functional remodeling. The aged artery is characterized by endothelial disruption, enhanced vascular smooth muscle cell (VMSC) migration and proliferation, extracellular matrix (ECM) deposition, elastin fracture, and matrix calcification/amyloidosis/glycation. Importantly, the molecular mechanisms of arterial aging are also relevant to the pathogenesis of hypertension and atherosclerosis. Age-associated arterial proinflammation is to some extent mutable, and interventions to suppress or delay it may have the potential to ameliorate or retard age-associated arterial diseases.

Topics: Aged; Aging; Angiotensin II; Animals; Antigens, Surface; Arteries; Arteritis; Atherosclerosis; Calpain; Chemokine CCL2; Endothelin-1; Humans; Hypertension; Inflammation; Inflammation Mediators; Matrix Metalloproteinase 2; Middle Aged; Milk Proteins; Muscle, Smooth, Vascular; Nitric Oxide; Reactive Oxygen Species; Receptors, CCR2; Transforming Growth Factor beta1

Endothelin-1 (ET-1) is the most potent vasoconstrictor peptide known. It exerts its actions through two pharmacologically different receptors: ETA and ETB receptors. In the renal vasculature, there is a majority of ETB receptors in the efferent arteriole, whereas a greater amount of ETA receptors are located in the afferent arteriole. The nephron is rich in ETB receptors, especially in the thick ascending limb and collecting ducts, while containing a smaller amount of ETA receptors. High levels of circulating or renal ET-1 have been described in cardiovascular diseases such as hypertension or diabetes, diseases also associated to renal inflammation. Despite extensive evidence associating high levels of ET-1 to increased renal inflammation, the molecular mechanism(s) by which ET-1 leads to renal immune infiltration and/or immune activation remains unknown. In this minireview, we propose that the ET-1/ETA pathway mediates an increase in renal endoplasmic reticulum (ER) stress, initially a survival mechanism that if prolonged, leads to the eventual death of the cell via apoptosis.

Topics: Animals; Endoplasmic Reticulum Stress; Endothelin-1; Inflammation; Kidney; Receptors, Endothelin; Vasoconstriction

Angiotensin II, through activation of the angiotensin II-type 1 receptor, induces generation of inflammatory mediators in the blood vessel wall and as such plays an active role in the inflammation process. Direct stimulation of reactive oxygen species and nuclear factors seem to be key mechanisms through which this receptor induces inflammation. Inflammatory molecules are also known to modify endothelial cell function, especially endothelium-derived vasoactive agents, and inflammation is increasingly recognized as primary cause of major vascular disorders. There is accumulating evidence that stimulation of the type 1 angiotensin II receptor participates in vascular dysfunction by reducing activity of the endothelium-derived relaxants nitric oxide and hyperpolarizing factors. Furthermore activation of this angiotensin II receptor also enhances generation of endothelium-derived constricting factors, such as endothelin-1. This change in endothelial cell output not only impairs blood vessel relaxation but leads to pro-inflammatory and pro-coagulation conditions that are associated with disease initiation and progression. Pharmacological inhibitors of the angiotensin II pathway and the type 1 receptor subtype are in current clinical use for the treatment of hypertension. However evidence supports that these agents have a positive therapeutic benefit in other vascular pathologies with recognized inflammatory etiology, such as atherosclerosis.

Topics: Animals; Cytokines; Endothelin-1; Endothelium-Dependent Relaxing Factors; Endothelium, Vascular; Humans; Inflammation; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Vascular Diseases; Vasoconstriction; Vasodilation

Biomarkers have been intensively studied in community-acquired pneumonia (CAP) in recent years. In the context of the CAPNETZ study we had the unique opportunity to evaluate old and new biomarkers in a multicentre study with a high number of patients.. In several substudies we found the following results: procalcitonin, CRP and leukocytes show highest values in patients with typical bacterial etiology of CAP, but do not allow individual prediction of etiology. Patients without antibiotic pre-treatment show higher values of biomarkers compared to patients with antibiotic pre-treatment. New cardiovascular biomarkers are good predictors for short- and long-term mortality in CAP, superior to the inflammatory markers procalcitonin, CRP and leukocytes and at least comparable to the clinical CRB-65 score. Pro-Adrenomedullin is among the new biomarkers the one with the best prognostic value.. Biomarkers correlate with the severity of CAP but do not allow individual prediction of etiology. New cardiovascular biomarkers are suitable for the evaluation of short- and long-term prognosis in CAP. The combination of several biomarkers reflecting different pathophysiological pathways has the potential to improve management of CAP in the future.

Topics: Adolescent; Adrenomedullin; Adult; Age Distribution; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Community-Acquired Infections; Comorbidity; Endothelin-1; Female; Germany; Humans; Inflammation; Leukocyte Count; Male; Middle Aged; Pneumonia; Predictive Value of Tests; Protein Precursors; Respiratory Rate; Survival Analysis; Vasopressins; Young Adult

Preeclampsia is a pregnancy-induced hypertensive disorder found most commonly in nulliparous women. Recent research performed in animal models of the disease has revealed some of the underlying mechanisms of preeclampsia. Specifically, placental insufficiency and the resulting hypoxia/ischemia have been shown to be crucial to disease progression. In response to placental hypoxia/ischemia, several pathways are activated, which contribute to the clinical manifestations of the disease: increased circulating levels of the anti-angiogenic protein sFlt-1, activation of the maternal inflammatory response, suppressed nitric oxide production, enhanced endothelin-1 production, and induction of reactive oxygen formation. Despite advances in the understanding of the disorder, therapeutic approaches to the treatment of preeclampsia are severely limited. New lines of research, however, indicate some possible new therapeutic approaches for the management of preeclampsia and offer hope for an effective pharmacologic intervention.

Topics: Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypoxia; Inflammation; Phosphodiesterase 5 Inhibitors; Piperazines; Placenta; Pre-Eclampsia; Pregnancy; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vascular Endothelial Growth Factor A

The endothelial integrity, as mechanical barrier against microorganisms and as natural "anticoagulant", is crucial for physiologic organ function. Systemic activation of the endothelium upon inflammation, sepsis, and septic shock is always ending in blood-tissue barrier disruption. With increasing dysfunction, uncontrolled clotting activation, capillary microthrombi formation, tissue edema, local hypoxia, and ischemia are initiated. This in turn enhances a vicious circle leading to multiple organ failure and death. Therefore, biomarkers reflecting this special compartment may help in the early detection of systemic inflammation and its complications. This review provides an overview of the most important endothelial biomarkers and their possible use in sepsis.

Topics: ADAM Proteins; ADAMTS13 Protein; Angiopoietin-1; Angiopoietin-2; Biomarkers; Child; Endothelin-1; Endothelium, Vascular; Fibrin Fibrinogen Degradation Products; Humans; Infant, Newborn; Inflammation; Multiple Organ Failure; Neoplasm Proteins; Plasminogen Activator Inhibitor 1; Platelet-Derived Growth Factor; Proteoglycans; Selectins; Sepsis; Shock, Septic; Urokinase-Type Plasminogen Activator; Vascular Endothelial Growth Factor A; von Willebrand Factor

ET (endothelin)-1 was first described as a potent vasoconstrictor. Since then, many other deleterious properties mediated via its two receptors, ETA and ETB, have been described, such as inflammation, fibrosis and hyperplasia. These effects, combined with a wide tissue distribution of the ET system, its up-regulation in pathological situations and a local autocrine/paracrine activity due to a high tissue receptor binding, make the tissue ET system a key local player in end-organ damage. Furthermore, ET-1 interacts in tissues with other systems such as the RAAS (renin-angiotensin-aldosterone system) to exert its effects. In numerous genetically modified animal models, non-specific or organ-targeted ET-1 overexpression causes intense organ damage, especially hypertrophy and fibrosis, in the absence of haemodynamic changes, confirming a local activity of the ET system. ET receptor antagonists have been shown to prevent and sometimes reverse these tissue alterations in an organ-specific manner, leading to long-term benefits and an improvement in survival in different animal models. Potential for such benefits going beyond a pure haemodynamic effect have also been suggested by clinical trial results in which ET receptor antagonism decreased the occurrence of new digital ulcers in patients with systemic sclerosis and delayed the time to clinical worsening in patients with PAH (pulmonary arterial hypertension). The tissue ET system allows therapeutic interventions to provide organ selectivity and beneficial effects in diseases associated with tissue inflammation, hypertrophy or fibrosis.

Topics: Animals; Cell Communication; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Fibrosis; Humans; Hypertrophy; Inflammation; Vasoconstriction

Vascular inflammation underlies the pathogenesis of atherosclerosis. Atherosclerotic changes in the vasculature lead to conditions such as coronary artery disease and stroke, which are the major causes of morbidity and mortality worldwide. Epidemiological studies in premenopausal women suggest a beneficial role for estrogen in preventing vascular inflammation and consequent atherosclerosis. However, the benefits of estrogen areabsent or even reversed in older postmenopausal subjects. The modulation of inflammation by estrogen under different conditions might explain this discrepancy. Estrogen exerts its antiinflammatory effects on the vasculature through different mechanisms such as direct antioxidant effect, generation of nitric oxide, prevention of apoptosis in vascular cells and suppression of cytokines and the renin-angiotensin system. On the other hand, estrogen also elicits proinflammatory changes under certain conditions, which are less completely understood. Some of the mechanisms underlying a possible proinflammatory role for estrogen include increased expression of the proinflammatory receptor for advanced glycation end products, increased tyrosine nitration of cellular proteins, and generation of reactive oxygen species through an uncoupled eNOS. In this review, we have presented evidence for both antiinflammatory and proinflammatory pathways modulated by estrogen and how interactions among such pathways might determine the effects of estrogen on the vascular system.

Topics: Aging; Animals; Antioxidants; Apoptosis; Atherosclerosis; Cytokines; Endothelin-1; Estrogens; Female; Humans; Inflammation; Models, Biological; Nitric Oxide; Permeability; Tumor Necrosis Factor-alpha

Heart disease is among the leading causes of death in all populations. Cardiac dysfunctions are major complications in patients with advanced viral or bacterial infection, severe trauma and burns accompanied with multiple organ failure - collectively known as systemic inflammatory response syndrome (SIRS). SIRS, which is often subsequent to sepsis, is clinically featured by hypotension, tachypnea, hypo- or hyperthermia, leukocytosis and myocardial dysfunction. The striking association between inflammation and cardiac dysfunction not only prognoses likelihood of survival in patients with SIRS but also prompts the necessity of understanding the pathophysiology of cardiac dysfunction in SIRS, so that effective therapeutic regimen may be identified. Compelling evidence has shown significant and independent link among inflammation, sepsis, insulin resistance and cardiac dysfunction. Several cytokine signaling molecules have been speculated to play important roles in the onset of cardiac dysfunction under SIRS including endothelin-1 and toll-like receptor. Involvement of these pathways in cardiac dysfunction has been convincingly validated with transgenic studies. Nevertheless, the precise mechanism of action underscoring inflammation-induced cardiac contractile dysfunction is far from being clear. Given the substantial impact of inflammation and SIRS on health care, ecosystems and national economy, it is imperative to understand the cellular mechanisms responsible for cardiac contractile dysfunction under inflammation and sepsis so that new and effective therapeutic strategy against such devastating heart problems may be developed.

Topics: Animals; Biopterins; Cytokines; Diabetes Mellitus; Endothelin-1; Heart Diseases; Humans; Inflammation; Insulin Resistance; Myocardium; Nitric Oxide; Sepsis; Shock, Septic; Systemic Inflammatory Response Syndrome; Toll-Like Receptors

Endothelial cells synthesize and release various factors that regulate angiogenesis, inflammatory responses, hemostasis, as well as vascular tone and permeability. Endothelial dysfunction has been associated with a number of pathophysiological processes. Oxidative stress appears to be a common denominator underlying endothelial dysfunction in cardiovascular diseases. However, depending on the pathology, the vascular bed studied, the stimulant, and additional factors such as age, sex, salt intake, cholesterolemia, glycemia, and hyperhomocysteinemia, the mechanisms underlying the endothelial dysfunction can be markedly different. A reduced bioavailability of nitric oxide (NO), an alteration in the production of prostanoids, including prostacyclin, thromboxane A2, and/or isoprostanes, an impairment of endothelium-dependent hyperpolarization, as well as an increased release of endothelin-1, can individually or in association contribute to endothelial dysfunction. Therapeutic interventions do not necessarily restore a proper endothelial function and, when they do, may improve only part of these variables.

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Hemostasis; Humans; Hypertension; Inflammation; Nitric Oxide; Oxidative Stress; Rats; Rats, Inbred SHR; Reactive Oxygen Species

When studying the impact of endothelins (ETs) on physiology and pathophysiology, this needs to be done in the context of nitric oxide (NO) synthesis and action, since these two are closely intertwined in their action. Here, we will review the work demonstrating the crosstalk between endothelin-1 (ET-1) and NO, and the recent developments regarding the role of these two mediators in inflammatory processes. Moreover, we will discuss the role of NO in pro-inflammatory diseases and the potential mechanisms of the anti-inflammatory activity of ET receptor antagonism.

Topics: Endothelin Receptor Antagonists; Endothelin-1; Humans; Inflammation; Nitric Oxide; Nitric Oxide Synthase

Endothelin (ET)-1 is a potent renal vasoconstrictor with pro-inflammatory, profibrotic and mitogenic potential. Animal studies support a pathogenetic contribution of ET-1 and its cognate receptors in several renal manifestations of autoimmune disorders. However, data in humans are limited. The present minireview thus summarizes the observations available in humans. Similar to animal models, ET-1 is overexpressed in glomerular and tubulointerstitial lesions, which is reflected by an increased urinary excretion of ET-1. Since antagonizing the ET system has beneficial effects in experimental models, this approach may be translated to the human kidney, thus counteracting vasoconstriction, inflammation and extracellular matrix deposition during the course of human autoimmune disease.

Topics: Autoimmune Diseases; Endothelin-1; Humans; Inflammation; Kidney Diseases; Receptors, Endothelin; Vasoconstriction

Endothelin-1 (ET-1) is a 21-amino acid polypeptide produced primarily by vascular endothelial cells. First discovered in 1988 as a potent vasoconstrictor, it has subsequently been appreciated to participate in several biologic activities, including vascular smooth muscle proliferation, fibrosis, cardiac and vascular hypertrophy, and inflammation. Increasing data demonstrate alterations in ET-1 signaling in newborns, infants, and children with congenital heart defects that are associated with alterations in pulmonary blood flow. This review outlines the pathophysiologic role of the ET-1 cascade in the development of altered pulmonary vascular tone and reactivity that occurs with congenital heart disease and its repair, following the use of cardiopulmonary bypass. In addition, therapeutic implications for the use of novel ET receptor antagonists will be emphasized.

Topics: Animals; Cardiopulmonary Bypass; Child, Preschool; Endothelin Receptor Antagonists; Endothelin-1; Heart Diseases; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Inflammation; Models, Biological; Peptides; Pulmonary Circulation; Pulmonary Veins; Signal Transduction; Vasoconstrictor Agents

Evidence suggests that vascular endothelium plays key role in the regulation of vascular tone, in the process of inflammation and in the thrombotic mechanisms. Recent studies indicate that it is an important component of the pathophysiological mechanisms of heart failure. Heart failure may induce endothelial dysfunction by different mechanisms, such as reduced synthesis and release of nitric oxide (NO), increased degradation of NO or by increased production of endothelin-1. In addition, endothelial dysfunction has been associated with the progression of heart failure. Alterations in neurotransmitters, hormones and also in physiological stimuli are present in heart failure and affect the vascular endothelium. Treatments with beneficial effects on endothelial dysfunction may also improve prognosis in patients with heart failure.

Topics: Animals; Apoptosis; Carnitine; Cell Adhesion Molecules; Endothelin-1; Endothelium, Vascular; Exercise; Heart Failure; Humans; Inflammation; Nitric Oxide; Tumor Necrosis Factor-alpha

Vascular inflammation is involved in the initiation and progression of atherosclerosis, and is also present in hypertension- and diabetes-induced vascular complications. Angiotensin II (Ang II), the key effector of the renin-angiotensin system (RAS), plays a central role in the regulation of blood pressure and electrolyte homeostasis. There is accumulating evidence to indicate that Ang II is also capable of inducing inflammatory response in the vascular wall. This review summarizes the current understanding of the molecular mechanisms and signal transduction pathways of Ang II-induced vascular inflammation. The roles of modulators of Ang II-induced inflammatory response, such as nitric oxide (NO), bradykinin, cyclooxygenase-2 (COX-2), endothelin-1 (ET-1), and epoxyeicosatrienoic acids (EETs), are also discussed. The current data suggest that Ang II modifies several steps of inflammatory response, such as increase of vascular permeability, leukocyte infiltration, tissue hypertrophy/proliferation, and fibrosis. Ang II, via the type 1 (AT1) receptors, enhances the production of reactive oxygen species (ROS) through stimulation of NAD(P)H oxidase in the vascular wall. Increased oxidative stress contributes to endothelial dysfunction and to vascular inflammation by stimulating the redox-sensitive transcription factors (NF-kappaB) and by upregulating adhesion molecules, cytokines, and chemokines. The pro-inflammatory action of Ang II may help us to understand the molecular mechanisms of hypertension- and diabetes-induced vascular complication as well as the pleiotropic actions of drugs interfering with RAS.

Topics: Angiotensin II; Animals; Blood Vessels; Capillary Permeability; Cyclooxygenase 2; Endothelin-1; Humans; Inflammation; Membrane Proteins; Nitric Oxide; Prostaglandin-Endoperoxide Synthases; Signal Transduction

Idiopathic pulmonary fibrosis (IPF) is a chronic and usually progressive lung disorder of unknown aetiology. Conventional management of patients with IPF has been primarily based on the concept that suppressing inflammation would prevent progression to fibrosis. Although the pathogenesis is incompletely understood, it is here suggested that IPF is a disease of abnormal wound repair and remodelling in the lung rather than an inflammatory disease. Therefore, treatment strategies are no longer aimed at reducing inflammation, but rather at preventing or inhibiting the fibroproliferative responses and enhancing efficient alveolar epithelial repair. So far, no cell-specific drugs for these purposes are clinically available. However, novel promising molecules or drugs are being studied in experimental models or ongoing clinical trials in patients with IPF. Evolving hypotheses on the pathogenesis of IPF are reviewed, focusing on possible implications for future therapies. A better understanding of the sequence of the pathogenic mechanisms that control the fibrotic response will hopefully lead to efficient therapies and finally a favourable outcome in patients with this disease.

Topics: Animals; Apoptosis; Cytokines; Endothelin-1; Epithelium; Fibrinolysis; Fibroblasts; Humans; Inflammation; Plasminogen Activator Inhibitor 1; Pulmonary Alveoli; Pulmonary Fibrosis; Signal Transduction; Wound Healing

It has long since been recognized that mast cells are critical effectors of anaphylactic reactions, and the existence of these potentially hazardous cells has solely been justified due to their beneficial role in some infections with extracellular parasites. A novel understanding of mast cells as sentinels of the immune system has been made possible by taking advantage of mast cell-deficient mice in order to study the roles of mast cells in vivo and by detailed analyses of mast cell activation in vitro. Collectively, these experiments have revealed a variety of IgE-independent stimuli, which lead to the activation of mast cells as crucial initiators of an inflammatory response. Besides their effector function, a variety of studies reviewed herein point towards important regulatory roles for mast cells, especially regarding their interaction with other cell types.

Topics: Adenosine; Animals; Cell Degranulation; Disease Models, Animal; Endothelin-1; Gene Expression Regulation; Immune System; Immunoglobulin G; Infections; Inflammation; Mast Cells; Neurosecretory Systems; Receptors, IgE

Some patients with COPD are prone to frequent exacerbations, which are an important determinant of health status. Such patients have elevated airway cytokine levels, suggesting the presence of increased inflammation that may increase their susceptibility to exacerbation. The inflammatory response during a COPD exacerbation is variable, but increases in interleukin-6 levels during the exacerbation are related to the presence of a common cold. Rhinovirus infection is the most important etiologic factor in COPD exacerbations and is an important target for preventive therapy. The reduction of COPD exacerbations will have an important impact on the considerable morbidity and mortality associated with COPD.

Topics: Endothelin-1; Environmental Pollution; Humans; Inflammation; Interleukin-6; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Infections

Topics: Animals; Cytokines; Endothelin-1; Humans; Inflammation; Lung; Mice; Mice, Transgenic; Pulmonary Fibrosis; Receptors, Endothelin; T-Lymphocyte Subsets

This review seeks to examine the potential contribution of the recently discovered peptide endothelin-1 to the pathophysiology of asthma. The actions of endothelin-1 which mimic features of asthma, the evidence for increased production of endothelin-1 in asthma and the potential for asthma therapy based on modification of the activity of endothelin-1 are reviewed.

Topics: Airway Obstruction; Animals; Asthma; Bronchial Provocation Tests; Endothelin Receptor Antagonists; Endothelin-1; Humans; Inflammation; Mucous Membrane

Lipid and nonlipid mechanisms contribute to the beneficial effects of some statins on endothelial function, plaque stability and thrombus formation. The nonlipid effects of statins may contribute to alleviation of tissue ischemia and prevention of acute cardiovascular syndromes. Endothelial dysfunction is reversed by a statin and this beneficial property results, in part, from direct actions on the endothelial vasoactive factors, nitric oxide and endothelin-1. Some statins have been shown to inhibit production of proinflammatory cytokines that regulate many key functions of the vascular wall including monocyte adhesion, chemotaxis, and metalloproteinase secretion. Vascular smooth muscle cell synthetic capacity and viability is inhibited by lipophilic agents, whereas a hydrophilic agent does not interfere with this reparative response. Some statins may impede thrombogenesis by reduced activation of the extrinsic coagulation pathway, inhibition of platelet adhesion and aggregation, and improvement in the rheologic profile.

Topics: Anticholesteremic Agents; Arteriosclerosis; Blood Coagulation; Cytokines; Endothelin-1; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Lovastatin; Nitric Oxide; Plasminogen Activator Inhibitor 1

Increased endothelin-1 (ET-1) levels in patients with sickle cell disease (SCD) and transgenic mouse models of SCD contribute to disordered hematological, vascular, and inflammatory responses. Mineralocorticoid receptor (MR) activation by aldosterone, a critical component of the Renin-Angiotensin-Aldosterone-System, modulates inflammation and vascular reactivity, partly through increased ET-1 expression. However, the role of MR in SCD remains unclear. We hypothesized that MR blockade in transgenic SCD mice would reduce ET-1 levels, improve hematological parameters, and reduce inflammation. Berkeley SCD (BERK) mice, a model of severe SCD, were randomized to either sickle standard chow or chow containing the MR antagonist (MRA), eplerenone (156 mg/Kg), for 14 days. We found that MRA treatment reduced ET-1 plasma levels (p = .04), improved red cell density gradient profile (D

Topics: Aldosterone; Anemia, Sickle Cell; Animals; Disease Models, Animal; Endothelial Cells; Endothelin-1; Humans; Inflammation; Mice; Mice, Transgenic; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Vascular Diseases

Experimental and clinical studies have demonstrated the effect of phytosterols (PS) on reducing plasma levels of cholesterol and LDL-c, but the effects of plant sterols beyond cholesterol-lowering are still questionable. Since inflammation and endothelial dysfunction are involved in the pathogenesis of atherosclerosis, this study aims to evaluate the effect of PS on biomarkers involved in atherosclerosis progression and whether these effects are independent of alterations in plasma LDL-c levels. Thirty-eight moderately hypercholesterolemic volunteers (58 ± 12 years; LDL-c ≥ 130 mg/dL) were randomly assigned to consume 400 mL/day of soy milk or soy milk + PS (1.6 g/day) for 4 weeks in a double-blind, placebo-controlled, cross-over study. Blood samples were collected and lipid profiles and biomarkers for inflammation and endothelial dysfunction determined. The results showed that PS treatment reduced endothelin-1 plasma concentration by 11% (

Topics: Adult; Aged; Apolipoproteins B; Atherosclerosis; Biomarkers; Brazil; C-Reactive Protein; Cholesterol; Cholesterol, LDL; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Endothelin-1; Female; Humans; Hypercholesterolemia; Inflammation; Lipids; Male; Middle Aged; Phytosterols; Plasma; Soy Milk; Sterols; Triglycerides

Childhood obesity is strongly associated with cardiovascular disease (CVD) development. It is necessary to combat unfavorable outcomes of obesity at a young age by utilizing effective interventions, such as exercise.. We sought to examine the effects of a jump rope exercise program on CVD risk factors, including body composition, vasoactive substances, inflammation, and vascular function in prehypertensive adolescent girls.. Forty girls (age 14-16) were recruited and randomly assigned to a jump rope exercise group (EX, n = 20) or control group (CON, n = 20). Body composition, nitrate and nitrite levels, endothelin-1 (ET-1), C-reactive protein (CRP), systolic blood pressure and diastolic blood pressure (SBP, DBP), and arterial stiffness were measured before and after 12 weeks.. There were significant group by time interactions following the 12-week program for body composition (from 33.8 ± 3.6 to 30.2 ± 3.1%), central adiposity (from 86.4 ± 4 to 83.3 ± 5 cm), SBP (from 126 ± 3.3 to 120 ± 2.1 mmHg), and brachial-to-ankle pulse wave velocity (from 8.2 ± 1.0 to 7.4 ± 0.2 m/s). Nitrate/nitrite levels increased (from 54.5 ± 5.1 to 57.2 ± 5.2 µmol) along a reduction in CRP levels (from 0.5 ± 0.4 to 0.2 ± 0.1 mg/L). There were no significant changes in ET-1 (P = 0.22).. These findings indicate that jump rope exercise may be an effective intervention to improve these CVD risk factors in prehypertensive adolescent girls. Jumping rope is an easily accessible exercise modality that may have important health implications for CVD prevention in younger populations.

Topics: Adiposity; Adolescent; Blood Pressure; Body Composition; C-Reactive Protein; Endothelin-1; Exercise Therapy; Female; Humans; Inflammation; Prehypertension; Treatment Outcome; Vascular Stiffness

This study investigated effects of grape consumption on biomarkers of cardiovascular health in obese participants in both postprandial and chronic settings. Twenty obese adults participated in this randomized, placebo controlled, double-blinded crossover trial. Participants were randomized to consume 60 g freeze-dried polyphenol-rich whole grape powder (GP) or placebo (PBO) followed by high fat high carbohydrate (HFHC) meal challenge. Following acute challenge, participants consumed their respective treatment daily for 4 weeks to determine effects of chronic consumption. Consumption of GP with HFHC meal significantly increased nuclear factor (erythroid-derived 2)-like 2 (NRF2) expression in peripheral blood mononuclear cells (PBMC) at 3 h (p < 0.05) and decreased plasma endothelin-1 (ET-1) concentration at 5 h (p < 0.05) after meal challenge compared with PBO. Following 4 weeks of daily GP consumption, soluble vascular cell adhesion molecule 1 (sVCAM-1) plasma concentration increased compared with PBO (p < 0.05), however baseline values differed between treatments. In conclusion, GP consumption resulted in decreased vasoconstrictor ET-1 concentration and increased gene expression related to oxidative stress defense following HFHC meal. Except for increase in sVCAM-1 concentration, 4 weeks of chronic GP consumption had little effect on cardiovascular biomarkers measured in this study. This trial was registered: clinicaltrials.gov NCT01674231.

Topics: Adult; Biomarkers; Cross-Over Studies; Diet, Carbohydrate Loading; Diet, High-Fat; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Female; Gene Expression; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Leukocytes, Mononuclear; Male; Middle Aged; NF-E2-Related Factor 2; Obesity; Oxidative Stress; Polyphenols; Postprandial Period; RNA, Messenger; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vitis

Childhood and adolescent obesity is a major international public health crisis. It is crucial to prevent the negative effects of obesity at an early age by implementing appropriate lifestyle interventions, such as exercise training. We evaluated the effects of a combined resistance and aerobic exercise training (CET) regimen on arterial stiffness, vasoactive substances, inflammatory markers, metabolic profile, and body composition in obese adolescent girls.. A total of 30 obese adolescent girls were randomly assigned to a CET (n = 15) or a control group (n = 15). The CET group trained for 3 days per week. Plasma nitric oxide, endothelin-1, C-reactive protein, arterial stiffness, glucose, insulin, the adiponectin/leptin ratio, and body fat were measured before and after 12 weeks.. There were significant increases (P < .05) in nitric oxide (4.0 μM) and adiponectin/leptin ratio (0.33); and decreases (P < .05) in arterial stiffness (-1.0 m/s), C-reactive protein (-0.5 mg/L), glucose (-1.2 mmol/L), insulin (-17.1 μU/mL), and body fat (-3.6%) following CET compared with control. There were no significant changes in endothelin-1 after CET or control.. The findings of this study indicate that CET improves arterial stiffness, nitric oxide, and inflammatory and metabolic markers in obese adolescent girls. CET may have important health implications for the prevention of atherosclerosis at an early age.

Topics: Adiponectin; Adolescent; Biomarkers; Blood Glucose; Body Composition; C-Reactive Protein; Endothelin-1; Exercise; Female; Humans; Inflammation; Insulin; Leptin; Metabolome; Nitric Oxide; Obesity; Resistance Training; Vascular Stiffness

Vascular risk factors, including inflammation, may contribute to dementia development. We investigated the associations between peripheral inflammatory biomarkers and cognitive decline in five domains (memory, construction, language, psychomotor speed, and executive function).. Community-dwelling older adults from the Ginkgo Evaluation of Memory Study (n = 1,159, aged 75 or older) free of dementia at baseline were included and followed for up to 7 years. Ten biomarkers were measured at baseline representing different sources of inflammation: vascular inflammation (pentraxin 3 and serum amyloid P), endothelial function (endothelin-1), metabolic function (adiponectin, resistin, and plasminogen activating inhibitor-1), oxidative stress (receptor for advanced glycation end products), and general inflammation (interleukin-6, interleukin-2, and interleukin-10). A combined z-score was created from these biomarkers to represent total inflammation across these sources. We utilized generalized estimating equations that included an interaction term between z-scores and time to assess effect of inflammation on cognitive decline, adjusting for demographics (such as age, race/ethnicity, and sex), cardiovascular risk factors, and apolipoprotein E ε4 carrier status. A Bonferroni-adjusted significance level of .01 was used. We explored associations between individual biomarkers and cognitive decline without adjustment for multiplicity.. The combined inflammation z-score was significantly associated with memory and psychomotor speed (p < .01). Pentraxin 3, serum amyloid P, endothelin-1, and interleukin-2 were associated with change in at least one cognitive domain (p < .05).. Our results suggest that total inflammation is associated with memory and psychomotor speed. In particular, systemic inflammation, vascular inflammation, and altered endothelial function may play roles in domain-specific cognitive decline of nondemented individuals.

Topics: Adiponectin; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Cognitive Dysfunction; Endothelin-1; Endothelium, Vascular; Female; Follow-Up Studies; Humans; Inflammation; Interleukins; Male; Neuropsychological Tests; Plasminogen Activator Inhibitor 1; Receptor for Advanced Glycation End Products; Resistin; Serum Amyloid P-Component

Psychological constructs are associated with cardiovascular health, but the biological mechanisms mediating these relationships are unknown. We examined relationships between psychological constructs and markers of inflammation, endothelial function, and myocardial strain in a cohort of post-acute coronary syndrome (ACS) patients.. Participants (N = 164) attended study visits 2 weeks and 6 months after ACS. During these visits, they completed self-report measures of depressive symptoms, anxiety, optimism, and gratitude; and blood samples were collected for measurement of biomarkers reflecting inflammation, endothelial function, and myocardial strain. Generalized estimating equations and linear regression analyses were performed to examine concurrent and prospective relationships between psychological constructs and biomarkers.. In concurrent analyses, depressive symptoms were associated with elevated markers of inflammation (interleukin-17: β = .047; 95% confidence interval [CI] = .010-.083]), endothelial dysfunction (endothelin-1: β = .020; 95% [CI] = .004-.037]), and myocardial strain (N-terminal pro-B-type natriuretic peptide: β = .045; 95% [CI] = .008-.083]), independent of age, sex, medical variables, and anxiety, whereas anxiety was not associated with these markers in multivariable adjusted models. Optimism and gratitude were associated with lower levels of markers of endothelial dysfunction (endothelin-1: gratitude: β = -.009; 95% [CI] = -.017 to - .001]; optimism: β = -.009; 95% [CI] = -.016 to - .001]; soluble intercellular adhesion molecule-1: gratitude: β = -.007; 95% [CI] = -.014 to - .000]), independent of depressive and anxiety symptoms. Psychological constructs at 2 weeks were not prospectively associated with biomarkers at 6 months.. Depressive symptoms were associated with more inflammation, myocardial strain, and endothelial dysfunction in the 6 months after ACS, whereas positive psychological constructs were linked to better endothelial function. Larger prospective studies may clarify the directionality of these relationships.. Clinicaltrials.gov identifier NCT01709669.

Topics: Acute Coronary Syndrome; Aged; Biomarkers; Depression; Endothelin-1; Female; Follow-Up Studies; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-17; Male; Middle Aged; Natriuretic Peptide, Brain; Optimism; Peptide Fragments

Obstructive sleep apnoea (OSA) is associated with cardiovascular disease. Intermittent hypoxia, endothelial dysfunction and adipose tissue-mediated inflammation have all been linked to cardiovascular disease in OSA. We therefore explored the effect of OSA on relevant associated blood markers: adrenomedullin (ADM), endocan, endothelin-1 (ET-1), resistin and vascular endothelial growth factor (VEGF).. Patients with OSA, established on and compliant with continuous positive airways pressure (CPAP) therapy for >1 year were included from three randomized controlled trials, conducted at two centres. Patients were randomized to either continued therapeutic CPAP or sham CPAP (CPAP withdrawal) for 2 weeks. Blood markers were measured at baseline and at 14 days and the treatment effect between sham CPAP and therapeutic CPAP was analysed.. A total of 109 patients were studied (therapeutic CPAP n = 54, sham CPAP n = 55). Sham CPAP was associated with a return of OSA (between-group difference in oxygen desaturation index (ODI) 36.0/h, 95% CI 29.9-42.2, P < 0.001). Sham CPAP was associated with a reduction in ADM levels at 14 days (-26.0 pg/mL, 95% CI -47.8 to -4.3, P = 0.02), compared to therapeutic CPAP. Return of OSA was not associated with changes in endocan, ET-1, resistin or VEGF.. Whilst CPAP withdrawal was associated with return of OSA, it was associated with an unexpected significant reduction in the vasodilator ADM and not with expected increases in hypoxia-induced markers, markers of endothelial function or resistin. We propose that the vascular effects occurring in OSA may be brought about by other mechanisms, perhaps partly through a reduction in ADM.

Topics: Adrenomedullin; Adult; Aged; Biomarkers; Continuous Positive Airway Pressure; Endothelin-1; Female; Humans; Hypoxia; Inflammation; Male; Middle Aged; Neoplasm Proteins; Patient Compliance; Proteoglycans; Resistin; Sleep Apnea, Obstructive; Vascular Endothelial Growth Factor A; Ventilator Weaning

A limited number of studies have demonstrated that some modulators of inflammation can be altered by the consumption of sweet cherries. We have taken a proteomics approach to determine the effects of dietary cherries on targeted gene expression. The purpose was then to determine changes caused by cherry consumption in the plasma concentrations of multiple biomarkers for several chronic inflammatory diseases in healthy humans with modestly elevated C-reactive protein (CRP; range, 1-14 mg/L; mean, 3.5 mg/L; normal, <1.0 mg/L). Eighteen men and women (45-61 y) supplemented their diets with Bing sweet cherries (280 g/d) for 28 d. Fasting blood samples were taken before the start of consuming the cherries (study d 7), 28 d after the initiation of cherry supplementation (d 35), and 28 d after the discontinuation (d 63). Of the 89 biomarkers assessed, cherry consumption for 28 d altered concentrations of 9, did not change those of 67, and the other 13 were below the detection limits. Cherry consumption decreased (P < 0.05) plasma concentrations of extracellular newly identified ligand for the receptor for advanced glycation end products (29.0%), CRP (20.1%), ferritin (20.3%), plasminogen activator inhibitor-1 (19.9%), endothelin-1 (13.7%), epidermal growth factor (13.2%), and IL-18 (8.1%) and increased that of IL-1 receptor antagonist (27.9%) compared with corresponding values on study d 7. The ferritin concentration continued to decrease between d 35 and 63 and it was significantly lower on d 63 than on d 7. Because the participants in this study were healthy, no clinical pathology end points were measured. However, results from the present study demonstrate that cherry consumption selectively reduced several biomarkers associated with inflammatory diseases.

Topics: Biomarkers; C-Reactive Protein; Chronic Disease; Diet; Dietary Supplements; Endothelin-1; Epidermal Growth Factor; Female; Ferritins; Fruit; Humans; Inflammation; Inflammation Mediators; Interleukin-18; Male; Middle Aged; Phytotherapy; Plant Preparations; Plasminogen Activator Inhibitor 1; Proteomics; Prunus; Receptors, Interleukin-1; Reference Values

To provide scientific evidence supporting the efficacy of forest bathing as a natural therapy for human hypertension.. Twenty-four elderly patients with essential hypertension were randomly divided into two groups of 12. One group was sent to a broad-leaved evergreen forest to experience a 7-day/7-night trip, and the other was sent to a city area in Hangzhou for control. Blood pressure indicators, cardiovascular disease-related pathological factors including endothelin-1, homocysteine, renin, angiotensinogen, angiotensin II, angiotensin II type 1 receptor, angiotensin II type 2 receptor as well as inflammatory cytokines interleukin-6 and tumor necrosis factor α were detected. Meanwhile, profile of mood states (POMS) evaluation was used to assess the change of mood state of subjects. In addition, the air quality in the two experimental sites was monitored during the 7-day duration, simultaneously.. The baselines of the indicators of the subjects were not significantly different. Little alteration in the detected indicators in the city group was observed after the experiment. While subjects exposed to the forest environment showed a significant reduction in blood pressure in comparison to that of the city group. The values for the bio-indicators in subjects exposed to the forest environment were also lower than those in the urban control group and the baseline levels of themselves. POMS evaluation showed that the scores in the negative subscales were lowered after exposure to the forest environment. Besides, the air quality in the forest environment was much better than that of the urban area evidenced by the quantitative detection of negative ions and PM10 (particulate matter < 10 μm in aerodynamic diameter).. Our results provided direct evidence that forest bathing has therapeutic effects on human hypertension and induces inhibition of the renin-angiotensin system and inflammation, and thus inspiring its preventive efficacy against cardiovascular disorders.

Topics: Affect; Aged; Blood Pressure; Cardiovascular Diseases; Cities; Endothelin-1; Environment; Homocysteine; Humans; Hypertension; Inflammation; Interleukin-6; Middle Aged; Renin-Angiotensin System; Treatment Outcome; Trees; Tumor Necrosis Factor-alpha

Endothelin (ET-1) is a potent vasoconstrictor. We compared patterns of ET-1 in percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) and correlated it with markers of inflammation. Patients with multivessel disease were enrolled in a prospective randomized study of PCI vs. on-pump CABG. Procedural myocardial injury was assessed biochemically (CK-MB) and with new late gadolinium enhancement (LGE) on magnetic resonance imaging (MRI) one week postprocedure. ET-1 was measured at baseline, 1 h, 6 h, 12 h, 24 h and one week postprocedure. Log ET-1 values were compared between PCI and CABG and between patients without significant myocardial injury. Measurement of ET-1 values was performed in 36 PCI and 31 CABG patients. Baseline ET-1 values were similar between PCI and CABG patients (0.91 ± 0.36 vs. 1.0 ± 49 pg/ml, P = 0.38). Peak values were reached at 1 h in PCI and at 24 h in CABG patients and patients undergoing CABG had significantly higher log ET-1 values at 6 h, 12 h and 24 h. ET-1 did not correlate with biochemical or morphological markers of myocardial injury or change of left ventricular ejection fraction (LV-EF) but good linear correlation between max logET-1 and max logCRP was found (r = 0.44, P = 0.0002). ET-1 rise is more pronounced in on-pump CABG and ET-1 production could be driven by periprocedural inflammatory reaction.

Topics: Aged; Analysis of Variance; Angioplasty, Balloon, Coronary; Biomarkers; Cardiopulmonary Bypass; Chi-Square Distribution; Contrast Media; Coronary Artery Bypass; Coronary Artery Disease; Creatine Kinase, MB Form; Endothelin-1; England; Female; Humans; Inflammation; Inflammation Mediators; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Infarction; Myocardium; Predictive Value of Tests; Prospective Studies; Stroke Volume; Time Factors; Treatment Outcome; Troponin I; Up-Regulation; Ventricular Function, Left

To explore the effects of Tongxinluo Capsule (TXLC) on platelet activating factor, vascular inflammation factor and vascular endothelial function in patients with essential hypertension (EH) complicated with diabetes mellitus (DM).. One hundred patients of EH with DM were equally assigned to the TXLC group (treated by TXLC) and the control group (treated with the conventional therapy). Their fasting blood drawn from the cubital vein on the next morning of hospitalization was taken for determining serum level of high sensitivity C-reactive protein (hs-CRP) by emulsion immunoenhancement turbidimetry; plasmal fibrinogen C (FIB-C) by diffusive turbidimetry; platelet activating indices, CD62p and glucose protein (GP) II b/III a receptor complex by flow cytometry; endothelin-1 (ET-1) by radioimmunoassay and nitrogen oxide (NO) content by enzyme method. The outcomes were compared with those of 50 healthy persons. After patients were treated for 8 weeks, all the above-mentioned indices were reexamined and compared between groups. Results Blood levels of hs-CRP, FIB-C, CD62p, GP II b/IIIa and ET-1 in patients were significantly higher than those in healthy persons (all P < 0.01). All the indices as well as the blood pressure (both systolic and diastolic) reduced in patients of both groups significantly (P < 0.05 or P < 0.01), but the reducing was more significant in the TXLC group than in the control group. Besides, level of NO significantly increased in the TXLC group (P < 0.05).. TXLC can inhibit the platelet activation and vascular inflammation response, also improve the vascular endothelial function in patients with EH complicated with DM. It may play a certain role in preventing and treatment of the occurrence of thrombotic complications in them.

Topics: Aged; Blood Pressure; C-Reactive Protein; Diabetes Mellitus; Drugs, Chinese Herbal; Endothelin-1; Female; Humans; Hypertension; Inflammation; Male; Middle Aged; Platelet Activation

In observational studies, statins are associated with lower mortality in patients with heart failure (HF), including those with nonischemic HF. Such benefits could be related to anti-inflammatory effects; however, the effects of statins on systemic inflammation in HF are not well-established. We conducted a 16-week, single-center, randomized, double-blind, placebo-controlled, crossover clinical trial of the effects of atorvastatin 10 mg/day on concentrations of systemic inflammatory markers in 22 patients with HF (including 20 with nonischemic HF) with New York Heart Association class II or III symptoms and left ventricular ejection fraction of <40%. The absolute and percentage of changes in inflammatory marker levels were evaluated using analysis of variance. Statin treatment reduced the concentrations of soluble tumor necrosis factor receptor-1 by 132 pg/ml (p = 0.04) and 8% (p = 0.056), C-reactive protein by 1.6 mg/L (p = 0.006) and 37% (p = 0.0002), and, after adjustment for treatment order, endothelin-1 by 0.21 pg/ml (p = 0.007) and 17% (p = 0.01). In post hoc analyses, the reduction in tumor necrosis factor receptor-1 levels was highest among patients with elevated levels at baseline (at or higher than the median of 1,055 pg/ml, p interaction = 0.001), among whom statin therapy reduced the levels by 306 pg/ml (p <0.001) and 22% (p <0.001). Statin treatment did not significantly affect the levels of other inflammatory markers, including interleukin-6 and brain natriuretic peptide. In conclusion, short-term atorvastatin therapy reduced the levels of several important inflammatory markers in patients with HF.

Topics: Adult; Aged; Atorvastatin; Biomarkers; C-Reactive Protein; Cross-Over Studies; Double-Blind Method; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Heart Failure; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Middle Aged; Pyrroles; Receptors, Tumor Necrosis Factor, Type I; Treatment Outcome

Endotoxin is a major stimulus for triggering the host response in septicaemia. The pathophysiology of sepsis involves activation of the vascular endothelium and leukocytes, resulting in the release of various mediators, e.g. cytokines, nitric oxide (NO), endothelin (ET-1) and complement factors. We evaluated the blood levels of complement activation, ET-1 and neuropeptide Y (NPY) in parallel with the haemodynamic and oxygen transport response during human experimental endotoxemia.. Eleven healthy men had venous, arterial and pulmonary arterial catheters placed for continuous haemodynamic measuring. After 30 min rest endotoxin (E. Coli 4 ng kg(-1), Lot G1) was intravenously administered. Blood samples from pulmonary and arterial catheters were collected hourly over 4 h.. Body temperature augmented significantly from baseline values (36.7 +/- 0.7 degrees C, mean +/- SEM) with a maximum after 3.5 h (39.1 +/- 0.3 degrees C, P < 0.001). Cardiac output increased by 100%, systemic vascular resistance decreased by 50%, the oxygen consumption and the tissue oxygen transport increased. Activation of the complement system was indicated by an increase in SC5b-9. Endothelin-1-like immunoreactivity (ET-1-LI) increased over time in arterial blood. NPY-like immunoreactivity (NPY-LI) did not change over time.. A dose of endotoxin associated with reproducible systemic vasodilation and fever in healthy subjects causes complement activation and increased systemic levels of ET-1-LI, illustrating that the model is a useful tool for inducing moderate systemic inflammation where several mediator systems are activated.

Topics: Adult; Body Temperature; Complement Activation; Endothelin-1; Endotoxemia; Endotoxins; Hemodynamics; Humans; Inflammation; Male; Neuropeptide Y; Oxygen Consumption; Pulmonary Alveoli; Pulmonary Gas Exchange

To study the effects of combined hormone replacement therapy on markers of endothelial function and inflammatory activity.. Prospective, randomized, controlled study.. Academic hospital.. Healthy postmenopausal women with an intact uterus.. For the first 12 months, the hormone replacement therapy group (n = 14) received oral E2, 1 mg daily, sequentially combined with 5 or 10 mg of dydrogesterone. Thereafter, they received oral E2, 2 mg daily, sequentially combined with 10 mg of dydrogesterone. The control group (n = 13) received no treatment. Data were collected at baseline and at 3, 12, and 15 months.. Parameters of endothelial function and inflammatory activity.. During 12 months of follow-up, we observed decreases of 15% in plasma levels of endothelin-l, of 21% in soluble thrombomodulin, of 14% in von Willebrand factor, and of 12% in clottable fibrinogen in the hormone replacement therapy group compared with the control group. There was a 5% decrease in soluble E-selectin tevels. All significant changes were observed by 3 months and sustained after 15 months. Brachial artery flow-mediated vasodilatation and C-reactive protein levels did not change significantly.. Long-term combined hormone replacement therapy with E2 and dydrogesterone in healthy women was associated with sustained improvement in some aspects of endothelial function and in clottable fibrinogen levels.

Topics: Dydrogesterone; E-Selectin; Endothelin-1; Endothelium, Vascular; Estradiol; Estrogen Replacement Therapy; Female; Fibrinogen; Humans; Inflammation; Middle Aged; Postmenopause; Prospective Studies; Solubility; Thrombomodulin; von Willebrand Factor

To assess the effects of the angiotensin-converting enzyme inhibitor enalaprilat on endothelial cells in septic patients.. Prospective, randomized, placebo-controlled, blinded study.. Clinical investigation on a surgical intensive care unit of a university hospital.. Forty surgical septic patients (noncardiac/nonneurosurgical patients).. After inclusion in the study and after baseline data were obtained, either 0.25 mg/hr (enalaprilat group, n = 20) or saline solution as placebo (control group, n = 20) was continuously given and continued throughout the following 5 days.. Extensive hemodynamic monitoring was carried out in all patients. Plasma concentrations of endothelin-1, angiotensin II, soluble thrombomodulin, and soluble adhesion molecules (endothelial leukocyte adhesion molecule-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and granule membrane protein-140) were measured from arterial blood samples. All measurements were carried out before the start of the infusion ("baseline" values) and daily during the following 5 days. All endothelial-derived substances (thrombomodulin, endothelin-1, and all soluble adhesion molecules) were similarly increased beyond normal in both group. Endothelin-1 increased only in the untreated control patients (from 6.9 +/- 0.7 to 14.3 +/- 1.4 mg/mL). Soluble thrombomodulin increased in the untreated control patients (from 58 +/- 9 to 79 +/- 14 ng/mL [p < .05]), but significantly decreased in the enalaprilat-treated patients. Soluble adhesion molecules increased in the untreated control group (endothelial leukocyte adhesion molecule from 92 +/- 14 to 192 +/- 29 ng/mL; intercellular adhesion molecule-1 from 480 +/- 110 to 850 +/- 119 ng/ mL) and returned almost to normal values in the enalaprilat patients. The survival rate did not differ significantly between the two groups. Control patients developed severe sepsis and septic shock more often than the enalaprilat-treated group.. The complex pathogenesis of endothelial function abnormalities in sepsis may offer a large number of pharmacologic interventions. Administration of the angiotensin-converting enzyme inhibitor enalaprilat resulted in a reduced release of soluble endothelial-derived substances into the circulating blood, which may indicate an improved endothelial function. The specific actions of enalaprilat on the endothelium have to be elucidated in further studies.

Topics: Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Cell Adhesion Molecules; Critical Illness; Double-Blind Method; Enalaprilat; Endothelin-1; Endothelium, Vascular; Female; Hemodynamics; Humans; Inflammation; Male; Middle Aged; Prospective Studies; Sepsis; Survival Analysis; Thrombomodulin

What is the central question of this study? Are biomarkers of endothelial function, oxidative stress and inflammation altered by non-freezing cold injury (NFCI)? What is the main finding and its importance? Baseline plasma [interleukin-10] and [syndecan-1] were elevated in individuals with NFCI and cold-exposed control participants. Increased [endothelin-1] following thermal challenges might explain, in part, the increased pain/discomfort experienced with NFCI. Mild to moderate chronic NFCI does not appear to be associated with either oxidative stress or a pro-inflammatory state. Baseline [interleukin-10] and [syndecan-1] and post-heating [endothelin-1] are the most promising candidates for diagnosis of NFCI.. Plasma biomarkers of inflammation, oxidative stress, endothelial function and damage were examined in 16 individuals with chronic NFCI (NFCI) and matched control participants with (COLD, n = 17) or without (CON, n = 14) previous cold exposure. Venous blood samples were collected at baseline to assess plasma biomarkers of endothelial function (nitrate, nitrite and endothelin-1), inflammation [interleukin-6 (IL-6), interleukin-10 (IL-10), tumour necrosis factor alpha and E-selectin], oxidative stress [protein carbonyl, 4-hydroxy-2-nonenal (4-HNE), superoxide dismutase and nitrotyrosine) and endothelial damage [von Willebrand factor, syndecan-1 and tissue type plasminogen activator (TTPA)]. Immediately after whole-body heating and separately, foot cooling, blood samples were taken for measurement of plasma [nitrate], [nitrite], [endothelin-1], [IL-6], [4-HNE] and [TTPA]. At baseline, [IL-10] and [syndecan-1] were increased in NFCI (P < 0.001 and P = 0.015, respectively) and COLD (P = 0.033 and P = 0.030, respectively) compared with CON participants. The [4-HNE] was elevated in CON compared with both NFCI (P = 0.002) and COLD (P < 0.001). [Endothelin-1] was elevated in NFCI compared with COLD (P < 0.001) post-heating. The [4-HNE] was lower in NFCI compared with CON post-heating (P = 0.032) and lower than both COLD (P = 0.02) and CON (P = 0.015) post-cooling. No between-group differences were seen for the other biomarkers. Mild to moderate chronic NFCI does not appear to be associated with a pro-inflammatory state or oxidative stress. Baseline [IL-10] and [syndecan-1] and post-heating [endothelin-1] are the most promising candidates for diagnosing NFCI, but it is likely that a combination of tests will be required.

Topics: Biomarkers; Cold Injury; Cold Temperature; Endothelin-1; Humans; Inflammation; Interleukin-10; Interleukin-6; Nitrates; Nitrites; Oxidative Stress; Syndecan-1; Tissue Plasminogen Activator

Comprehensive studies investigating sustained hypercoagulability, endothelial function, and/or inflammation in relation to post-COVID-19 (PCC) symptoms with a prolonged follow-up are currently lacking. Therefore, the aim of this single-centre cohort study was to investigate serum biomarkers of coagulation activation, microvascular dysfunction, and inflammation in relation to persisting symptoms two years after acute COVID-19.. Patients diagnosed with acute SARS-CoV-2 infection between February and June 2020 were recruited. Outcome measures included the CORona Follow-Up (CORFU) questionnaire, which is based on an internationally developed and partially validated basic questionnaire on persistent PCC symptoms. Additionally, plasma biomarkers reflecting coagulation activation, endothelial dysfunction and systemic inflammation were measured.. 167 individuals were approached of which 148 (89%) completed the CORFU questionnaire. At 24 months after acute infection, fatigue was the most prevalent PCC symptom (84.5%). Over 50% of the patients experienced symptoms related to breathing, cognition, sleep or mobility; 30.3% still experienced at least one severe or extreme (4 or 5 on a 5-point scale) PCC symptom. Multiple correlations were found between several PCC symptoms and markers of endothelial dysfunction (endothelin-1 and von Willebrand factor) and systemic inflammation (Interleukin-1 Receptor antagonist). No positive correlations were found between PCC symptoms and coagulation complexes.. In conclusion, this study shows that at 24 months after acute COVID-19 infection patients experience a high prevalence of PCC symptoms which correlate with inflammatory cytokine IL-1Ra and markers of endothelial dysfunction, especially endothelin-1. Our data may provide a rationale for the selection of treatment strategies for further clinical studies.. This study was performed in collaboration with the CORona Follow-Up (CORFU) study (NCT05240742, https://clinicaltrials.gov/ct2/show/ NCT05240742).

Topics: Biomarkers; Cohort Studies; COVID-19; Endothelin-1; Humans; Inflammation; SARS-CoV-2

Topics: Anti-Allergic Agents; C-Reactive Protein; Chronic Disease; Chronic Urticaria; Endothelin-1; Histamine Antagonists; Histamine H1 Antagonists; Humans; Inflammation; Interleukin-33; Omalizumab; Urticaria

Endothelial damage and thrombosis caused by COVID-19 may imperil cardiovascular health. More than a year since the WHO declared COVID-19 pandemic, information on its effects beyond the acute phase is lacking. We investigate endothelial dysfunction, coagulation and inflammation, 3 months post-COVID-19.. A cohort study was conducted including 203 patients with prior COVID-19. Macrovascular dysfunction was assessed by measuring the carotid artery diameter in response to hand immersion in ice-water. A historic cohort of 312 subjects served as controls. Propensity score matching corrected for baseline differences. Plasma concentrations of endothelin-1 were measured in patients post-COVID-19, during the acute phase, and in matched controls. Coagulation enzyme:inhibitor complexes and inflammatory cytokines were studied.. The prevalence of macrovascular dysfunction did not differ between the COVID-19 (18.6%) and the historic cohort (22.5%, RD -4%, 95%CI: -15-7, p = 0.49). Endothelin-1 levels were significantly higher in acute COVID-19 (1.67 ± 0.64 pg/mL) as compared to controls (1.24 ± 0.37, p < 0.001), and further elevated 3 months post-COVID-19 (2.74 ± 1.81, p < 0.001). Thrombin:antithrombin(AT) was high in 48.3%. Markers of contact activation were increased in 16-30%. FVIIa:AT (35%) and Von Willebrand Factor:antigen (80.8%) were elevated. Inflammatory cytokine levels were high in a majority: interleukin(IL)-18 (73.9%), IL-6 (47.7%), and IL-1ra (48.9%). At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction; there was evidence, however, of sustained endothelial cell involvement, coagulation activity and inflammation. Our data highlight the importance of further studies on SARS-CoV-2 related vascular inflammation and thrombosis, as well as longer follow-up in recovered patients.

Topics: Cohort Studies; COVID-19; Endothelin-1; Humans; Inflammation; Pandemics; SARS-CoV-2

Diabetes and sarcopenia are verified as mutual relationships, which seriously affect the quality of life of the elderly. Endothelin-1 is well investigated, is elevated in patients with diabetes, and is related to muscle cellular senescence and fibrosis. However, the mechanism of ET-1 between diabetes and myopathy is still unclear. The aim of this study was to evaluate the prevalence of sarcopenia in the elderly with diabetes and to clarify its relationship with ET-1 molecular biological mechanism, progress as well as changes in muscle and fat.. We recruited 157 type 2 diabetes patients over 55 years old and investigated the prevalence of sarcopenia in diabetes patients and examined the association of ET-1 alterations with HbA1c, creatinine, or AMS/ht2. Next, sought to determine how ET-1 regulates inflammation in muscle cells by western blot and qPCR assay. Using XF Seahorse Technology, we directly quantified mitochondrial bioenergetics in 3T3-L1 cells.. ET-1 was positively correlated with HbA1c, creatinine levels, and duration of disease, and negatively correlated with AMS/ht2. We found that ET-1 dose-dependently induces tumor necrosis factor-α (TNF-α) and interleukin (IL)-6β expression through the PI3K/AKT, and NF-κB signaling pathways in C2C12 cells. Also identified that TNF-α, IL-6β, and visfatin releases were found in co-cultured with conditioned medium of ET-1/C2C12 in 3T3-L1 cells. ET-1 also reduces the energy metabolism of fat and induces micro-environment inflammation which causes myopathy. ET-1 also suppresses miR-let-7g-5p expression in myocytes and adipocytes.. We describe a new mechanism of ET-1 triggering chronic inflammation in patients with hyperglycemia.

Topics: Aged; Creatinine; Diabetes Mellitus, Type 2; Endothelin-1; Glycated Hemoglobin; Humans; Inflammation; MicroRNAs; Muscular Diseases; Phosphatidylinositol 3-Kinases; Quality of Life; Sarcopenia; Tumor Necrosis Factor-alpha

Endothelin-1 and its prohormone C-terminal pro-endothelin-1 (CT-proET-1) have been linked to metabolic alterations, inflammatory responses and cardiovascular events in selected study populations. We analyzed the association of CT-proET-1 with cardiovascular events and mortality, carotid intima-media-thickness as surrogate for early atherosclerotic lesions, biomarkers of subclinical inflammation and adipokines in a population-based study.. The cross-sectional and prospective analyses used data from the KORA F4 study with a median follow-up time of 9.1 (8.8-9.4) years. Data on CT-proET-1 and mortality were available for 1554 participants, data on the other outcomes in subgroups (n = 596-1554). The associations were estimated using multivariable linear regression and Cox proportional hazard models adjusted for sex, age, body mass index, estimated glomerular filtration rate, arterial hypertension, diabetes, low-density and high-density lipoprotein cholesterol, current and former smoking and physical activity. The Bonferroni method was used to correct for multiple testing.. In the fully adjusted model, CT-proET-1 was associated with cardiovascular (hazard ratio (HR) per standard deviation increase: 1.66; 95% confidence interval (CI): 1.10-2.51; p = 0.017) and all-cause mortality (HR: 2.03; 95% CI 1.55-2.67; p < 0.001), but not with cardiovascular events, and was inversely associated with the intima-media thickness (β: -0.09 ± 0.03; p = 0.001). CT-proET-1 was positively associated with five out of ten biomarkers of subclinical inflammation and with two out of five adipokines after correction for multiple testing. After inclusion of biomarkers of subclinical inflammation in the Cox proportional hazard model, the association of CT-proET-1 with all-cause mortality persisted (p < 0.001).. These results emphasize the complexity of endothelin-1 actions and/or indicator functions of CT-proET-1. CT-proET-1 is a risk marker for all-cause mortality, which is likely independent of vascular endothelin-1 actions, cardiovascular disease and inflammation.

Topics: Adipokines; Biomarkers; Cardiovascular Diseases; Carotid Intima-Media Thickness; Cross-Sectional Studies; Endothelin-1; Humans; Inflammation; Mortality; Peptide Fragments; Prospective Studies

Inflammation is a major pathological feature of pulmonary arterial hypertension (PAH), particularly in the context of inflammatory conditions such as systemic sclerosis (SSc). The endothelin system and anti-endothelin A receptor (ET. Serum levels of anti-ET. Anti-ET. This study provides evidence for an anti-inflammatory role of ET

Topics: Animals; Autoantibodies; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertrophy, Right Ventricular; Inflammation; Mice; Pulmonary Arterial Hypertension; Receptor, Endothelin B; Scleroderma, Systemic

Aging is a risk factor for many chronic noncommunicable diseases, including chronic obstructive pulmonary disease (COPD), which is often associated with cardiovascular disease (CVD). Moreover, aging is associated with a mild form of systemic inflammation. The aim of our study was to analyze the relationship between age, systemic and vascular inflammation, and the presence of CVD comorbidities in a stable COPD population. Forty COPD patients were divided into 2 age groups (<65 and ≥65 years of age), from which we collected the following inflammatory biomarkers: C-reactive protein, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and endothelin-1 (ET-1). Elderly COPD patients had more frequent exacerbation events per year (2 vs 1, P = .06), a higher prevalence of CVD (3 vs 2, P = .04), more limited exercise tolerance (6-minute walking test distance, 343 [283-403] vs 434 [384-484]; P = .02), and mild systemic inflammation (TNF-α, 9.02 [7.08-10.96] vs 6.48 [5.21-7.76]; P = .03; ET-1, 2.24 [1.76-2.71] vs 1.67 [1.36-1.98] pg/mL; P = .04). A weak correlation between age and ET-1 (r = 0.32, P = .04) was observed. Mild systemic inflammation, characterized by a slightly increased level of TNF-α, and endothelial dysfunction, marked by elevated ET-1, could be liaisons between aging, COPD, and CVD comorbidities.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Endothelin-1; Humans; Inflammation; Lung; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha; Vascular Diseases

Critical limb ischemia (CLI) is a severe manifestation of peripheral artery disease characterized by ischemic pain, which is frequently associated with diabetes and non-healing lesions to inferior limbs. The clinical management of diabetic patients with CLI typically includes percutaneous transluminal angioplasty (PTA) to restore limb circulation and surgical treatment of diabetic foot ulcers (DFU). However, even after successful treatment, CLI patients are prone to post-procedure complications, which may lead to unplanned revascularization or foot surgery. Unfortunately, the factors predicting adverse events in treated CLI patients are only partially known. This study aimed to identify potential biomarkers that predict the disease course in diabetic patients with CLI. For this purpose, we measured the circulating levels of a panel of 23 molecules related to inflammation, endothelial dysfunction, platelet activation, and thrombophilia in 92 patients with CLI and DFU requiring PTA and foot surgery. We investigated whether these putative biomarkers were associated with the following clinical endpoints: (1) healing of the treated DFUs; (2) need for new revascularization of the limb; (3) appearance of new lesions or relapses after successful healing. We found that sICAM-1 and endothelin-1 are inversely associated with DFU healing and that PAI-1 and endothelin-1 are associated with the need for new revascularization. Moreover, we found that the levels of thrombomodulin and sCD40L are associated with new lesions or recurrence, and we show that the levels of these biomarkers could be used in a decision tree to assign patients to clusters with different risks of developing new lesions or recurrences.

Topics: Amputation, Surgical; Biomarkers; Chronic Limb-Threatening Ischemia; Diabetes Mellitus; Diabetic Foot; Endothelin-1; Humans; Inflammation; Ischemia; Plasminogen Activator Inhibitor 1; Retrospective Studies; Thrombomodulin; Treatment Outcome

The wide application of copper oxide nanoparticles (CuO NPs) in industry, agriculture, environmental remediation, and biomedicine has increased the risk of human exposure to CuO NPs. Recent studies suggested that CuO NPs have genotoxic and cytotoxic effects on various cells. However, little is known about the toxicity of CuO NPs on major peripheral organs after respiratory exposure.. We investigated the toxicities of CuO NPs on human bronchial epithelial (BEAS-2B) and human cardiomyocytes (AC16) cells in vitro, and on the lungs, liver, kidneys, and heart of spontaneously hypertensive rats (SHRs) at 24 and 72 h after intrabronchial instillation in vivo.. CuO NPs induced concentration-dependent toxicities in both BEAS-2B and AC16 cells mainly through hierarchical oxidative stress mechanisms, involving generation of reactive oxygen species (ROS), upregulation of heme oxygenase-1 (HO-1), mitochondrial dysfunction, and secretion of proinflammatory and profibrogenic cytokines. Respiratory exposure to CuO NPs induced acute multiple organ injuries in SHRs manifesting through inflammation and fibrosis. However, cardiac injury was relatively less severe than injuries in the lungs, liver, and kidneys. Upregulation of serum C-reaction protein (CRP), tumor necrosis factor α (TNF-α), intercellular adhesion molecule 1 (ICAM-1), endothelin-1 (ET-1), angiotensin converting enzyme (ACE), and von Willebrand factor (vWF) after exposure to CuO NPs indicated systematic inflammation, endothelial injury, and potential prothrombosis.. Respiratory exposure to CuO NPs induced acute injuries in main peripheral organs, including the lungs, liver, kidneys, and heart. Individuals with existing cardiovascular diseases were susceptible to exposure to CuO NPs. This study provides a warning about the extensive toxic effects of CuO NPs, especially in the susceptible population.

Topics: Animals; Copper; Endothelin-1; Heme Oxygenase-1; Humans; Inflammation; Intercellular Adhesion Molecule-1; Metal Nanoparticles; Nanoparticles; Oxidative Stress; Oxides; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Reactive Oxygen Species; Tumor Necrosis Factor-alpha; von Willebrand Factor

A double-hit biological alteration involving exposure to oxygen deprivation in hypothyroid condition may exacerbate cellular oxidative and inflammatory disturbances comparative to a one-hit biological exposure. This study investigated the therapeutic effect of Ginkgo biloba as cardioprotective against aortic oxido-inflammatory disturbances following oxygen deprivation in hypothyroid mice. Male Swiss mice were partitioned into 5 groups (n = 6) for hypothyroidism (Carbimazole 1.2 mg/kg) and hypoxia induction. Group 1 (normal control), group 2 (hypoxic stress control), group 3 (hypoxic and hypothyroid stress), group 4 (hypoxic and hypothyroid stress and Ginkgo biloba 20 mg/kg; p.o) and group 5 (hypoxic and hypothyroid stress and Levothyroxine 10 μg/kg; p.o) for 14 days. Thereafter, serum and aorta was collected for biochemical evaluation. GBS did not up-regulate the serum thyroid hormone imbalances (tri-iodothyronine (T3), thyroxin (T4)) but maintains the TSH levels. The blood glucose level was reduced with decrease oxidative stress and inflammatory mediators in the serum/aorta indicated by inhibited redox status following treatment with GBS. Moreover, endothelin-1/nitric oxide signaling pathways were markedly regulated in the aorta. Conclusively, GBS acts as a therapeutic agent and may be consider as a potential vasodilator candidate in the management and control of hypoxic stress in hypothyroid condition. PRACTICAL APPLICATIONS: Treatment with Gingko biloba supplement abated endothelial abnormalities via elevation of nitric oxide release and suppression of endothelin activity in hypothyroid mice exposed to hypoxic hypoxia. The activity of myeloperoxidase enzyme and redo-inflammatory status was downregulated following treatment with Gingko biloba supplement in hypothyroid mice exposed to hypoxic hypoxia. Treatment with Gingko biloba supplement modulates hypothalamic-pituitary-adrenal (HPA) axis by inhibiting corticosterone release in hypothyroid mice exposed to hypoxic hypoxia.

Topics: Animals; Endothelin-1; Ginkgo biloba; Hypothyroidism; Hypoxia; Inflammation; Male; Mice; Nitric Oxide; Oxidation-Reduction; Oxidative Stress; Oxygen

Topics: Animals; Brain; Brain Ischemia; Endothelin-1; Heart Diseases; Infarction, Middle Cerebral Artery; Inflammation; Mice; Molecular Imaging; Positron-Emission Tomography; Stroke; Vasoconstrictor Agents

Zebrafish larvae were fed with high-cholesterol diet (HCD) to establish a zebrafish AS model. Then, we used DH water extracts (DHWE) to pretreat AS zebrafish. The plaque formation was detected by HE, EVG, and oil red O staining. Neutrophil and macrophage counts were calculated to evaluate the inflammation level. Reactive oxygen species (ROS) activity, malondialdehyde (MDA) content, and superoxide dismutase (SOD) activity in zebrafish were measured to reflect oxidative stress. The cholesterol accumulation and the levels of lipid, triglyceride (TG), and total cholesterol (TC) were measured to reflect lipid metabolism disorder. Then, parallel flow chamber was utilized to establish a low shear stress- (LSS-) induced endothelial cell (EC) dysfunction model. EA.hy926 cells were exposed to LSS (3 dyn/cm. The results showed that DHWE significantly reduced cholesterol accumulation and macrophage infiltration in early AS. Finally, DHWE significantly alleviate the lipid metabolism disorder, oxidative stress, and inflammation to reduce the plaque formation of AS zebrafish larval model. Meanwhile, we also found that DHWE significantly improved LSS-induced EC dysfunction and oxidative stress. Our results indicate that DHWE could be used as a prevention method to prevent AS.

Topics: Animals; Atherosclerosis; Cell Line; Cholesterol, Dietary; Dendrobium; Drugs, Chinese Herbal; Endothelin-1; Epoprostenol; Heart; Humans; Inflammation; Intercellular Adhesion Molecule-1; Nitric Oxide; Oxidative Stress; Reactive Oxygen Species; Shear Strength; Stress, Mechanical; Triglycerides; Umbilical Veins; Water; Zebrafish

Smoking increases systemic inflammation and circulating endothelin-1 (ET-1), both of which contribute to an elevated risk of cardiovascular disease (CVD). The present study sought to test the hypothesis that a 12-week smoking cessation intervention would contribute to a long-term reduction in circulating ET-1, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). 30 individuals participated in a 12-week evidence-based smoking cessation program at Augusta University. Serum cotinine, plasma inflammatory cytokines, and plasma ET-1 were determined at baseline, immediately after the 12-week cessation program (end of treatment, EOT), and 12-months (12M) following the cessation program. Serum cotinine was significantly reduced (p < 0.001) at EOT and 12M following the smoking cessation program. Compared to BL (7.0 ± 1.6 pg/mL), TNF-α was significantly reduced at EOT (6.3 ± 1.5 pg/mL, p = 0.001) and 12M (5.2 ± 2.7 pg/mL, p < 0.001). ET-1 was significantly lower at EOT (1.9 ± 0.6 pg/mL, p = 0.013) and at 12M (2.0 ± 0.8 pg/mL, p = 0.091) following smoking cessation compared with BL (2.3 ± 0.6 pg/mL). BL concentrations of cotinine were significantly associated with basal ET-1 (r = 0.449, p = 0.013) and the change in cotinine at 12M following smoking cessation was significantly associated with the change in plasma ET-1 at 12M (r = 0.457, p = 0.011). Findings from the present pilot investigation demonstrate that a 12-week smoking cessation program reduces circulating concentrations of ET-1 and TNF-α for at least a year. The reduction in serum cotinine was associated with the decrease in circulating ET-1. The attenuation in ET-1 and inflammation may in part, contribute to the lower risk of CVD that is observed with smoking cessation.

Topics: Adult; Cotinine; Endothelin-1; Female; Heart Disease Risk Factors; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Male; Middle Aged; Pilot Projects; Risk; Smoking; Smoking Cessation; Tumor Necrosis Factor-alpha; Young Adult

Knowledge on endothelial dysfunction and its relation to atherosclerosis in mastocytosis is limited.. To investigate the endothelial function in mastocytosis by flow-mediated dilatation (FMD) and biomarkers related to vascular endothelia and to evaluate its relationship with the presence of subclinical atherosclerosis by carotid intima media thickness (CIMT).. A total of 49 patients with mastocytosis and 25 healthy controls (HCs) were included. The FMD and CIMT during transthoracic echocardiography biomarkers including endocan, endothelin-1, and vascular endothelial growth factor (VEGF) were measured in the sera of participants. Tumor necrosis factor-alpha, interleukin 6, and high-sensitive C-reactive protein were determined as inflammatory biomarkers.. The mean FMD % was lower in the patients than HCs (11.26% ± 5.85% vs 17.84% ± 5.27% P < .001) and was the lowest in the advanced systemic mastocytosis and smoldering systemic mastocytosis group among the patients (P = .03). The median value of VEGF was considerably higher in patients than HCs (73.30 pg/mL; minimum-maximum 32.46-295.29 pg/mL vs 46.64 pg/mL; minimum-maximum, 11.09-99.86 pg/mL; P = .001) and it was the highest in the advanced systemic mastocytosis and smoldering systemic mastocytosis group (P = .01). The FMD was inversely correlated with endocan (r = -0.390; P = .006), endothelin-1 (r = -0.363; P = .01) and VEGF (r = -0.402; P = .004) but there were no correlations between FMD and tumor necrosis factor-alpha, interleukin 6, and high-sensitive C-reactive protein. No differences in CIMT values between patients and HCs and no correlation between CIMT and the biomarkers were observed.. Endothelial dysfunction in mastocytosis becomes evident with decreased FMD and elevated serum VEGF in the absence of atherosclerosis or systemic inflammation and is related to disease severity.

Topics: Adult; Atherosclerosis; Biomarkers; Carotid Intima-Media Thickness; Case-Control Studies; Endothelin-1; Endothelium, Vascular; Female; Humans; Inflammation; Male; Mastocytosis; Middle Aged; Neoplasm Proteins; Proteoglycans; ROC Curve; Severity of Illness Index; Vascular Endothelial Growth Factor A; Vasodilation

This study is aimed at identifying the roles of AGE/RAGE and ET-1 in deep vein thrombosis (DVT). Advanced glycation end products (AGEs) in glycated human serum albumin (M-HSA) were detected by ELISA. The viability of HUVECs was examined by CCK-8 assay. Flow cytometry was performed to detect cell apoptosis, followed by ELISA for the detection of inflammatory cytokine level and oxidative stress level in HUVECs. Immunofluorescence was performed to detect ET-1 and eNOS expression. The expression of specific proteins was assayed by western blot. As a result, decreased HUVEC viability was observed after stimulation with M-HSA, whereas RAGE inhibitor improved it. Cell apoptosis showed the opposite trend. Additionally, M-HSA-induced inflammatory cytokine release and oxidative stress of HUVECs were both alleviated by RAGE inhibitor. RAGE inhibitor also increased the levels of NO and eNOS while decreasing the level of ET-1 in M-HSA-stimulated HUVECs. Furthermore, decreased protein expression of Bax, cleaved-caspase3, RAGE, p65, ET-1 and iNOS was observed after treatment with RAGE inhibitor, in addition to increased protein expression of Bcl-2 and eNOS. In conclusion, blocking AGE/RAGE pathway downregulates ET-1, thereby mitigating HUVEC damage in DVT.

Topics: Antigens, Neoplasm; bcl-2-Associated X Protein; Caspase 3; Cell Survival; Down-Regulation; Endothelin-1; Glycation End Products, Advanced; Glycosylation; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Mitogen-Activated Protein Kinases; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Serum Albumin; Venous Thrombosis

Neonatal arterial ischemic stroke is one of the more severe birth complications. The injury can result in extensive neurological damage and is robustly associated with later diagnoses of cerebral palsy (CP). An important part of efforts to develop new therapies include the on-going refinement and understanding of animal models that capture relevant clinical features of neonatal brain injury leading to CP. The potent vasoconstrictor peptide, Endothelin-1 (ET-1), has previously been utilised in animal models to reduce local blood flow to levels that mimic ischemic stroke. Our previous work in this area has shown that it is an effective and technically simple approach for modelling ischemic injury at very early neonatal ages, resulting in stable deficits in motor function. Here, we aimed to extend this model to also examine the impact on cognitive function. We show that focal delivery of ET-1 to the cortex of Sprague Dawley rats on postnatal day 0 (P0) resulted in impaired learning in a touchscreen-based test of visual discrimination and correlated with important clinical features of CP including damage to large white matter structures.

Topics: Animals; Animals, Newborn; Association Learning; Atrophy; Brain Ischemia; Cell Count; Cerebral Cortex; Cerebral Palsy; Cognition Disorders; Corpus Striatum; Disease Models, Animal; Endothelin-1; Inflammation; Injections; Microglia; Movement Disorders; Neurons; Perceptual Disorders; Rats; Rats, Sprague-Dawley; Rotarod Performance Test; Vasoconstrictor Agents; White Matter

Topics: Amylases; Animals; Ceruletide; Disease Models, Animal; Endothelin-1; Endothelin-Converting Enzymes; Gene Expression Regulation; Humans; Inflammation; Mice; Oncogenes; Pancreatic Neoplasms; Pancreatitis; Proto-Oncogene Proteins p21(ras); Receptor, Endothelin A; Receptor, Endothelin B

Topics: Animals; Blood Glucose; Cell Hypoxia; Cell Line; Cognitive Dysfunction; Culture Media; Diabetes Complications; Disease Models, Animal; Endothelin-1; Humans; Inflammation; Ischemic Stroke; Lipopolysaccharides; Mice; Microglia; Signal Transduction

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been identified previously in the pathogenesis of hypertension and some gestational diseases. However, the biological functions of MALAT1 in pregnancy-induced hypertension (PIH) are still poorly understood. Herein, we aim to explore the functional relevance of MALAT1 in PIH and to explain the potential underlying mechanisms. We found that the levels of ET-1 and MALAT1 were upregulated and that of miR-150-5p were downregulated in the serum of pregnant women with PIH and the aortic endothelial cells (ECs) of reduced uterine perfusion pressure (RUPP)-induced rat models. In aortic ECs, MALAT1 could competitively bind to miR-150-5p to upregulate the expression of ET-1. The MALAT1/miR-150-5p/ET-1 axis regulated the expression of endothelin B receptor (ETBR) in aortic ECs leading to oxidative stress imbalance and increased the release of proinflammatory cytokines (IL-18 and IL-1β), which concurrently activated the NF-κB pathway to regulate the ETBR expression and to stimulate smooth muscle cell (SMC) contraction. Furthermore, silencing MALAT1 could alleviate the hypertensive symptoms of RUPP-induced rat models. Taken conjointly, the upregulation of MALAT1 can reduce the expression of ET-1 by competitively binding to miR-150-5p, which enhances the expression of ETBR via the activation of the NF-κB pathway in SMCs, thus exacerbating the hypertensive symptoms in the RUPP-induced rat models.

Topics: Adult; Animals; Apoptosis; Cell Proliferation; Endothelin-1; Female; Gene Expression Regulation; Humans; Hypertension, Pregnancy-Induced; Inflammation; Interleukin-1beta; Male; MicroRNAs; NF-kappa B; Oxidative Stress; Pregnancy; Rats; Rats, Wistar; RNA, Long Noncoding; Signal Transduction; Young Adult

Elevated levels of endothelin-1 (ET-1) were recorded in sera of scorpion sting patients. However, no studies focused on the mechanism of ET-1 involvement in the pathogenesis of scorpion envenomation, particularly in the cardiovascular system which is seriously affected in severe cases of scorpion stings. Inflammation induced by

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Diseases; Cardiovascular System; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Inflammation; Inflammation Mediators; Male; Mice; Peptides, Cyclic; Receptor, Endothelin A; Scorpion Stings; Scorpion Venoms; Signal Transduction

Fibrosis is the most characteristic pathological hallmark of SSc, a connective tissue disease characterized by vascular and immunological abnormalities, inflammation and enhanced extracellular matrix production, leading to progressive fibrosis of skin and internal organs. We previously demonstrated that parvovirus B19 (B19V) can infect normal human dermal fibroblasts (NHDFs) and that B19V persists in SSc fibroblasts. In this study, we investigated whether parvovirus B19V is able to activate in vitro NHDFs and to induce in these cells some phenotypic features similar to that observed in the SSc fibroblasts.. We preliminarily analysed the time course of B19V infection in cultured NHDFs, then we investigated the ability of B19V to induce cell migration, invasive phenotype and mRNA expression of some profibrotic and/or proinflammatory genes.. We confirmed our previous findings that B19V infects NHDFs, but the infection is not productive. After incubation with B19V, NHDFs showed a significant increase of both migration and invasiveness, along with mRNA expression of different profibrotic genes (α-SMA, EDN-1, IL-6, TGF-β1 receptors 1 and 2, Col1α2), some genes associated with inflammasome platform (AIM2, IFI16, IL-1β, CASP-1) and genes for metalloprotease (MMP 2, 9 and 12).. These data suggest that B19V can activate dermal fibroblasts and may have a role in the pathogenesis of fibrosis. B19V-induced fibroblast migration and invasiveness could be due to the B19V-associated MMP9 overexpression and activation. Moreover, the up-regulation of MMP12, typical of SSc, could link the B19V infection of fibroblasts to the anti-angiogenic process.

Topics: Actins; Caspase 1; Cell Movement; Cells, Cultured; Collagen Type I; DNA-Binding Proteins; Endothelin-1; Fibroblasts; Fibrosis; Humans; In Vitro Techniques; Inflammation; Interleukin-1beta; Interleukin-6; Matrix Metalloproteinase 12; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Nuclear Proteins; Parvoviridae Infections; Parvovirus B19, Human; Phosphoproteins; Receptors, Transforming Growth Factor beta; RNA, Messenger; Scleroderma, Systemic; Skin; Transcriptome

Trichloroethylene (TCE) is a widely used industrial solvent that causes trichloroethylene hypersensitivity syndrome (THS) with multi-system damage, including kidney injury. Clinical studies have shown that the complement system is important for TCE-induced kidney injury. Our previous study found excessive deposition of complement C3, mainly on the glomerulus, indicating that local renal complement is activated after TCE sensitisation. However, whether local renal complement activation mediates TCE-induced immune kidney injury and the underlying mechanisms remain unknown. Therefore, we established a TCE percutaneous sensitisation BALB/c mouse model to explore the mechanisms by pretreating with or without the complement activation antagonist, cathepsin L inhibitor (CatLi). As expected, more C3 and C3a were detected mainly on glomerulus of TCE positive sensitisation (TCE

Topics: Animals; Complement Activation; Disease Models, Animal; Endothelin-1; Female; Hypersensitivity; Inflammation; Kidney; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; NF-kappa B; Renal Insufficiency; Signal Transduction; Trichloroethylene

Direct recognition of invading pathogens by innate immune cells is a critical driver of the inflammatory response. However, cells of the innate immune system can also sense their local microenvironment and respond to physiological fluctuations in temperature, pH, oxygen and nutrient availability, which are altered during inflammation. Although cells of the immune system experience force and pressure throughout their life cycle, little is known about how these mechanical processes regulate the immune response. Here we show that cyclical hydrostatic pressure, similar to that experienced by immune cells in the lung, initiates an inflammatory response via the mechanically activated ion channel PIEZO1. Mice lacking PIEZO1 in innate immune cells showed ablated pulmonary inflammation in the context of bacterial infection or fibrotic autoinflammation. Our results reveal an environmental sensory axis that stimulates innate immune cells to mount an inflammatory response, and demonstrate a physiological role for PIEZO1 and mechanosensation in immunity.

Topics: Animals; Endothelin-1; Female; Hydrostatic Pressure; Hypoxia-Inducible Factor 1, alpha Subunit; Immunity, Innate; Inflammation; Ion Channels; JNK Mitogen-Activated Protein Kinases; Lung; Macrophages; Male; Mechanotransduction, Cellular; Mice; Pseudomonas aeruginosa; Pseudomonas Infections; Signal Transduction

Obesity is a state of chronic low-level inflammation closely associated with oxidative stress. Childhood obesity is associated with endothelial dysfunction, inflammation, and oxidative stress markers individually. This study was aimed at determining the association between the biomarkers of inflammation, oxidative stress, and endothelial dysfunction in urine samples of healthy, overweight, and obese children. Eighty-eight elementary school children aged between 6 and 10 years participated in this study. Anthropometric measurements were measured using WHO recommendations. The biomarkers of low-grade inflammation such as C-reactive protein (CRP), interleukin-6 (IL-6), and

Topics: Biomarkers; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Child; Dinoprost; Early Diagnosis; Endothelial Cells; Endothelin-1; Female; Humans; Inflammation; Male; Oxidative Stress; Pediatric Obesity

Brain death (BD) induces hemodynamic instability with microcirculatory hypoperfusion, leading to increased organ inflammation and dysfunction. This study investigated the effects of 7.5% hypertonic saline solution (HSS) on mesenteric microcirculatory dysfunction and inflammation in a rat model of BD.. Male Wistar rats were anesthetized and mechanically ventilated. BD was induced by rapidly inflating an intracranial balloon catheter. The rats were randomly divided into: SH, sham-operated rats subjected to trepanation; NS, rats treated with NaCl 0.9%, 4 mL/kg immediately after BD; T1, rats treated with HSS (NaCl 7.5%, 4 mL/kg) immediately or 60 min after BD, T60. All groups were analyzed 180 min after the start of the experiment.. Rats in BD groups presented with a similar hypertensive peak, followed by hypotension. Proportion of perfused small vessels was decreased in the NS group (46%) compared with the SH group (74%, P = 0.0039). HSS restored the proportion of perfused vessels (T1 = 71%, P = 0.0018). The anti-endothelial nitric oxide synthase (eNOS) protein expression significantly increased in rats given HSS (T1, and T60, P = 0.0002). Similar results were observed regarding endothelin-1 (P < 0.0001). Increased numbers of rolling (P = 0.0015) and migrated (P = 0.0063) leukocytes were observed in the NS group compared with the SH group. Rats given HSS demonstrated an overall reduction in leukocyte-endothelial interactions. The ICAM-1 levels increased in the NS group compared with the SH group, and decreased in the HSS-treated groups (P = 0.0002).. HSS may improve the density of mesenteric perfused small vessels due to its effects on eNOS and endothelin-1 protein expression, and reduces inflammation by decreasing leukocyte adhesion and migration in a rat model of BD.

Topics: Animals; Brain Death; Electrolytes; Endothelin-1; Hemodynamics; Immunohistochemistry; Inflammation; Intercellular Adhesion Molecule-1; Male; Microcirculation; Nitric Oxide Synthase Type III; P-Selectin; Rats; Rats, Wistar; Saline Solution, Hypertonic

Identifying pathways linking neuroinflammation and neurodegeneration is essential to help prevent disability progression in people with multiple sclerosis (MS). Endothelin-1 (ET-1) is a potent vasoconstrictor thought to contribute to cerebral hypoperfusion and tissue damage in MS. Its link with the neuroinflammatory process remains poorly investigated.. To determine plasma ET-1 levels in treatment-naïve people with MS and controls, and the relationship between ET-1 and other peripheral immune mediator levels as potential markers of the disease process.. This is a retrospective study that included specimens previously collected from 35 treatment-naïve patients with clinically isolated syndrome highly suggestive of MS or definite MS and 35 sex- and age-matched controls. ET-1 plasma levels were measured by enzyme-linked immunosorbent assay (ELISA), and plasma cytokine levels [interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12(p70), IL-13, interferon (IFN)-γ and tumor necrosis factor (TNF)-α] were simultaneously measured by Multiplex assay.. ET-1 levels were significantly increased in MS patients compared to controls. No significant difference in cytokine levels between the groups were found. However, a significant increase in IFN-γ/IL-4 ratio was observed in patients with MS in comparison with controls, suggestive of Th1 skewed response. Binary logistic regression was performed to ascertain the effects of age, sex, ET-1 and cytokine levels on the likelihood of MS diagnosis. In the final model, ET-1, IL-4 and IFN-γ levels remained as predictors of MS. There was no significant correlation between ET-1 and cytokine levels.. Patients with MS presented increased levels of ET-1 and an immune response biased towards a Th1 profile. Although both ET-1 and Th1 cytokine profile were predictors of MS diagnosis, ET-1 levels were not associated with peripheral immune markers, suggesting that these changes may occur independently.

Topics: Adult; Biomarkers; Endothelin-1; Female; Humans; Inflammation; Male; Multiple Sclerosis; Retrospective Studies

BACKGROUND The aim of this study was to investigate the effects of puerarin on vascular endothelial function and inflammatory factors in coronary artery disease (CAD) patients with stable angina pectoris (SAP). MATERIAL AND METHODS To evaluate the effects of angina pectoris, the differences of scores of the Seattle angina questionnaire (SAQ), vascular endothelial function [endothelial progenitor cells (EPCs), nitric oxide (NO) and endothelin 1 (ET-1)], and inflammatory factors [tumor necrosis factor a (TNF-α), hypersensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6)] in 2 groups were assessed before and after treatment. RESULTS Regarding the curative effect of angina pectoris, the total effective rate of the treatment group was significantly superior to that of the control group (89% vs. 65%, P<0.05). The duration of angina pectoris, the number of abnormal leads, the improvement of the ST segment depression of electrocardiogram, and the scores of SAQ life quality indexes in the treatment group were better than those of the control group (P<0.05). In the 2 groups, EPCs and NO were both elevated, while ET-1 was decreased, and the improvements of the treatment group were superior to those of the control group (P<0.05). After treatment, the average levels of serum TNF-α, hs-CRP and IL-6 in the 2 groups were all decreased, which the treatment group showed a much sharper decrease than in the control group (P<0.05). CONCLUSIONS Puerarin effectively improves clinical symptoms and vascular endothelial function and reduces the levels of inflammatory factors in patients with CAD.

Topics: Aged; Angina Pectoris; Angina, Stable; C-Reactive Protein; China; Coronary Artery Disease; Endothelial Cells; Endothelial Progenitor Cells; Endothelin-1; Female; Humans; Inflammation; Interleukin-6; Isoflavones; Male; Middle Aged; Nitric Oxide; Treatment Outcome; Tumor Necrosis Factor-alpha

Previous studies have demonstrated that excess aldosterone impairs glucose metabolism. However, the underlying mechanism is still misty. Aldosterone has been proved a risk factor of fibrosis and inflammation. And the histology of islets from patients with type 2 diabetes (T2D) also displays inflammation and fibrosis. But it is unclear whether aldosterone has direct impact on islet inflammation and fibrosis in T2D. Islet endothelium plays a significant role in the maintenance of islet beta cell function and has a close relationship with islet fibrosis and inflammation. Therefore, we focused on the effect of aldosterone on the islet endothelium. In this study, we utilized a diabetic db/db mouse model and examined serum aldosterone levels, islet macrophages infiltration, and islet fibrosis. After we confirmed that there was an increased expression of intercellular cell adhesion molecule-1 (ICAM-1) and endothelin-1 (ET-1) in islet of diabetic mice compared with wild type mice. We next determined that aldosterone increased expression of ICAM-1 and ET-1 in both mRNA and protein levels in islet endothelium in vitro. And then we tested the expression of mineralocorticoid receptor (MR) in islet endothelium in vitro and in vivo. Our results showed that aldosterone can up-regulate the expression levels of ICAM-1 and ET-1 through MR. These findings suggest excess aldosterone might participate in islet inflammation and fibrosis in T2D.

Topics: Aldosterone; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Progression; Endothelin-1; Endothelium; Fibrosis; Inflammation; Intercellular Adhesion Molecule-1; Islets of Langerhans; Mice; Up-Regulation

The effect of sulfated polysaccharide from brown alga Fucus evanescens (fucoidan) administered via different routes (peroral and parenteral) on the dynamic of some lipid metabolism parameters and markers of systemic inflammation in mice with experimental dyslipidemia induced by prolonged administration of poloxamer P-407. It was found that fucoidan corrected the main parameters of lipid metabolism, reduced the level of endothelial dysfunction marker endothelin-1 and proinflammatory cytokines TNFα, IFNγ in blood serum in animals with experimental dyslipidemia. These findings open prospects for using fucoidan in the complex treatment of metabolic disorders and atherosclerotic inflammation.

Topics: Animals; Anti-Inflammatory Agents; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Dyslipidemias; Endothelin-1; Fucus; Gene Expression Regulation; Inflammation; Interferon-gamma; Lipid Metabolism; Male; Mice; Mice, Inbred BALB C; Poloxamer; Polysaccharides; Triglycerides; Tumor Necrosis Factor-alpha

Chronic inflammation, as a consequence of the persistent infection with Trypanosoma cruzi, leads to continuous activation of the immune system in patients with chronic Chagas disease. We have previously shown that increased sera levels of soluble P-selectin are associated with the severity of the cardiomyopathy distinctive of chronic Chagas disease. In this study, we explored the expression of biomarkers of platelet and endothelial activation, tissue remodeling, and mediators of the coagulation cascade in patients at different clinical stages of chronic Chagas heart disease. The frequencies of activated platelets, measured by the expression of CD41a and CD62P were decreased in patients with chronic Chagas disease compared with those in uninfected subjects, with an inverse association with disease severity. Platelet activation in response to adenosine diphosphate was also decreased in T. cruzi-infected subjects. A major proportion of T. cruzi infected subjects showed increased serum levels of fibrinogen. Patients with severe cardiac dysfunction showed increased levels of endothelin-1 and normal values of procollagen I. In conclusion, chronic infection with T. cruzi induced hemostatic alterations, even in those patients who do not yet present cardiac symptoms.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Platelets; Chagas Cardiomyopathy; Chagas Disease; Chronic Disease; Endothelin-1; Female; Fibrinogen; Humans; Inflammation; Male; Middle Aged; P-Selectin; Procollagen; Trypanosoma cruzi; Young Adult

Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide that is upregulated in obesity. Herein, we tested the hypothesis that ET-1 signaling promotes visceral adipose tissue (AT) inflammation and disrupts glucose homeostasis. We also tested if reduced ET-1 is a required mechanism by which exercise ameliorates AT inflammation and improves glycemic control in obesity. We found that

Topics: Animals; Body Mass Index; Endothelin-1; Exercise; Female; Gene Expression; Glucose Intolerance; Humans; Inflammation; Intra-Abdominal Fat; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Physical Conditioning, Animal; Running

Hyperglycemia-induced production of endothelin (ET)-1 is a hallmark of endothelial dysfunction in diabetes. Although the detrimental vascular effects of increased ET-1 are well known, the molecular mechanisms regulating endothelial synthesis of ET-1 in the setting of diabetes remain largely unidentified. Here, we show that adapter molecule TRAF3 interacting protein 2 (TRAF3IP2) mediates high glucose-induced ET-1 production in endothelial cells and ET-1-mediated endothelial cell inflammation. Specifically, we found that high glucose upregulated TRAF3IP2 in human aortic endothelial cells, which subsequently led to activation of JNK and IKKβ. shRNA-mediated silencing of TRAF3IP2, JNK1, or IKKβ abrogated high-glucose-induced ET-converting enzyme 1 expression and ET-1 production. Likewise, overexpression of TRAF3IP2, in the absence of high glucose, led to activation of JNK and IKKβ as well as increased ET-1 production. Furthermore, ET-1 transcriptionally upregulated TRAF3IP2, and this upregulation was prevented by pharmacological inhibition of ET-1 receptor B using BQ-788, or inhibition of NADPH oxidase-derived reactive oxygen species using gp91ds-tat and GKT137831. Notably, we found that knockdown of TRAF3IP2 abolished ET-1-induced proinflammatory and adhesion molecule (IL-1β, TNF-α, monocyte chemoattractant protein 1, ICAM-1, VCAM-1, and E-selectin) expression and monocyte adhesion to endothelial cells. Finally, we report that TRAF3IP2 is upregulated and colocalized with CD31, an endothelial marker, in the aorta of diabetic mice. Collectively, findings from the present study identify endothelial TRAF3IP2 as a potential new therapeutic target to suppress ET-1 production and associated vascular complications in diabetes. NEW & NOTEWORTHY This study provides the first evidence that the adapter molecule TRAF3 interacting protein 2 mediates high glucose-induced production of endothelin-1 by endothelial cells as well as endothelin-1-mediated endothelial cell inflammation. The findings presented herein suggest that TRAF3 interacting protein 2 may be an important therapeutic target in diabetic vasculopathy characterized by excess endothelin-1 production.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Adhesion; Cell Adhesion Molecules; Cells, Cultured; Coculture Techniques; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelial Cells; Endothelin-1; Female; Glucose; Humans; I-kappa B Kinase; Inflammation; Inflammation Mediators; Male; Mice, Inbred NOD; Mitogen-Activated Protein Kinase 8; Monocytes; Signal Transduction; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

Topics: Adaptor Proteins, Signal Transducing; Diabetes Mellitus, Type 1; Endothelial Cells; Endothelin-1; Glucose; Humans; Inflammation; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

Oxidative stress and inflammation are associated with endothelial injury and coronary artery disease. Inflammatory factors that promote oxidative damage include endothelin-1 (ET-1), myeloperoxidase (MPO), and C-reactive protein (CRP). Current guidelines recommend the use of statins in patients with risk of atherosclerotic cardiovascular disease (ASCVD).. To assess the impact of atorvastatin on plasma inflammatory and oxidant biomarkers in patients with moderate to very high risk of ASCVD.. Two hundred ten patients presented to the cardiology clinic were included and stratified into low, moderate, high, and very high risk of ASCVD. Moderate- (20 mg/d) to high-intensity (40 mg/d) atorvastatin was prescribed. Plasma levels of lipids, ET-1, CRP, MPO, total nitrite, lipid peroxides (thiobarbituric acid reactive substances [TBARS]), and superoxide dismutase (SOD) activities were measured at baseline and 12 weeks after treatment.. Relative to low-risk patients, baseline plasma inflammatory markers of CRP, MPO, ET-1, and nitrite were higher in patients with very high risk of ASCVD, whereas plasma SOD was lower (all P < .05). Use of high and moderate atorvastatin therapy significantly reduced low-density lipoprotein and total cholesterol levels, as well as plasma levels of CRP, MPO, nitrite, and TBARS, and increased plasma SOD activity in patients with moderate to very high risk of ASCVD, independent of lipid-lowering effects.. Key markers of oxidative stress/inflammation such as CRP, ET-1, total nitrite, and MPO are associated with an increased risk of ASCVD. Moderate- and high-intensity atorvastatin use reduces plasma oxidative stress and inflammation regardless of ASCVD risk and independent of its lipid-lowering effect.

Topics: Adult; Aged; Atherosclerosis; Atorvastatin; C-Reactive Protein; Dose-Response Relationship, Drug; Endothelin-1; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Lipids; Male; Middle Aged; Oxidants; Oxidative Stress; Peroxidase; Prospective Studies; Risk Factors; Superoxide Dismutase

Relative bradycardia is the term used to describe the mechanism where there is dissociation between pulse and temperature. This finding is important to recognize since it may provide further insights into the potential underlying causes of disease. There is no known proposed mechanism to explain this phenomenon. We hypothesize that relative bradycardia is the central mechanism reflecting and influenced potentially by the direct pathogenic effect on the sinoatrial node as well as cross-talk between the autonomic nervous system and immune system. Cardiac pacemaker cells may act as a target for inflammatory cytokines leading to alteration in heart rate dynamics or their responsiveness to neurotransmitters during systemic inflammation. These factors account for the important role of how the host response to infectious and non-infectious causes influences the appearance of relative bradycardia. We propose several methods that may be useful to confirm the proposed theoretical framework to further enhance our understanding of this paradoxical phenomenon. This includes measuring, during the episode of relative bradycardia, proinflammatory and anti-inflammatory cytokines, monitoring heart rate variability (HRV), and assessing underlying comorbidities and outcomes in patients with the same disease.

Topics: Autonomic Nervous System; Bradycardia; Comorbidity; Cytokines; Endothelin-1; Heart Rate; Humans; Immune System; Inflammation; Interleukin-6; Lipopolysaccharides; Models, Theoretical; NADPH Oxidases; Neurotransmitter Agents; Nitric Oxide; Pulse; Sepsis; Sinoatrial Node; Temperature; Treatment Outcome; Tumor Necrosis Factor-alpha

Airborne particulate matter (PM) exposure remains the leading environmental risk factor for disease globally. Interventions to mitigate the adverse effects of PM are required, since there is no discernible threshold for its effects, and exposure reduction approaches are limited. The mitigation of PM (specifically diesel exhaust particles (DEP))-induced release of pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8) and vasoconstrictor endothelin-1 (ET-1) after 24 and 48 h of exposure by pre-treatment with individual pure, combined pure, and an oil formulation of two fish oil omega-3 polyunsaturated fatty acids (ω-3 PUFAs), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) were all tested at an equivalent concentration of 100 µM in vitro in human umbilical vein endothelial cells. The PUFAs and fish oil formulation completely mitigated or diminished the DEP-induced release of IL-6, IL-8, and ET-1 by 14⁻78%. DHA was more effective in reducing the levels of the DEP-induced release of the cytokines, especially IL-6 after 48 h of DEP exposure in comparison to EPA (

Topics: Docosahexaenoic Acids; Eicosapentaenoic Acid; Endothelin-1; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Interleukin-6; Interleukin-8; Particulate Matter; Protective Agents; Vasoconstrictor Agents

Hepatopulmonary syndrome (HPS) is a serious complication of advanced liver disease, which markedly increases mortality. Pulmonary vascular remodelling (PVR) induced by circulating mediators plays an important role in the pathogenesis of HPS, while the underlying mechanism remains undefined. In the present study, we reported that endothelin-1 (ET-1) is up-regulated and annexin A1(ANXA1) is down-regulated in HPS rat, and ET-1 decreases the ANXA1 expression in a dose-dependent manner in rat pulmonary arterial smooth muscle cells (PASMCs). Then, we showed that ANXA1 can decrease nuclear p-ERK1/2 accumulation and decrease the cyclin D1 expression, thus resulting in the subsequent inhibition of PASMCs proliferation. As previously reported, we confirmed that ET-1 decreases the ANXA1 protein levels by the carbonylation and degradation of ANXA1. In conclusion, our research links the signaling cascade of ET1-ANXA1-cell proliferation to a potential therapeutic strategy for blocking IPS-associated PVR.

Topics: Animals; Annexin A1; Cell Proliferation; Cells, Cultured; Cyclin D1; Down-Regulation; Endothelin-1; Hepatopulmonary Syndrome; Inflammation; MAP Kinase Signaling System; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Protein Carbonylation; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Signal Transduction; Up-Regulation

Contrast-induced acute kidney injury (CI-AKI) is one of the most serious complications in patients who undergo percutaneous coronary intervention (PCI), especially in those with acute coronary syndrome. It has been shown that inflammation may play an important role in the pathophysiology of CI-AKI.. Inflammatory factors may play a predominant role in the prediction of CI-AKI in patients who undergo emergency PCI.. Patients who underwent emergency PCI from 2013 to 2015 were consecutively enrolled and were divided into CI-AKI and non-CI-AKI groups. Logistic analysis was used to identify the risk factors of CI-AKI. Receiver operator characteristic curve analysis was performed to evaluate the area under the curve (AUC) and to establish the optimal cutoff.. A total of 1061 patients were included, and the CI-AKI rate was 5.47% (58/1061). Logistic analysis showed that the white blood cell (WBC) count (odds ratio [OR]: 1.103, 95% confidence interval [CI]: 1.018-1.195, P = 0.016), neutrophil (N) count (OR: 1.134, 95% CI: 1.045-1.232, P = 0.003), neutrophil to lymphocyte ratio (NLR) (OR: 1.105, 95% CI: 1.044-1.169, P = 0.001), C-reactive protein (CRP) level (OR: 1.006, 95% CI: 1.001-1.011, P = 0.020), high-sensitivity C-reactive protein (hs-CRP) level (OR: 1.099, 95% CI: 1.020-1.184, P = 0.013), and big endothelin-1 (ET-1) level (OR: 4.030, 95% CI: 1.989-8.165, P < 0.001) were all significant predictors for CI-AKI, as was the left ventricular ejection fraction and diuretic administration. The AUC of the big ET-1 level was the highest (0.793, 95% CI: 0.733-0.853), followed by the NLR (0.708, 95% CI: 0.641-0.774), hs-CRP level (0.705, 95% CI: 0.627-0.782), CRP level (0.684, 95% CI: 0.607-0.761), N count (0.655, 95% CI: 0.584-0.726), WBC count (0.620, 95% CI: 0.544-0.695), and erythrocyte sedimentation rate (0.611, 95% CI: 0.527-0.695).. The WBC count, N count, NLR, CRP level, hs-CRP level, and big ET-1 level are all associated with an increased risk of CI-AKI, and among which, the big ET-1 level, NLR, and the hs-CRP level might have high predictive value for CI-AKI after an emergency PCI.

Topics: Acute Kidney Injury; Aged; Area Under Curve; Biomarkers; C-Reactive Protein; Chi-Square Distribution; Contrast Media; Emergencies; Endothelin-1; Female; Humans; Inflammation; Inflammation Mediators; Logistic Models; Lymphocyte Count; Lymphocytes; Male; Middle Aged; Multivariate Analysis; Neutrophils; Odds Ratio; Percutaneous Coronary Intervention; Predictive Value of Tests; Radiography, Interventional; Retrospective Studies; Risk Factors; ROC Curve; Treatment Outcome

The aim of this study was to examine the cardioprotective effects and latent mechanism of tannic acid (TA) on cardiac hypertrophy.. Abdominal aortic banding (AAB) was used to induce pressure overload-induced cardiac hypertrophy in male Wistar rats, sham-operated rats served as controls. AAB rats were treated with TA (20 and 40 mg/kg) or captoril.. Tannic acid displayed obvious suppression of AAB-induced cardiac hypertrophy in rats. The cardioprotective effects of TA may be attributed to multitargeted inhibition of oxidative stress, inflammation, fibrosis and apoptosis in addition to an increase in NO levels, decrease in ET-1 levels, and downregulation of angiotensin receptors and the phosphorylation of ERK1/2.

Topics: Animals; Apoptosis; Captopril; Cardiomegaly; Cardiotonic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Endothelin-1; Fibrosis; Inflammation; Male; Nitric Oxide; Oxidative Stress; Rats; Rats, Wistar; Receptors, Angiotensin; Tannins

Polysaccharides (PSs) produced by the red microalga Porphyridium sp. were reported to exhibit anti-inflammatory bioactivities in the human skin. The primary goal of the present research was to assess whether PSs attenuate inflammatory processes by interfering with tumour necrosis factor-alpha (TNF-α)-induced inflammation, in human coronary artery endothelial cells (HCAECs).. Functional and inflammatory markers were quantified in TNF-α-stimulated HCAECs, with and without pre-treatment with PSs. The expression/activation of these markers was assessed by Western immunoblotting and a luciferase reporter assay. NO levels were measured using the Griess method and intracellular reactive oxygen stress (ROS) was determined with the fluorescent probe 2',7'-dichlorodihydro-fluorescein diacetate (H. The TNF-α-induced up-regulation of inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation, as well as IκB degradation were significantly attenuated in cells pre-treated with PSs. In addition, PSs were able to inhibit NF-κB activation as well as TNF-α-induced oxidative stress in HCAECs. Endothelial function was also improved, as measured by increased nitric oxide (NO) formation and decreased endothelin (ET-1) protein expression.. This is the first report that demonstrates the anti-inflammatory effect and vaso-relaxing property of red microalgae PSs in a HCAEC-TNF-α induced system. This study lays the foundation for basic research concerning the PS mode of action in biochemical processes involving endothelial dysfunction, and it also holds potential for applied research, possibly promoting the use of PSs as a therapeutic agent or food additive to improve vascular health.

Topics: Anti-Inflammatory Agents; Cell Survival; Cells, Cultured; Coronary Vessels; Dose-Response Relationship, Drug; Endothelial Cells; Endothelin-1; Humans; I-kappa B Proteins; Inflammation; Intercellular Adhesion Molecule-1; NF-kappa B; Nitric Oxide; Polysaccharides; Reactive Oxygen Species; Rhodophyta; Signal Transduction; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Uric acid (UA) plays important roles in inducing renal inflammation, intra-renal vasoconstriction and renal damage. Endothelin-1 (ET-1) is a well-known profibrotic factor in the kidney and is associated with fibroblast expansion. We examined the role of hyperuricemia conditions in causing elevation of ET-1 expression and kidney injury.. Hyperuricemia was induced in mice using daily intraperitoneal injection of uric acid 125 mg/Kg body weight. An NaCl injection was used in control mice. Mice were euthanized on days-7 (UA7) and 14 (UA14). We also added allopurinol groups (UAL7 and UAL14) with supplementation of allopurinol 50 mg/Kg body weight orally. Uric acid and creatinine serum were measured from blood serum. Periodic Acid Schiff (PAS) and Sirius Red staining were done for glomerulosclerosis, tubular injury and fibrosis quantification. mRNA expression examination was performed for nephrin, podocin, preproEndothelin-1 (ppET-1), MCP-1 and ICAM-1. PDGFRβ immunostaining was done for quantification of fibroblast, while α-SMA immunostaining was done for localizing myofibroblast. Western blot analysis was conducted to quantify TGF-β1, α-SMA and Endothelin A Receptor (ETAR) protein expression.. Uric acid and creatinine levels were elevated after 7 and 14 days and followed by significant increase of glomerulosclerosis and tubular injury score in the uric acid group (p < 0.05 vs. control). Both UA7 and UA14 groups had higher fibrosis, tubular injury and glomerulosclerosis with significant increase of fibroblast cell number compared with control. RT-PCR revealed down-regulation of nephrin and podocin expression (p < 0.05 vs. control), and up-regulation of MCP-1, ET-1 and ICAM-1 expression (p < 0.05 vs. control). Western blot revealed higher expression of TGF-β1 and α-SMA protein expression. Determination of allopurinol attenuated kidney injury was based on reduction of fibroblast cell number, inflammation mediators and ppET-1 expression with reduction of TGF-β1 and α-SMA protein expression.. UA induced glomerulosclerosis, tubular injury and renal fibrosis with reduction of podocyte function and inflammatory mediator elevation. ET-1 and fibroblast expansion might modulate hyperuricemia induced renal fibrosis.

Topics: Acute Kidney Injury; Animals; Cell Proliferation; Endothelin-1; Fibroblasts; Gene Expression; Hyperuricemia; Inflammation; Mice; Uric Acid

Atherosclerosis is an important predictor of mortality in patients with chronic kidney disease (CKD) and is associated with a wide inflammatory response. The aim of this study is to evaluate in vitro how different membranes can remove mediators associated with this pathology in a closed loop dialysis model. We performed experimental hemofiltration in vitro using three different membrane materials. Human plasma was preliminarily incubated with various inflammatory mediators and filtered in a closed loop circulation model for 240 min. Respective concentrations of 17 different mediators were measured over time to study the removal mechanisms of each membrane, including associated removal time course. The experiment was repeated three times for the assay of tumor necrosis factor (TNF)-α to document the model variability. Means were compared using Mann-Whitney test. Most of the investigated mediators were effectively removed with the different dialysis membranes. Adsorption mechanism was mainly at the origin of the decrease in mediators circulating concentrations and was maximized in the region 10 000-20 000 Da. Especially, the HeprAN membrane showed fast removal capacities of mediators with elevated isoelectric point including complement factors and chemokines or having basic groups located in the protein periphery, plasminogen activator inhibitor (PAI-1), and TNF-α-like. The latter was further significantly removed with HeprAN and polymethylmethacrylate (PMMA) compared to polyethersulfone (PES) material (P < 0.01). We concluded that dialysis using ionic adsorptive membrane could have a beneficial impact for CKD patients with atherosclerosis and would deserve further clinical investigations.

Topics: Adsorption; Atherosclerosis; Chemokine CCL2; Endothelin-1; Equipment Design; Hemofiltration; Humans; Inflammation; Inflammation Mediators; Membranes, Artificial; Pilot Projects; Plasminogen Activator Inhibitor 1; Polymers; Polymethyl Methacrylate; Renal Insufficiency, Chronic; Sulfones; Tumor Necrosis Factor-alpha

Glucosamine is a possible cause of vascular endothelial injury in the initial stages of atherosclerosis, through endoplasmic reticulum (ER) stress resulting in fatty streaks in the vascular wall. Quercetin is an anti‑diabetic and cardiovascular protective agent that has previously been demonstrated to reduce ER stress in human umbilical vein endothelial cells (HUVECs). The present study aimed to investigate whether quercetin prevents glucosamine‑induced apoptosis and inflammation via ER stress pathway in HUVECs. The effect of quercetin on cell viability, apoptosis, and protein expression levels of inflammatory cytokines and ER stress markers was investigated in glucosamine‑supplemented HUVECs. Quercetin was demonstrated to protect against glucosamine‑induced apoptosis, improved cell viability, and inhibited expression of pro‑inflammatory factors and endothelin‑1. Quercetin treatment also reduced the expression levels of glucose‑regulated protein 78, phosphorylated protein kinase‑like ER kinase, phosphorylated c‑Jun N‑terminal kinase and C/EBP homologous protein. In conclusion, quercetin may have auxiliary therapeutic potential against glucosamine‑induced cell apoptosis and inflammation, which may be partially due to alleviation of ER stress.

Topics: Antioxidants; Apoptosis; CCAAT-Enhancer-Binding Proteins; Cytokines; Down-Regulation; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Glucosamine; Heat-Shock Proteins; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; JNK Mitogen-Activated Protein Kinases; Phosphorylation; Quercetin; Vascular Cell Adhesion Molecule-1

Arterial stiffness and calcification are nontraditional cardiovascular risk factors in chronic kidney disease (CKD). Using a rat model of CKD with mineral imbalance, medial vascular calcification has been associated with inflammation and increased endothelin-1 (ET-1) production. We therefore hypothesized that ET-1, through the endothelin type A (ETA) receptor, induces vascular inflammation, calcification and stiffness in CKD.. CKD was induced in Wistar rats by renal mass ablation. To induce medial vascular calcification, mineral imbalance was established with a identified as calcium-rich/phosphate-rich diet and vitamin D supplementation (Ca/P/VitD). One group of CKD + Ca/P/VitD rats was given the ETA receptor antagonist atrasentan (10 mg/kg/day) for 6 weeks. Hemodynamic parameters including SBP, pulse pressure (PP) and pulse wave velocity (PWV) were determined. Vascular calcification, smooth muscle cells osteoblastic differentiation and expression of inflammatory markers such as inflammatory cytokines and calgranulins S100A8 and S100A9 were assessed in the thoracic aorta.. As compared with CKD control rats, CKD + Ca/P/VitD rats developed medal vascular calcification that was associated with increased SBP, PP and PWV. These changes were also associated with increased macrophage infiltration and expression of IL-6, calgranulins and osteoblastic markers. Treatment of CKD + Ca/P/VitD rats with atrasentan reduced vascular calcification, SBP, PP and PWV, macrophage infiltration and expression of IL-1β, IL-6, tumor necrosis factor, calgranulins and osteoblastic markers.. This study shows that ETA receptor blockade reduced vascular inflammation, smooth muscle cells differentiation, calcification and stiffness indicating a pivotal role for ET-1 in medial vascular calcification in this rat remnant kidney model of CKD with mineral imbalance. Therefore, the endothelin system may be a potential therapeutic target for improving cardiovascular morbidity in patients with CKD.

Topics: Animals; Aorta, Thoracic; Atrasentan; Biomarkers; Blood Pressure; Calcium; Calgranulin A; Calgranulin B; Endothelin A Receptor Antagonists; Endothelin-1; Inflammation; Interleukin-1beta; Interleukin-6; Macrophages; Male; Phosphorus, Dietary; Pulse Wave Analysis; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Renal Insufficiency, Chronic; Tumor Necrosis Factor-alpha; Vascular Calcification; Vascular Stiffness; Vitamin D

Peroxisome proliferator-activated receptor γ (PPARγ) agonists reduce blood pressure and vascular injury in hypertensive rodents. Pparγ inactivation in vascular smooth muscle cells (VSMC) enhances vascular injury. Transgenic mice overexpressing endothelin (ET)-1 selectively in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Pparγ gene in VSMC (smPparγ-/-) would exaggerate ET-1-induced vascular injury.. eET-1, smPparγ-/- and eET-1/smPparγ-/- mice were treated with tamoxifen for 5 days and studied 4 weeks later. SBP was higher in eET-1 and unaffected by smPparγ inactivation. Mesenteric artery vasodilatory responses to acetylcholine were impaired only in smPparγ-/-. N(omega)-Nitro-L-arginine methyl ester abrogated relaxation responses, and the Ednra/Ednrb mRNA ratio was decreased in eET-1/smPparγ-/-, which could indicate that nitric oxide production was enhanced by ET-1 stimulation of endothelin type B receptors. Mesenteric artery media/lumen was greater only in eET-1/smPparγ-/-. Mesenteric artery reactive oxygen species increased in smPparγ and were further enhanced in eET-1/smPparγ-/-. Perivascular fat monocyte/macrophage infiltration was higher in eET-1 and smPparγ and increased further in eET-1/smPparγ-/-. Spleen CD11b+ cells were increased in smPparγ-/- and further enhanced in eET-1/smPparγ-/-, whereas Ly-6C(hi) monocytes increased in eET-1 and smPparγ-/- but not in eET-1/smPparγ-/-. Spleen T regulatory lymphocytes increased in smPparγ and decreased in eET-1, and decreased further in eET-1/smPparγ-/-.. VSMC Pparγ inactivation exaggerates ET-1-induced vascular injury, supporting a protective role for PPARγ in hypertension through modulation of pro-oxidant and proinflammatory pathways. Paradoxically, ET-1 overexpression preserved endothelial function in smPparγ-/- mice, presumably by enhancing nitric oxide through stimulation of endothelin type B receptors.

Topics: Animals; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Inflammation; Male; Mesenteric Arteries; Mice; Mice, Transgenic; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; PPAR gamma; Reactive Oxygen Species

The markers of endothelium dysfunction and factors of inflammation in pregnant women with hypertension with hypertension disorders of various genesis were analyzed. The clinical laboratory study was carried out on the basis of sampling of 158 women at pregnancy period of22-3 7 weeks. Out of this sampling 30 women had previously present chronic arterial hypertension, 3 0 women had chronic arterial hypertension and consecutive preeclampsia, 43 women had preeclampsia and 55 women had uncomplicated course of pregnancy without hypertension disorders (control group). It is established that in pregnant women with hypertension disorders of various genesis endothelial dysfunction and inflammation are developed/ This occurrence is confirmed by increasing of in blood of number of circulating desquamated endotheliocytes, C-reactive protein and homocystein in all groups; by increasing of serum level of t-PA, endothelin (1-21), MMP-2, sVCAM-1 and IL-6 under preeclampsia, including one consecutive to chronic arterial hypertension; by increasing of content of IL-6 in blood serum under chronic arterial hypertension with consecutive preeclampsia. The criteria are developed concerning serum content of t-PA, sVCAM-1, endothelin (1-21) and MMP-2 permitting to diagnose differentially previously present hypertension and preeclampsia, including consecutive one to chronic arterial hypertension.

Topics: Adult; Biomarkers; Endothelin-1; Endothelium; Female; Humans; Hypertension, Pregnancy-Induced; Inflammation; Interleukin-6; Matrix Metalloproteinase 2; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Tissue Plasminogen Activator; Vascular Cell Adhesion Molecule-1

The association between lead exposure and respiratory diseases including asthma is controversial. Some studies indicate that exposure to environmental lead pollution may cause asthma; however, there is not sufficient data in this regard. The effect of lead on lung pathological findings and serum inflammatory mediators in sensitized and non-sensitized guinea pigs exposed to inhaled lead was examined. Eleven animal groups including control, sensitized, three groups of non sensitized animals, three groups during sensitization, and three groups after sensitization exposed to aerosol of three lead concentrations (n = 6 for each group) were studied. Serum inflammatory mediators levels and lung pathological changes were evaluated. All pathological changes and serum ET-1, EPO, NO levels were significantly higher in the sensitized and non sensitized animals exposed to lead than control group (p < 0.05 to p < 0.001). There was no significant difference between non sensitized groups exposed to high lead concentration and sensitized group. Serum inflammatory mediators levels and pathological findings in sensitized groups exposed to lead both during and after sensitization were significantly higher than sensitized non exposed group (p < 0.05 to p < 0.001). The data of exposed animals to high lead concentration were significantly higher than those of medium and low concentrations; those of medium concentration were also higher than low concentration (p < 0.05 to p < 0.001). In summary, the present study indicates that exposure to inhaled lead is able to induce respiratory changes similar to asthma. In addition, the results indicated that exposure to environmental lead is able to aggravate asthma severity both during development of asthma or after its manifestation.

Topics: Administration, Inhalation; Animals; Endothelin-1; Eosinophil Peroxidase; Female; Guinea Pigs; Hypersensitivity; Inflammation; Lead; Lung; Male; Nitric Oxide; Ovalbumin

Nonocclusive mesenteric ischemia (NOMI) can evolve in a variety of low-flow states. Although the mechanisms leading to NOMI-related intestinal necrosis are largely unknown, circumstantial evidence suggests that excessive vasoconstriction and complement activation both play important roles in this process. Because targeting of the circulatory malfunction of the splanchnic area could be of therapeutic relevance, we set out to investigate the long-term effects of treatment with a complement C5a antagonist in a rat model of partial aortic occlusion (PAO)-induced transient mesenteric hypoperfusion.. The mean arterial pressure of the splanchnic area was kept between 30 and 40 mm Hg by 60 minutes of PAO in anesthetized male Sprague-Dawley rats. C5a inhibitor acetyl-peptide-A (AcPepA; 4 mg kg(-1) intravenously) or vehicle administration was initiated at the 45th minute of PAO. After 24 hours, the animals were reanesthetized to record the macrohemodynamics and ileal microcirculation, and plasma and tissue samples were taken for determination of high-mobility group box protein-1 (HMGB-1), endothelin-1, tumor necrosis factor (TNF)-α levels, and small intestinal leukocyte infiltration. Epithelial structural changes were visualized by in vivo confocal laser scanning endomicroscopy.. At 24 hours after PAO, mean arterial pressure, heart rate, and cardiac output were significantly greater, the intestinal intramural microcirculation was significantly impaired, and plasma HMGB-1, endothelin-1, TNF-α levels, the degree of epithelial damage and leukocyte infiltration was increased. The AcPepA treatment moderated the hemodynamic and microcirculatory changes, and decreased inflammatory activation and histologic signs of mucosal damage.. C5a inhibition ameliorated the potentially harmful local mesenteric hypoperfusion and global long-term inflammatory consequences of PAO. This approach is of promise for use in NOMI-associated situations.

Topics: Analysis of Variance; Animals; Biomarkers; Disease Models, Animal; Endothelin-1; Hemodynamics; HMGB1 Protein; Ileum; Inflammation; Male; Mesenteric Ischemia; Microcirculation; Microscopy, Video; Multivariate Analysis; Pilot Projects; Random Allocation; Rats; Rats, Sprague-Dawley; Serine Endopeptidases; Statistics, Nonparametric; Tumor Necrosis Factor-alpha; Vascular Patency

Obstructive sleep apnea (OSA) is a major risk factor for cardiovascular mortality, and apnea-induced intermittent hypoxia (IH) is known to promote various cardiovascular alterations such as vascular remodeling. However, the mechanisms that underlie IH remain incompletely investigated. We previously demonstrated that the hypoxia-inducible factor-1 (HIF-1) and endothelin-1 (ET-1) are involved in arterial hypertension and myocardial susceptibility to infarction induced by IH. Thus the objective of the present study was to investigate whether both ET-1 and HIF-1 were also involved in the vascular inflammatory remodeling induced by IH. Mice partially deficient for the Hif1α gene (HIF-1α(+/-)) and their wild-type equivalents, as well as C57BL/6J mice, treated or not with bosentan, a dual endothelin receptor antagonist, were exposed to IH or normoxia for 2 wk, 8 h/day. Splenocyte proliferative and secretory capacities, aortic nuclear factor-κB (NF-κB) and HIF-1 activities, and expression of cytokines and intima-media thickness (IMT) were measured. IH induced a systemic and aortic inflammation characterized by an increase in splenocyte proliferative and secretory capacities, aortic NF-κB activity, and cytokine expression in the aortic wall. This was accompanied by an increase in IMT. These modifications were prevented in HIF-1α(+/-) and bosentan-treated mice. The results of this study suggest that ET-1 is a major contributor to the vascular inflammatory remodeling induced by OSA-related IH, probably through HIF-1-dependent activation of NF-κB.

Topics: Animals; Aorta; Carotid Intima-Media Thickness; Cytokines; Endothelin-1; Hypertension; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Mice; Mice, Inbred C57BL; NF-kappa B; Sleep Apnea, Obstructive; Vascular Remodeling

The role of endothelium in the progression of atheromasic disease has already been demonstrated. Endothelin-1 (ET-1) is released from endothelial cells during acute and chronic vascular damage and it appears to be the strongest vasoconstrictor agent known.The aim of this study is to investigate the amount of endothelial damage in patients with unstable angina (UA), as defined by serum levels of ET-1, to verify a possible correlation with increased ischaemic damage by evaluation of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and interleukin 8 (IL-8) levels.Serum levels of ET-1, IL-8 and NT-proBNP obtained from 10 patients affected by low-risk UA were compared to those belonging to eight healthy subjects. In order to compare the laboratory data pertaining to the two populations, a Student's t-test and a Mann-Whitney U test were performed.Levels of ET-1, IL-8 and NT-proBNP in samples of peripheral blood of patients affected by UA were significantly elevated, compared with those of the control group. The linear correlation analysis demonstrated a positive and significant correlation between levels of ET-1 and IL-8, between levels of ET-1 and NT-proBNP, and between levels of IL-8 and NT-proBNP in subjects affected by UA.Early elevated levels of ET-1, IL-8 and NT-proBNP in patients with UA show a coexistence between ischaemic insults and endothelial damages. A positive and significant linear correlation between levels of ET-1 and IL-8, between levels of ET-1 and NT-proBNP, and between levels of IL-8 and NT-proBNP confirms that an increased ischaemic insult is correlated to inflammation signs and endothelium damage signs.In patients with UA, ischaemia is always associated with a systemic immuno-mediated activity induced by acute endothelial damage. We suggest early administration of ET-1-selective receptor blockers and anti-inflammatory drugs.

Topics: Acute Disease; Adult; Angina, Unstable; Endothelial Cells; Endothelin-1; Endothelium; Female; Humans; Immunologic Factors; Inflammation; Interleukin-8; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Peptide Fragments

Besides their importance for the vascular tone, vascular smooth muscle cells (VSMC) also contribute to pathophysiological vessel alterations. Various G-protein coupled receptor ligands involved in vascular dysfunction and remodeling can transactivate the epidermal growth factor receptor (EGFR) of VSMC, yet the importance of EGFR transactivation for the VSMC phenotype is incompletely understood. The aims of this study were (i) to characterize further the importance of the VSMC-EGFR for proliferation, migration and marker gene expression for inflammation, fibrosis and reactive oxygen species (ROS) homeostasis and (ii) to test the hypothesis that vasoactive substances (endothelin-1, phenylephrine, thrombin, vasopressin and ATP) rely differentially on the EGFR with respect to the abovementioned phenotypic alterations. In primary, aortic VSMC from mice without conditional deletion of the EGFR, proliferation, migration, marker gene expression (inflammation, fibrosis and ROS homeostasis) and cell signaling (ERK 1/2, intracellular calcium) were analyzed. VSMC-EGFR loss reduced collective cell migration and single cell migration probability, while no difference between the genotypes in single cell velocity, chemotaxis or marker gene expression could be observed under control conditions. EGF promoted proliferation, collective cell migration, chemokinesis and chemotaxis and leads to a proinflammatory gene expression profile in wildtype but not in knockout VSMC. Comparing the impact of five vasoactive substances (all reported to transactivate EGFR and all leading to an EGFR dependent increase in ERK1/2 phosphorylation), we demonstrate that the importance of EGFR for their action is substance-dependent and most apparent for crowd migration but plays a minor role for gene expression regulation.

Topics: Adenosine Triphosphate; Animals; Cell Movement; Cell Proliferation; Cells, Cultured; Endothelin-1; Enzyme Activation; Epidermal Growth Factor; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Gene Expression Regulation; Genotype; Inflammation; Ligands; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oxidative Stress; Phenotype; Phenylephrine; Primary Cell Culture; Signal Transduction; Thrombin; Time Factors; Vasopressins

Experimental autoimmune encephalomyelitis (EAE) is a mouse model that reproduces cardinal signs of clinical, histopathological, and immunological features found in Multiple Sclerosis (MS). Mast cells are suggested to be involved in the main inflammatory phases occurring during EAE development, possibly by secreting several autacoids and proteases. Among the latter, the chymase mouse mast cell protease 4 (mMCP-4) can contribute to the inflammatory response by producing endothelin-1 (ET-1). The aim of this study was to determine the impact of mMCP-4 on acute inflammatory stages in EAE. C57BL/6 wild type (WT) or mMCP-4 knockout (KO) mice were immunized with MOG35-55 plus complete Freund's adjuvant followed by pertussis toxin. Immunized WT mice presented an initial acute phase characterized by progressive increases in clinical score, which were significantly reduced in mMCP-4 KO mice. In addition, higher levels of spinal myelin were found in mMCP-4 KO as compared with WT mice. Finally, whereas EAE triggered significant increases in brain levels of mMCP-4 mRNA and immunoreactive ET-1 in WT mice, the latter peptide was reduced to basal levels in mMCP-4 KO congeners. Together, the present study supports a role for mMCP-4 in the early inflammatory phases of the disease in a mouse model of MS.

Topics: Animals; Astrocytes; Brain; Encephalomyelitis, Autoimmune, Experimental; Endothelin-1; Female; Fluorescent Antibody Technique; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Serine Endopeptidases

What is the central question of this study? This study addresses the relative impact of obesity and intermittent hypoxia in the pathophysiological process of obstructive sleep apnoea by investigating the metabolic, inflammatory and cardiovascular consequences of intermittent hypoxia in lean and obese Zucker rats. What is the main finding and its importance? We found that obesity and intermittent hypoxia have mainly distinct consequences on the investigated inflammatory and cardiometabolic parameters in Zucker rats. This suggests that, for a given severity of sleep apnea, the association of obesity and obstructive sleep apnoea may not necessarily be deleterious. Obstructive sleep apnoea is associated with obesity with a high prevalence, and both co-morbidities are independent cardiovascular risk factors. Intermittent hypoxia (IH) is thought to be the main factor responsible for the obstructive sleep apnoea-related cardiometabolic alterations. The aim of this study was to assess the respective impact of obesity and IH on the inflammatory and cardiometabolic state in rats. Lean and obese Zucker rats were exposed to normoxia or chronic IH, and we assessed metabolic and inflammatory parameters, such as plasma lipids and glucose, serum leptin and adiponectin, liver cytokines, nuclear factor-κB activity and cardiac endothelin-1 levels. Myocardial infarct size was also evaluated following in vitro ischaemia-reperfusion. Circulating lipids, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), leptin and adiponectin levels were higher in obese versus lean rats. Chronic IH did not have a significant impact on metabolic parameters in lean rats. In obese rats, IH increased glycaemia and HOMA-IR. Liver interleukin-6 and tumour necrosis factor-α levels were elevated in lean rats exposed to IH; obesity prevented the increase in interleukin-6 but not in tumour necrosis factor-α. Finally, IH exposure enhanced myocardial sensitivity to infarction in both lean and obese rats and increased cardiac endothelin-1 in lean but not obese rats. In conclusion, this study shows that the dyslipidaemia and insulin resistance induced by obesity of genetic origin does not enhance the deleterious cardiovascular response to IH and may even partly protect against IH-induced inflammation.

Topics: Adiponectin; Animals; Blood Glucose; Cardiovascular Diseases; Cytokines; Disease Models, Animal; Endothelin-1; Hypoxia; Inflammation; Insulin; Interleukin-6; Leptin; Lipids; Liver; Male; Myocardium; NF-kappa B; Obesity; Rats; Rats, Zucker; Tumor Necrosis Factor-alpha

Recent studies in type 2 diabetes have reported an association between hypoglycemia and severe cardiovascular adverse events, which are relatively increased in standard versus intensively treated individuals. The aim of this study was to determine the effects of equivalent sympathetic nervous system (SNS) activity during moderate hypoglycemia on in-vivo endothelial function, pro-inflammatory, pro-atherothrombotic, and pro-coagulant responses in healthy and standard treated type 2 diabetes individuals.. Eleven type 2 diabetes and 16 healthy individuals participated in single 2day studies. Day 1 involved a 2h hyperinsulinemic/euglycemic clamp and day 2, a 2h hyperinsulinemic/hypoglycemic clamp of 3.2±1mmol/L in type 2 diabetes and (2.9±0.1mmol/L) in healthy individuals.. ICAM-1, VCAM-1, P-selectin, PAI-1, VEGF and endothelin-1 (ET-1) fell during hyperinsulinemic euglycemia but increased during hypoglycemia in type 2 diabetes and healthy individuals. Epinephrine and norepinephrine levels were equivalent during hypoglycemia in type 2 DM and healthy individuals. However, despite similar SNS drive but milder and hypoglycemia there were greater ICAM-1, VCAM-1, PAI-1, VEGF and ET-1 responses in the type 2 diabetes group. Endogenous and exogenous nitric oxide mediated arterial vasodilation were also impaired only during hypoglycemia in type 2 diabetes.. We conclude that, milder hypoglycemia but equivalent SNS activation results in more diffuse endothelial dysfunction and a greater pro-inflammatory, pro-atherothrombotic and pro-coagulant state in standard treated type 2 diabetes as compared to healthy individuals.

Topics: Adult; Atherosclerosis; Blood Coagulation; Case-Control Studies; Diabetes Mellitus, Type 2; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Inflammation; Intercellular Adhesion Molecule-1; Male; Middle Aged; Obesity; P-Selectin; Plasminogen Activator Inhibitor 1; Sympathetic Nervous System; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

Although the role of endothelium in varicose vein development is indisputable, the effect of the pathology on biological properties of endothelial cells remains unclear. Here we examined if the presence of varicose veins affects senescence of endothelial cells (HUVECs) and, if so, what will be the local and systemic outcome of this effect. Experiments showed that HUVECs subjected to serum from varicose patients display improved proliferation, increased expression of senescence marker, SA-

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Case-Control Studies; Cell Proliferation; Cells, Cultured; Cellular Senescence; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Middle Aged; Reactive Oxygen Species; Varicose Veins; Vascular Cell Adhesion Molecule-1; Young Adult

Periodontitis is a very common oral inflammatory disease that results in the destruction of supporting connective and osseous tissues of the teeth. Although the exact etiology is still unclear, Gram-negative bacteria, especially Porphyromonas gingivalis in subgingival pockets are thought to be one of the major etiologic agents of periodontitis. Endothelin (ET) is a family of three 21-amino acid peptides, ET-1, -2, and -3, that activate G protein-coupled receptors, ETA and ETB. Endothelin is involved in the occurrence and progression of various inflammatory diseases. Previous reports have shown that ET-1 and its receptors, ETA and ETB are expressed in the periodontal tissues and, that ET-1 levels in gingival crevicular fluid are increased in periodontitis patients. Moreover, P. gingivalis infection has been shown to induce the production of ET-1 along with other inflammatory cytokines. Despite these studies, however, the functional significance of endothelin in periodontitis is still largely unknown. In this study, we explored the cellular and molecular mechanisms of ET-1 action in periodontitis using human gingival epithelial cells (HGECs). ET-1 and ETA, but not ETB, were abundantly expressed in HGECs. Stimulation of HGECs with P. gingivalis or P. gingivalis lipopolysaccharide increased the expression of ET-1 and ETA suggesting the activation of the endothelin signaling pathway. Production of inflammatory cytokines, IL-1β, TNFα, and IL-6, was significantly enhanced by exogenous ET-1 treatment, and this effect depended on the mitogen-activated protein kinases via intracellular Ca2+ increase, which resulted from the activation of the phospholipase C/inositol 1,4,5-trisphosphate pathway. The inhibition of the endothelin receptor-mediated signaling pathway with the dual receptor inhibitor, bosentan, partially ameliorated alveolar bone loss and immune cell infiltration. These results suggest that endothelin plays an important role in P. gingivalis-mediated periodontitis. Thus, endothelin antagonism may be a potential therapeutic approach for periodontitis treatment.

Topics: Animals; Calcium; Cytokines; Disease Progression; Endothelin-1; Epithelial Cells; Humans; Inflammation; Male; Mice; Periodontitis; Porphyromonas gingivalis; Signal Transduction

To examine the relationships of serum markers of inflammation and endothelial function to diabetic retinopathy.. We recruited 224 patients with diabetes (85 with Type 1 and 139 with Type 2 diabetes) aged 18-70 years. Serum markers of inflammation (high-sensitivity C-reactive protein) and endothelial function (soluble intercell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, endothelin-1 and total nitrite) were assessed using nephelometry, immunoassays and spectroscopy. Diabetic retinopathy was graded from two-field fundus photographs according to the Airlie House Classification system and was categorized into no diabetic retinopathy, mild non-proliferative diabetic retinopathy, moderate non-proliferative diabetic retinopathy and vision-threatening diabetic retinopathy, the latter comprising severe non-proliferative diabetic retinopathy, proliferative diabetic retinopathy or clinically significant macular oedema. Multinomial logistic regression was used to assess the associations between serum markers and diabetic retinopathy.. In the study, 64% of patients (144/224) had diabetic retinopathy and 25% (57/244) had vision-threatening diabetic retinopathy. After controlling for age, gender, diabetes duration, HbA1c , systolic blood pressure, total and HDL cholesterol, smoking, the use of insulin or oral hypoglycaemic agents, nephropathy and cardiovascular disease, a positive association was found between increasing high-sensitivity C-reactive protein levels and the presence of vision-threatening diabetic retinopathy (odds ratio 1.26; 95% CI 1.05-1.51, per sd increase in high-sensitivity C-reactive protein). After stratifying by BMI ( ≥ 30 and < 30 kg/m(2) ), this association was found to be more pronounced in people with a BMI ≥ 30 kg/m(2) (odds ratio 2.9; P for interaction = 0.019). No associations were found between serum markers of endothelial activation and diabetic retinopathy.. Higher C-reactive protein levels, but not markers of endothelial function, may be related to more severe diabetic retinopathy. This finding suggests that inflammatory processes are involved in severe diabetic retinopathy, particularly in patients with a BMI ≥ 30 kg/m(2) .

Topics: Adolescent; Adult; Aged; Biomarkers; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; E-Selectin; Endothelin-1; Endothelium, Vascular; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Logistic Models; Male; Middle Aged; Nitrates; Ophthalmoscopes; Severity of Illness Index; Vascular Cell Adhesion Molecule-1; Young Adult

Renal ischemia/reperfusion (I/R) is a common risk factor for renal failure. Expression of endothelin‑1 (ET‑1) and its receptor ETA were also reported to be involved in the development of acute and chronic renal disease. The present study was designed to investigate the association between inflammation and ET‑1/ETA expression in mouse kidneys following acute I/R. The results demonstrated that acute renal I/R caused a significant increase in ET‑1 and ETA gene and transcriptional levels compared with those of the sham group (P<0.01). Ischemia alone also resulted in a marked increase of ET‑1 and ETA expression compared with that of the sham group (P<0.05). In addition, ET‑1 and ETA expression was significantly increased in the I/R group compared with that of the ischemia group (P<0.05 or P<0.01). Of note, the altered expression levels of inflammatory cytokines tumor necrosis factor (TNF)‑α and interleukin (IL)‑6 in kidneys following I/R and ischemia alone were correlated with the expression of ET‑1 and ETA. Hypoxia is the most important stimulus of I/R for tissue injury. In kidneys, ET‑1 is primarily produced by renal glomerular endothelial cells (RGECs). In the present study, treatment with hypoxia alone or hypoxia/reoxygenation were found to increase ET‑1 and ETA expression in human RGECs (P<0.05 or P<0.01). In order to elucidate the role of inflammation in the ischemia‑ and hypoxia‑induced upregulation of ET‑1 and ETA, human RGECs were exposed to different concentrations of TNF‑α. As expected, TNF‑α increased ET‑1 and ETA expression in a dose‑dependent manner; furthermore, application of the TNF‑α inhibitor CAY10500 partially inhibited hypoxia‑induced ET‑1 and ETA expression. In conclusion, these results indicated that I/R induced upregulation of ET‑1 and ETA in the kidneys, which was, at least in part, dependent on the production of inflammatory cytokines.

Topics: Animals; Disease Models, Animal; Endothelial Cells; Endothelin-1; Gene Expression; Humans; Hypoxia; Inflammation; Interleukin-6; Male; Mice; Receptor, Endothelin A; Reperfusion Injury; RNA, Messenger; Tumor Necrosis Factor-alpha

Endothelial dysfunction is a major precursor of atherosclerosis. The aim of this study was to assess the interrelationships between plasma endothelin-1 (ET-1) levels and cardiovascular risk among young and healthy individuals.. We performed a population-based study among 2160 healthy adults aged between 25 and 41 years in the Principality of Liechtenstein. Individuals with prevalent cardiovascular disease, diabetes or a body mass index >35 kg/m(2) were excluded. Plasma ET-1 was measured using a novel high-sensitive, single-molecule counting technology. The relationships between plasma levels of ET-1 and various cardiovascular risk factors were assessed by multivariable regression analyses.. Median age of our population was 37 years. Median ET-1 levels across ET-1 quartiles were 1.86, 2.33, 2.76 and 3.48 pg/mL. After multivariable adjustment, there were significant correlations of ET-1 with systolic blood pressure (β per 1-unit increase in log transformed ET-1 2.30 (95% confidence interval (CI) 1.03; 3.58, p = 0.0004), C-reactive protein (β 0.19 (95% CI 0.03; 0.34, p = 0.021), glomerular filtration rate (β -1.73 (95% CI -3.17; -0.29, p = 0.019), and current smoking (Odds ratio 1.94 (95% CI 1.39; 2.71, p < 0.0001). We also found a highly significant association between ET-1 levels and overall cardiovascular risk estimated by the "Prospective Cardiovascular Münster" (PROCAM) and the Framingham score (β 0.18 (95% CI 0.06; 0.31, p = 0.004, and β 0.11 (95% CI 0.05; 0.16), p < 0.0001, respectively).. Plasma ET-1 levels are easily measurable in healthy adults and correlate with major cardiovascular risk factors and global cardiovascular risk.

Topics: Adult; Cardiovascular Diseases; Cohort Studies; Endothelin-1; Female; Glomerular Filtration Rate; Healthy Volunteers; Humans; Inflammation; Liechtenstein; Male; Multivariate Analysis; Phenotype; Risk Factors; Smoking; Surveys and Questionnaires; Systole; Young Adult

Topics: Animals; Arachidonate 5-Lipoxygenase; Asthma, Exercise-Induced; Bronchial Spasm; Bronchoconstriction; Cells, Cultured; Cytokines; Endothelin-1; Endotoxins; Exercise; Female; Gene Expression Regulation; Gonadal Steroid Hormones; Humans; Inflammation; Male; Mice; Physical Endurance; Rats; Receptors, Adrenergic, beta-2; Receptors, Immunologic; Receptors, Prostaglandin; Running; Sex Characteristics; Th1 Cells; Th2 Cells; Up-Regulation

Custodiol-N, a new preservation solution, has been shown particularly suitable for hypothermic machine perfusion preservation (HMP) in isolated porcine kidneys. These preliminary results should be confirmed in an actual transplant model in vivo. Kidney function after 21 h of HMP was studied in an autotransplant model using Landrace pigs (25-30 kg; n = 6 per group). Perfusion was performed with oxygenated perfusate, using either Custodiol-N solution including 50 g/l dextran 40 (CND) or kidney perfusion solution 1 (KPS-1) as gold standard. Viability of the grafts was followed for 1 week after bilateral nephrectomy in the recipient pigs. HMP with CND resulted in less acute tubular injury, evaluated by levels of fatty acid-binding protein and better clearance function during the first 24 h after Tx than with KPS-1 (P < 0.05, resp.). Serum creatinine tended to be lower in the CND group during the whole observation period. Histological tissue scores one week after Tx were similar in both groups. Expression of endothelin-1 as well as of Toll-like receptor 4 15 min after reperfusion was lower in the CND group (P < 0.05), suggesting less endothelial stress response. The data provide first in vivo evidence for the suitability of Custodiol-N as an effective perfusate for renal machine perfusion.

Topics: Animals; Cell Survival; Creatinine; Disease Models, Animal; Endothelin-1; Endothelium; Fatty Acid-Binding Proteins; Graft Survival; Inflammation; Kidney; Kidney Function Tests; Kidney Transplantation; Kidney Tubules; Nephrectomy; Organ Preservation; Organ Preservation Solutions; Oxygen; Perfusion; Reperfusion; Swine; Toll-Like Receptor 4

Vascular endothelial dysfunction and inflammatory response are early events during initiation and progression of atherosclerosis. In vitro studies have described that CIT markedly upregulates expressions of ICAM-1 and VCAM-1 of endothelial cells, which result from NF-κB activation induced by CIT. In order to determine whether it plays a role in atherogenesis in vivo, we conducted the study to investigate the effects of CIT on atherosclerotic plaque development and inflammatory response in apolipoprotein E deficient (apoE-/-) mice. Five-week-old apoE-/- mice were fed high-fat diets and treated with CIT for 15 weeks, followed by assay of atherosclerotic lesions. Nitric oxide (NO), vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were detected in serum. Levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), VEGF, and ET-1 in plaque areas of artery walls were examined. NF-κB p65 expression and NF-κB activation in aorta also were assessed. CIT treatment significantly augmented atherosclerotic plaques and increased expressions of ICAM-1, VCAM-1, VEGF and ET-1 in aorta. Mechanistic studies showed that activation of NF-κB was significantly elevated by CIT treatment, indicating the effect of CIT on atherosclerosis may be regulated by activation of NF-κB.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Aurovertins; Body Weight; Diet, High-Fat; Endothelin-1; Endothelium, Vascular; Hypercholesterolemia; Inflammation; Intercellular Adhesion Molecule-1; Lipids; Male; Mice, Inbred C57BL; NF-kappa B; Nitric Oxide; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

The aim of this study was to determine the actions of caffeic acid phenethyl ester (CAPE) on the changes of endothelin-1 (ET-1) level, tumor necrosis factor- (TNF-) alpha, and oxidative stress parameters such as superoxide dismutase (SOD) activities and malondialdehyde (MDA) levels in experimental sepsis model in rats.. Twenty-four rats were randomly divided into three experimental groups: sham (group 1), sepsis (group 2), and sepsis + CAPE (group 3), n = 8 each. CAPE was administered (10 µmol/kg) intraperitoneally to group 3 before sepsis induction. Serum ET-1, serum TNF-alpha, tissue SOD activity, and tissue MDA levels were measured in all groups.. Pretreatment with CAPE decreased ET-1, TNF-alpha, and MDA levels in sepsis induced rats. Additionally SOD activities were higher in rats pretreated with CAPE after sepsis induction.. Our results demonstrate that CAPE may have a beneficial effect on ET and TNF-alpha levels and oxidative stress parameters induced by sepsis in experimental rat models. Therefore treatment with CAPE can be used to avoid devastating effects of sepsis.

Topics: Animals; Caffeic Acids; Disease Models, Animal; Endothelin-1; Inflammation; Male; Malondialdehyde; Oxidative Stress; Oxygen; Phenylethyl Alcohol; Random Allocation; Rats; Rats, Wistar; Sepsis; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

Endothelin-1 (ET-1) plays a pivotal role in vasoconstriction, fibrosis, and inflammation, the key features of systemic sclerosis (SSc). ET-1 receptors (ETA and ET(B)) are expressed on endothelial cells, smooth muscle cells, and fibroblasts, but their presence on immune cells has not been deeply investigated so far. Endothelin receptors antagonists such as bosentan have beneficial effects on vasoconstriction and fibrosis, but less is known about their potential anti-inflammatory effects. We studied the expression of ET-1 receptors on immune cells (T and B lymphocytes, monocytes, and neutrophils) and the link between ET-1 and inflammation in patients with SSc. We show here that ET-1 exerts a proinflammatory effect in CD4+ T cells, since it induces an increased IFN-γ production; preincubation with antagonists of both receptors reduces IFN-γ production. Moreover, following ET-1 stimulation, neutrophils produce proinflammatory mediators, thus amplifying the effects of activated CD4+ T cells. Our data indicate that ET-1 system is involved in the pathogenesis of inflammation and fibrosis typical of SSc, through the activation of T lymphocytes and neutrophils and the consequent release of proinflammatory and profibrotic cytokines. These findings suggest that dual ET-1 receptors antagonist therapy, besides its effect on vasculopathy, has a profound impact on the immune system favouring antiinflammatory and antifibrogenic effects.

Topics: Anti-Inflammatory Agents; Bosentan; CD4-Positive T-Lymphocytes; Endothelin Receptor Antagonists; Endothelin-1; Female; Fibroblasts; Fibrosis; Humans; Inflammation; Interferon-gamma; Male; Middle Aged; Monocytes; Receptors, Endothelin; Scleroderma, Systemic; Sulfonamides

To investigate mechanism underlying the role of nuclear factor Kappa B (NF-κB) which induced inflammatory injury and functional lesions of aortic endothelial cells in rat with emphysema and intermittent hypoxia.. Sixty male Wistar rats were divided randomly into 4 experimental groups (n = 15 each group): control group, emphysema group, intermittent hypoxia (IH) group, emphysema with intermittent hypoxia group. The rats in control group had ad libitum access to food and water under normal circumstance. The rats in the emphysema group were exposed to cigarette smoke twice daily (30 min each time). As for IH group, the rats were exposed to intermittent hypoxia circumstance (8 h/day). Both cigarette smoke twice a day (30 min each time) and intermittent hypoxia circumstance (8 h/day) were imposed on the rats in emphysema with intermittent hypoxia group. All the rats were exposed for 8 weeks. Five rats were randomly selected from each group to measure the blood gas on the ninth week. We collected lung and endothelial tissues of thoracic aorta from the rest sacrificed rats, and observed the pathological changes of lung tissue through HE staining. The levels of ET-1, TNF-α and IL-8 in rat endothelial tissues of thoracic aorta were measured by ELISA testing. Nitrate reductase was used to measure the levels of NO, and RT-PCR to detect the levels of NF-κB mRNA, ICAM-1 mRNA, MMP-9 mRNA and eNOS mRNA.. Lung pathology and blood gas results showed that the rat model of emphysema with intermittent hypoxia was established successfully. The levels of ET-1, TNF-α, IL-8 in emphysema with intermittent hypoxia group were (172.4 ± 1.6) ng/L, (104.1 ± 1.4) ng/L, (272.1 ± 3.6) ng/L respectively, significantly higher than the control group, emphysema group and intermittent hypoxia group (all P < 0.05). The level of NO was (27.07 ± 0.57) µmol/L, which was significant reduced; the expression of NF-κB mRNA, ICAM-1 mRNA, MMP-9 mRNA in emphysema with intermittent hypoxia group was significantly upregulated compared with the control goup, emphysema group and intermittent hypoxia group (all P < 0.05). The levels of eNOS mRNA expression were significantly lower than other three groups. The expression of NF-κB mRNA was positively correlated with MMP-9 mRNA level (r = 0.572, P < 0.001) and the expression of NF-κB mRNA was negatively correlated with eNOS mRNA level (r = 0.534, P < 0.001); there was no statistical difference in levels of NF-κB mRNA and eNOS mRNA expression between intermittent hypoxia and emphysema group (P > 0.05).. Compared with only emphysema or intermittent hypoxia exposure, inflammatory injury of aortic endothelial cells of rats induced by emphysema with intermittent hypoxia was more serious, and may result in more serious cardiovascular complications. The activation of NF-κB pathway may be an important mechanism of its inflammatory response.

Topics: Animals; Aorta; Disease Models, Animal; Endothelial Cells; Endothelin-1; Hypoxia; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; Lung; Male; Matrix Metalloproteinase 9; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type III; Pulmonary Emphysema; Rats; Rats, Wistar; Smoke; Tumor Necrosis Factor-alpha

To evaluate the association of obstructive sleep apnea hypopnea syndrome (OSAHS) with carotid atherosclerosis and the efficacy of continuous positive airway pressure (CPAP) treatment.. A total of 93 OSAHS patients diagnosed by polysomnography (PSG) were selected from Sleep Disorders Center at Affiliated Hospital of Xuzhou Medical College between March 2013 and December 2014. Based on the results of apnea-hypopnea index (AHI), they were divided into mild (n=22), moderate (n=37), and severe OSAHS group (n=34). Meanwhile, 28 healthy adult individuals matched for age and body mass index (BMI) were enrolled as the control group. The carotid intima-mesa thickness (IMT) was measured by color Doppler uhrasonography, and plasma levels of tumor necrosis factor-α (TNF-α), endothelin-1 (ET-1) and nitric oxide (NO) were determined by Enzyme-Linked Immunosorbent Assay (ELISA). The correlations between carotid IMT and plasma levels of TNF-α, ET-1 and NO were analyzed. A total of 24 patients with moderate to severe OSAHS underwent CPAP treatment and the carotid IMT, plasma levels of TNF-α, ET-1 and NO were compared before and after CPAP treatment.. OSAHS patients had significant increase of carotid IMT with the increasing disease severity, and the carotid IMT in mild, moderate and severe OSAHS groups were all significantly higher than that in the control group ((0.73 ± 0.31), (0.86 ± 0.07), (1.07 ± 0.14) vs (0.65 ± 0.10) mm, all P<0.05). The plasma levels of TNF-α and ET-1 in mild to severe OSAHS group were significantly higher than those in controls ((17.45 ± 3.02), (23.81 ± 2.91), (35.16 ± 3.43) vs (12.53 ± 3.48) ng/L and (0.81 ± 0.13), (1.06 ± 0.21), (1.66 ± 0.30) vs (0.64 ± 0.12) ng/L, all P<0.05 ), whereas plasma levels of NO in the three OSAHS groups were significantly decreased compared with the control group ((35.46 ± 10.12), (29.32 ± 9.47), (20.16 ± 7.41) vs (45.43 ± 7.92) µmol/L, all P<0.05). Furthermore, there were significant differences in plasma levels of TNF-α, ET-1 and NO among the three OSAHS groups (all P<0.05). Carotid IMT was positively correlated with plasma TNF-α and ET-1 (r=0.56 and 0.51) and negatively correlated with plasma NO (r=-0.46) (all P<0.05). After 3 months of CPAP treatment, plasma levels of TNF-α and ET-1 in OSAHS patients were significantly reduced ((19.64 ± 5.28), (0.94 ± 0.21) vs (28.72 ± 5.36), (1.36 ± 0.36) ng/L), and plasma NO was markedly increased ((33.57 ± 6.32) vs (24.34 ± 4.46) µmol/L, all P<0.05). However, CPAP treatment did not have a significant effect on carotid IMT ((0.91 ± 0.21) vs (0.96 ± 0.14) mm), P>0.05).. Systemic inflammation and vascular endothelial dysfunction may play an important role in pathogenesis and development of carotid artery atherosclerosis in OSAHS. Short-term CPAP therapy alleviates systemic inflammation and improves endothelial function, but does not influence the increased carotid IMT in OSAHS patients.

Topics: Atherosclerosis; Body Mass Index; Carotid Artery Diseases; Continuous Positive Airway Pressure; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Humans; Inflammation; Nitric Oxide; Polysomnography; Sleep Apnea, Obstructive; Tumor Necrosis Factor-alpha; Tunica Intima

Although recent studies have underscored the role of the heme-oxygenase (HO) inducer hemin, on insulin-signaling and glucose metabolism, the underlying mechanisms are not completely understood. In this study, two-dimensional-gel electrophoresis, massspectrometry and MSACOT-analyses were used to identify and characterize novel proteins modulated by hemin in spontaneoushypertensive rat (SHR), a model of essential hypertension with insulin resistance/impaired glucose metabolism. In addition, the effects of hemin on endothelin-1 (ET-1), protein-tyrosine-phosphatase-1B (PTP-1B), atrial-natriuretic-peptide (ANP) and its surrogate-marker urinary cGMP, and inflammatory cytokines including TNF-α, IL-6 and IL-1β were investigated. In hemin-treated SHR, several proteins related to oxidative-stress and metabolism were modulated. Particularly, hemin enhanced aldolase- B, fumarylacetoacetate hydrolase, purine-nucleoside phosphorylase, adenosine-kinase, argininosuccinate synthetase and carbonic anhydrase-3 all of which are enzymes involved in glucose/energy metabolism and pH homeostasis. Similarly, hemin potentiated antioxidant pathways including, NADP(+)-dependant isocitrate-dehydrogenase, catalase, glutathione-S-transferase-Yb1 and hsp70, a pleiotropic agent that regulates protein-folding, oxidative/pro-inflammatory events. Hemin also increased enzymes implicated in cell-growth such as the nitrilase-protein-family, but reduced betaine-homocysteine methyltransferase, an enzyme associated with insulin resistance and dysfunctional glucose metabolism. Furthermore, hemin increased ANP and its surrogate marker, urinary cGMP, but reduced ET-1, PTP-1B, TNF-α, IL-6, IL-1β, whereas the HO-inhibitor, chromium-mesoporphyrin abolished the effects. The potentiation of ANP, urinary-cGMP, aldolade-B, fumarylacetoacetate hydrolase, purine-nucleoside phosphorylase, adenosine-kinase, argininosuccinate synthetase, carbonic anhydrase-3, hsp70 and the corresponding reduction of betaine-homocysteine methyltransferase, PTP-1B, TNF-α, IL-6, IL-1β, and ET-1 may be responsible for the improved glucose metabolism in hemin-treated animals. Collectively, these findings underscore the pleiotropic effects of the HO-system in cellular homeostasis with important roles in metabolism and defence.

Topics: Animals; Cyclic GMP; Cytokines; Electrophoresis, Gel, Two-Dimensional; Endothelin-1; Essential Hypertension; Female; Glucose; Heme Oxygenase (Decyclizing); Hemin; Hypertension; Inflammation; Inflammation Mediators; Insulin Resistance; Male; Mass Spectrometry; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley

Scleroderma (SSc) is a complex and heterogeneous connective tissue disease mainly characterized by autoimmunity, vascular damage, and fibrosis that mostly involve the skin and lungs. Epstein-Barr virus (EBV) is a lymphotropic γ-herpesvirus that has co-evolved with human species, infecting >95% of the adult population worldwide, and has been a leading candidate in triggering several autoimmune diseases. Here we show that EBV establishes infection in the majority of fibroblasts and endothelial cells in the skin of SSc patients, characterized by the expression of the EBV noncoding small RNAs (EBERs) and the increased expression of immediate-early lytic and latency mRNAs and proteins. We report that EBV is able to persistently infect human SSc fibroblasts in vitro, inducing an aberrant innate immune response in infected cells. EBV-Toll-like receptor (TLR) aberrant activation induces the expression of selected IFN-regulatory factors (IRFs), IFN-stimulated genes (ISGs), transforming growth factor-β1 (TGFβ1), and several markers of fibroblast activation, such as smooth muscle actin and Endothelin-1, and all of these genes play a key role in determining the profibrotic phenotype in SSc fibroblasts. These findings imply that EBV infection occurring in mesenchymal, endothelial, and immune cells of SSc patients may underlie the main pathological features of SSc including autoimmunity, vasculopathy, and fibrosis, and provide a unified disease mechanism represented by EBV reactivation.

Topics: Actins; Endothelin-1; Epstein-Barr Virus Infections; Fibroblasts; Humans; Immunity, Innate; In Situ Hybridization; Inflammation; Interferon Regulatory Factors; Monocytes; Muscle, Smooth; Myofibroblasts; Phenotype; RNA, Small Untranslated; Scleroderma, Systemic; Toll-Like Receptor 7; Toll-Like Receptor 9; Toll-Like Receptors; Transforming Growth Factor beta1

Severe pulmonary arterial hypertension (PAH) is an incurable disease whose exact mechanisms remain unknown. However, growing evidence highlights the role of inflammation and endothelin (ET) signaling. The lack of reliable models makes it difficult to investigate the pathophysiology of this disease. Our aim was therefore to develop a mouse model of severe PAH closely mimicking the human condition to explore the role of interleukin-6 (IL-6), and ET signaling in advanced PAH progression.. Young male SV129 mice received vascular endothelial growth factor receptor inhibitor (SU5416) three times a week and were exposed to hypoxia (10% O2) for three weeks. Molecular analysis and histological assessment were examined using real-time PCR, Western blot and immunostaining, respectively.. The developed murine model presented important characteristics of severe PAH in human: concentric neointimal wall thickening, plexogenic lesions, recruitment of macrophages, and distal arteriolar wall muscularization. We detected an increase of IL-6 production and a stronger macrophage recruitment in adventitia of remodeled arterioles developing plexogenic lesions. Moreover, ET-1 and ET receptor A were up-regulated in lung lysates and media of remodeled arterioles. Recombinant IL-6 stimulated the proliferation and regulated endothelial cells in increasing ET-1 and decreasing ET receptor B.. These data describe a murine model, which displays the most important features of human severe PAH. We assume that inflammation, particularly IL-6 regulating ET signaling, plays a crucial role in forming plexogenic lesions. This model is thus reliable and might be used for a better understanding of severe PAH progression and treatment.

Topics: Animals; Biomarkers; Body Weight; Cell Hypoxia; Cell Line; Disease Models, Animal; Endothelial Cells; Endothelin-1; Heart Rate; Humans; Hypertension, Pulmonary; Indoles; Inflammation; Interleukin-6; Lung; Male; Mice; Pulmonary Artery; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Up-Regulation

Although inflammation is clearly associated with obesity, diabetes, and insulin resistance, the role of chronic inflammation in the etiology of polycystic ovary syndrome (PCOS) is unclear.. To determine whether chronic inflammation plays a causal role in the etiology of PCOS, we tested for an association between PCOS and genetic markers mapping to 80 members of the inflammatory pathway.. This was a case-control association study.. The setting was an academic medical center.. A total of 905 index case patients with PCOS and 955 control women (108 intensively phenotyped subjects with normal androgen levels and regular menses and 847 minimally phenotyped subjects with regular menses and no history of PCOS).. Subjects were genotyped at single nucleotide polymorphisms mapping to 80 inflammatory genes. Logistic regression was used to test for an association between 822 single nucleotide polymorphisms and PCOS after adjustment for population stratification, body mass index, and/or age. In the index patients, we also tested for association with 11 quantitative traits (body mass index and testosterone, fasting insulin, fasting glucose, 2-hour postchallenge glucose, LH, FSH, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels).. The evidence for an association with PCOS and with 11 quantitative traits was investigated.. Nominally significant evidence for an association was observed with MAP3K7, IKBKG, TNFRS11A, AKT2, IL6R, and IRF1, but no results remained statistically significant after adjustment for multiple testing.. Genetic variation in the inflammatory pathway is not a major contributor to the etiology of PCOS or related quantitative traits in women with PCOS.

Topics: Case-Control Studies; Cholesterol, HDL; Endothelin-1; Female; Gene Frequency; Glucose Tolerance Test; Humans; Inflammation; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Signal Transduction

Erythropoietin used to correct anaemia in chronic kidney disease (CKD) has been shown to increase blood pressure (BP) in CKD patients and experimental animals. Endothelin (ET)-1 expression is increased in CKD animals and patients, and enhanced by erythropoietin. Erythropoietin-induced BP rise was blunted by ETA receptor blockers. This study was designed to determine whether preexisting endothelin (ET)-1 overexpression is required for erythropoietin to cause adverse vascular effects and whether this could be prevented by exercise training.. Eight to 10-week old male wild-type mice and mice with endothelial-specific ET-1 overexpression (eET-1) were treated or not with EPO (100  IU/kg, SC, 3  times/week). eET-1 was subjected or not to swimming exercise training (1  h/day, 6 days/week) for 8 weeks. SBP, mesenteric artery endothelial function and remodelling, NADPH oxidase activity, reactive oxygen species (ROS) generation, vascular cell adhesion protein (VCAM)-1, monocyte/macrophage infiltration, T regulatory cells (Tregs) and tissue ET-1 and plasma endothelin were determined.. Erythropoietin increased SBP by 24  mmHg (P < 0.05) and decreased by 25% vasodilatory responses to acetylcholine (P < 0.01) in eET-1 mice. Erythropoietin enhanced ET-1 induced increase in resistance artery media/lumen ratio (31%, P < 0.05), aortic NADPH oxidase activity (50%, P < 0.05), ROS generation (93%, P < 0.001), VCAM-1 (80%, P < 0.01) and monocyte/macrophage infiltration (159%, P < 0.001), and raised plasma and aortic ET-1 levels (≥130%, P < 0.05). EPO had no effect in wild-type mice. Exercise training prevented all of the above (P < 0.05).. Erythropoietin-induced adverse vascular effects are dependent on preexisting elevated ET-1 expression. Exercise training prevented erythropoietin-induced adverse vascular effects in part by inhibiting ET-1 overexpression-induced oxidative stress, inflammation and immune activation.

Topics: Animals; Blood Pressure; Endothelin-1; Erythropoietin; Hematocrit; Humans; Hypertension; Immune System; Inflammation; Male; Mice; Mice, Transgenic; NADPH Oxidases; Oxidative Stress; Physical Conditioning, Animal; Reactive Oxygen Species; Swimming; Systole

The growing incidence of chronic kidney disease remains a global health problem. Obesity is a major risk factor for type-2 diabetes and renal impairment. Perirenal adiposity, by virtue of its anatomical proximity to the kidneys may cause kidney disease through paracrine mechanisms that include increased production of inflammatory cytokines. Although heme-oxygenase (HO) is cytoprotective, its effects on perirenal adiposity and diabetic nephropathy in Zucker-diabetic fatty rats (ZDFs) remains largely unclear. Upregulating the HO-system with hemin normalised glycemia, reduced perirenal adiposity and suppressed several pro-inflammatory/oxidative mediators in perirenal fat including macrophage-inflammatory-protein-1α (MIP-1α), endothelin (ET-1), 8-isoprostane, TNF-α, IL-6 and IL-1β. Furthermore, hemin reduced ED1, a marker of pro-inflammatory macrophage-M1-phenotype, but interestingly, enhanced markers associated with anti-inflammatory M2-phenotype such as ED2, CD206 and IL-10, suggesting that hemin selectively modulates macrophage polarization towards the anti-inflammatory M2-phenotype. These effects were accompanied by increased adiponectin, HO-1, HO-activity, atrial-natriuretic peptide (ANP), and its surrogate marker, urinary-cGMP. Furthermore, hemin reduced renal histological lesions and abated pro-fibrotic/extracellular-matrix proteins like collagen and fibronectin that deplete nephrin, an important transmembrane protein which forms the scaffolding of the podocyte slit-diaphragm allowing ions to filter but not massive excretion of proteins, hence proteinuria. Correspondingly, hemin increased nephrin expression in ZDFs, reduced markers of renal damage including, albuminuria/proteinuria, but increased creatinine-clearance, suggesting improved renal function. Conversely, the HO-blocker, stannous-mesoporphyrin nullified the hemin effects, aggravating glucose metabolism, and exacerbating renal injury and function. The hemin effects were less-pronounced in Zucker-lean controls with healthy status, suggesting greater selectivity of HO in ZDFs with disease. We conclude that the concomitant reduction of pro-inflammatory/oxidative mediators, macrophage infiltration and profibrotic/extracellular-matrix proteins, coupled to increased nephrin, adiponectin, ANP, cGMP and creatinine clearance may account for improved renal function in hemin-treated ZDFs. These findings suggest that HO-inducers like hemin may be explored against the co-morbidity of perirenal adiposity an

Topics: Adiposity; Animals; Atrial Natriuretic Factor; Blood Glucose; Chemokine CCL3; Diabetic Nephropathies; Dinoprost; Endothelin-1; Extracellular Matrix Proteins; Heme Oxygenase (Decyclizing); Hemin; Inflammation; Interleukins; Kidney; Macrophages; Male; Rats; Rats, Zucker; Tumor Necrosis Factor-alpha

Vascular leakage and oedema formation are key components in sepsis. In septic patients, plasma levels of the vasoconstrictive and pro-inflammatory peptide endothelin-1 (ET-1) correlate with mortality. During sepsis, neutrophils release heparin-binding protein (HBP) known to increase vascular permeability and to be a promising biomarker of human sepsis. As disruption of ET-signalling in endotoxemia attenuates formation of oedema, we hypothesized that this effect could be related to decreased levels of HBP. To investigate this, we studied the effects of ET-receptor antagonism on plasma HBP and oedema formation in a porcine model of sepsis. In addition, to further characterize a potential endothelin/HBP interaction, we investigated the effects of graded ET-receptor agonist infusions.. Sixteen anesthetized pigs were subjected to 5 h of endotoxemia and were randomized to receive either the ET-receptor antagonist tezosentan or vehicle after 2 h. Haemodynamics, gas-exchange and lung water were monitored. In separate experiments, plasma HBP was measured in eight non-endotoxemic animals exposed to graded infusion of ET-1 or sarafotoxin 6c.. Endotoxemia increased plasma ET-1, plasma HBP, and extravascular lung water. Tezosentan-treatment markedly attenuated plasma HBP and extravascular lung water, and these parameters correlated significantly. Tezosentan decreased pulmonary vascular resistance and increased respiratory compliance. In non-endotoxemic pigs graded ET-1 and sarafotoxin 6c infusions caused a dose-dependent increase in plasma HBP.. ET-receptor antagonism reduces porcine endotoxin-induced pulmonary oedema and plasma levels of the oedema-promoting protein HBP. Moreover, direct ET-receptor stimulation distinctively increases plasma HBP. Together, these results suggest a novel mechanism by which ET-1 contributes to formation of oedema during experimental sepsis.

Topics: Animals; Antimicrobial Cationic Peptides; Blood Proteins; Capillary Leak Syndrome; Carrier Proteins; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Endotoxins; Extravascular Lung Water; Female; Hemodynamics; Inflammation; Infusions, Intravenous; Leukocyte Count; Male; Neutrophil Activation; Pulmonary Edema; Pyridines; Random Allocation; Receptor, Endothelin B; Sus scrofa; Swine; Tetrazoles; Viper Venoms

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. However, the molecular and cellular mechanisms driving inflammation have not been fully elucidated.. To elucidate the roles of high mobility group box 1 protein (HMGB1), a ubiquitous DNA-binding protein with extracellular pro-inflammatory activity, in a rat model of PAH.. Male Sprague-Dawley rats were administered monocrotaline (MCT). Concentrations of HMGB1 in bronchoalveolar lavage fluid (BALF) and serum, and localization of HMGB1 in the lung were examined over time. The protective effects of anti-HMGB1 neutralizing antibody against MCT-induced PAH were tested.. HMGB1 levels in BALF were elevated 1 week after MCT injection, and this elevation preceded increases of other pro-inflammatory cytokines, such as TNF-α, and the development of PAH. In contrast, serum HMGB1 levels were elevated 4 weeks after MCT injection, at which time the rats began to die. Immunohistochemical analyses indicated that HMGB1 was translocated to the extranuclear space in periarterial infiltrating cells, alveolar macrophages, and bronchial epithelial cells of MCT-injected rats. Anti-HMGB1 neutralizing antibody protected rats against MCT-induced lung inflammation, thickening of the pulmonary artery wall, and elevation of right ventricular systolic pressure, and significantly improved the survival of the MCT-induced PAH rats.. Our results identify extracellular HMGB1 as a promoting factor for MCT-induced PAH. The blockade of HMGB1 activity improved survival of MCT-induced PAH rats, and thus might be a promising therapy for the treatment of PAH.

Topics: Animals; Bronchoalveolar Lavage Fluid; Chemokine CCL2; Disease Models, Animal; DNA-Binding Proteins; Endothelin-1; Hemodynamics; HMGB1 Protein; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Inflammation; Interleukin-1beta; Male; Monocrotaline; Pulmonary Artery; Random Allocation; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Vascular Resistance; Ventricular Dysfunction, Right

The purpose of this study is to understand the role of rho-kinase (ROCK-2) in the regulation of liver microcirculation after inflammatory stress. Endothelin-1 (ET-1)-induced nitric oxide (NO) is essential in the regulation of blood flow in hepatic sinusoids. Lipopolysaccharide (LPS) inhibits this ET-1-induced NO production and disrupts liver microcirculation; however, the exact molecular mechanism is unknown. Liver sinusoidal endothelial cells were isolated, pretreated with 10 ng/mL LPS for 6 h, and treated with 10 μM Y27632 (ROCK-2 inhibitor) for 30 min and 10 nM ET-1 for 30 min. Lipopolysaccharide induced RhoA membrane translocation that was attenuated by methyl-β-cyclodextrin (cholesterol sequester) or targeted mutation of caveolin-1. Lipopolysaccharide increased ROCK-2 expressions (+60%) and ROCK-2 activity (+36%). Endothelin-1 increased endothelial NO synthase (eNOS) activity (+70%), but LPS inhibited this ET-1-mediated eNOS response. Treatment with Y27632 restored ET-1-mediated eNOS activity (+61%) and stimulated NO production in the perinuclear region after LPS pretreatment. This treatment reduced cofilin-Ser3 phosphorylation (-73%), increased vasodilator-stimulated phosphoprotein-Ser239 phosphorylation (+88%), and stimulated globular actin/eNOS association. Lipopolysaccharide induces Rho/ROCKs signaling pathway to disrupt the ET-1-mediated eNOS activation in liver sinusoidal endothelial cells. Rho-kinase ROCK-2 inhibition restores ET-1-mediated NO production after the LPS pretreatment, in part, through an increase in actin depolymerization.

Topics: Actins; Amides; Animals; Caveolin 1; Cells, Cultured; Cofilin 1; Endothelial Cells; Endothelin-1; Enzyme Activation; Inflammation; Lipopolysaccharides; Liver; Male; Microcirculation; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Protein Binding; Protein Structure, Tertiary; Pyridines; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Sepsis; Serine

The aim of the present study was to evaluate the potential association between dietary nutrients and alterations in DNA methylation in a set of five candidate genes, including CD14, Et-1, iNOS, HERV-w and TNFα, in a population of overweight/obese subjects. We evaluated possible associations between gene methylation and clinical blood parameters, including total cholesterol (TC), low- and high-density lipoprotein cholesterol (LDL-C and HDL-C), triglyceride and homocysteine levels. We employed validated methods to assess anthropometric, clinical and dietary data, as well as pyrosequencing to evaluate DNA methylation of the five candidate genes in 165 overweight/obese subjects. There was no association between body mass index and DNA methylation of the five candidate genes in this group of subjects. Positive associations were observed between TNFα methylation and blood levels of LDL-C (β = 0.447, p = 0.002), TC/HDL-C (β = 0.467, p = 0.001) and LDL-C/HDL-C (β = 0.445, p = 0.002), as well as between HERV-w methylation and dietary intakes of β-carotene (β = 0.088, p = 0.051) and carotenoids (β = 0.083, p = 0.029). TNFα methylation showed negative associations with dietary intakes of cholesterol (β = -0.278, p = 0.048), folic acid (β = -0.339, p = 0.012), β-carotene (β = -0.332, p = 0.045), carotenoids (β = -0.331, p = 0.015) and retinol (β = -0.360, p = 0.008). These results suggest a complex relationship among nutrient intake, oxidative stress and DNA methylation.

Topics: Adult; Aged; beta Carotene; Body Mass Index; Carotenoids; Cholesterol; Cholesterol, HDL; DNA Methylation; Eating; Endothelin-1; Energy Intake; Female; Folic Acid; Gene Products, env; Humans; Inflammation; Lipopolysaccharide Receptors; Lipoproteins, LDL; Male; Middle Aged; Nitric Oxide Synthase Type II; Nutritional Status; Obesity; Overweight; Pregnancy Proteins; Triglycerides; Tumor Necrosis Factor-alpha; Vitamin A

Endoplasmic reticulum stress (ER stress)-associated thioredoxin-interacting protein (TXNIP) and NOD-like receptor pyrin domain containing-3 (NLRP3) signaling is a key event in the endothelial dysfunction. It induces the IL-1β production and thus accounts for inflammation and cell death. Quercetin, luteolin and epigallocatechin gallate (EGCG) are flavonoids with beneficial effects on cardiovascular functions, and we wondered whether these flavonoids protect endothelial functions against ER stress-associated impairments. Palmitate stimulation evoked oxidative stress and then induced TXNIP and NLRP3 inflammasome activation in the endothelial cells. Quercetin, luteolin and EGCG reduced reactive oxygen species production and inhibited TXNIP and NLRP3 inflammasome activation, lead to the downregulation of IL-1β expression. Meanwhile, these agents protected cells from apoptosis by restoration of mitochondrial membrane potential (Δψm) and inhibition of caspase-3 activity. PA stimulation induced inflammation accompanied by the loss of NO production in endothelial cells, but these alterations were reversed by treatment with quercetin, luteolin and EGCG. Co-treatment with AMPK inhibitor compound C diminished the beneficial effects of these flavonoids, suggesting the involvement of AMPK. In conclusion, quercetin, luteolin and EGCG inhibited ER stress-associated TXNIP and NLRP3 inflammasome activation, and thereby protected endothelial cells from inflammatory and apoptotic damage.

Topics: AMP-Activated Protein Kinases; Apoptosis; Carrier Proteins; Catechin; Cell Line; Endoplasmic Reticulum Stress; Endothelial Cells; Endothelin-1; Gene Expression; Human Umbilical Vein Endothelial Cells; Humans; Inflammasomes; Inflammation; Luteolin; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Palmitic Acid; Protein Kinase Inhibitors; Quercetin

Endothelial cells form a highly specialised lining of all blood vessels where they provide an anti-thrombotic surface on the luminal side and protect the underlying vascular smooth muscle on the abluminal side. Specialised functions of endothelial cells include their unique ability to release vasoactive hormones and to morphologically adapt to complex shear stress. Stem cell derived-endothelial cells have a growing number of applications and will be critical in any organ regeneration programme. Generally endothelial cells are identified in stem cell studies by well-recognised markers such as CD31. However, the ability of stem cell-derived endothelial cells to release vasoactive hormones and align with shear stress has not been studied extensively. With this in mind, we have compared directly the ability of endothelial cells derived from a range of stem cell sources, including embryonic stem cells (hESC-EC) and adult progenitors in blood (blood out growth endothelial cells, BOEC) with those cultured from mature vessels, to release the vasoconstrictor peptide endothelin (ET)-1, the cardioprotective hormone prostacyclin, and to respond morphologically to conditions of complex shear stress. All endothelial cell types, except hESC-EC, released high and comparable levels of ET-1 and prostacyclin. Under static culture conditions all endothelial cell types, except for hESC-EC, had the typical cobblestone morphology whilst hESC-EC had an elongated phenotype. When cells were grown under shear stress endothelial cells from vessels (human aorta) or BOEC elongated and aligned in the direction of shear. By contrast hESC-EC did not align in the direction of shear stress. These observations show key differences in endothelial cells derived from embryonic stem cells versus those from blood progenitor cells, and that BOEC are more similar than hESC-EC to endothelial cells from vessels. This may be advantageous in some settings particularly where an in vitro test bed is required. However, for other applications, because of low ET-1 release hESC-EC may prove to be protected from vascular inflammation.

Topics: Cell Differentiation; Cells, Cultured; Embryonic Stem Cells; Endothelial Cells; Endothelin-1; Epoprostenol; Hormones; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Interleukin-8; Leukocytes, Mononuclear; Platelet Endothelial Cell Adhesion Molecule-1; Shear Strength; Stem Cells; Stress, Mechanical; Vasoconstrictor Agents

In the article the concentration of endothelin-1 in patients with different variants of APS was analyzed and its relationship with disease course, dyslipidemia, levels of antiphospholipid antibodies and ath rosclerotic vascular lesions was assessed. It was established that high levels of endothelin-1 is a circulating marker of early atherosclerosis, since !it was closely associated'with subclinical manifestations of atherosclerotic vascular lesions, lipid profile. The concentration of endothelin-1 significantly increased with active inflammation and with high levels of antiphospholipid antibodies and does not depend on age, sex, smoking, obesity and physical inactivity.

Topics: Adult; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Atherosclerosis; Biomarkers; Case-Control Studies; Disease Progression; Dyslipidemias; Early Diagnosis; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Female; Humans; Inflammation; Lipid Metabolism; Male; Middle Aged; Motor Activity; Obesity; Smoking

Trypanosoma cruzi, the causative agent of Chagas' disease, induces multiple responses in the heart, a critical organ of infection and pathology in the host. Among diverse factors, eicosanoids and the vasoactive peptide endothelin-1 (ET-1) have been implicated in the pathogenesis of chronic chagasic cardiomyopathy. In the present study, we found that T. cruzi infection in mice induces myocardial gene expression of cyclooxygenase-2 (Cox2) and thromboxane synthase (Tbxas1) as well as endothelin-1 (Edn1) and atrial natriuretic peptide (Nppa). T. cruzi infection and ET-1 cooperatively activated the Ca(2+)/calcineurin (Cn)/nuclear factor of activated T cells (NFAT) signaling pathway in atrial myocytes, leading to COX-2 protein expression and increased eicosanoid (prostaglandins E(2) and F(2α), thromboxane A(2)) release. Moreover, T. cruzi infection of ET-1-stimulated cardiomyocytes resulted in significantly enhanced production of atrial natriuretic peptide (ANP), a prognostic marker for impairment in cardiac function of chagasic patients. Our findings support an important role for the Ca(2+)/Cn/NFAT cascade in T. cruzi-mediated myocardial production of inflammatory mediators and may help define novel therapeutic targets.

Topics: Animals; Atrial Natriuretic Factor; Calcineurin; Calcium; Cyclooxygenase 2; Endothelin-1; Gene Expression Profiling; Inflammation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monocytes; Myocytes, Cardiac; Natriuretic Peptide, C-Type; NFATC Transcription Factors; Protein Precursors; Signal Transduction; Thromboxane-A Synthase; Trypanosoma cruzi

Some studies have shown that serum resistin levels increase in hypertensive patients. Whether the increase of resistin is related to inflammatory or vascular endothelial function is still unknown. We investigated the relationship of increased resistin levels to inflammatory factors and circulating biomarkers of vascular endothelial function in hypertensive patients.. One hundred and forty-four nondiabetic patients with new onset, hypertension were recruited. Blood pressure, blood glucose, insulin, resistin, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), von Willebrand factor (vWF), endothelin-1 (ET-1) and nitric oxide (NO) were measured. The homeostasis model assessment, insulin resistance index (HOMA-IR) was calculated. Patients were divided into two groups according to the median level of resistin. Cytokine levels and indicators of vascular endothelial function were compared. Multiple linear regression was used to determine factors influencing resistin.. Serum resistin ranged from 2.57 ng/ml to 20.18 ng/ml in hypertensive patients. High resistin group (> 8.36 ng/ml) had higher levels of TNF-α, IL-6, vWF and ET-1 but lower level of NO compared with low resistin group (P < 0.01). Resistin was positively correlated with body mass index, systolic blood pressure, HOMA-IR, low-density lipoprotein cholesterol, TNF-α and ET-1 but negatively correlated with NO (all P < 0.05). Multiple linear regression analysis revealed that HOMA-IR, TNF-α, NO and ET-1 are independent predictors of resistin with standardized regression coefficients of 0.625, 0.368, -0.260 and 0.222, respectively (all P < 0.01).. We conclude that higher resistin levels are associated with inflammatory activation and endothelial dysfunction, because patients with essential hypertension have increased TNF-α, IL-6, vWF and ET-1 and decreased NO. Moreover, the statistical association of resistin with TNF-α, NO and ET-1 suggests involvement of resistin in the progression of hypertension by influencing inflammation and endothelial function.

Topics: Endothelin-1; Enzyme-Linked Immunosorbent Assay; Humans; Hypertension; Inflammation; Interleukin-6; Resistin; Tumor Necrosis Factor-alpha

Recent investigations have associated airborne particulate matter (PM) with increased coagulation and thrombosis, but underlying biological mechanisms are still incompletely characterised. DNA methylation is an environmentally sensitive mechanism of gene regulation that could potentially contribute to PM-induced hypercoagulability. We aimed to test whether altered methylation mediates environmental effects on coagulation.. We investigated 63 steel workers exposed to a wide range of PM levels, as a work-related condition with well-characterised prothrombotic exposure. We measured personal PM10 (PM≤10 µm in aerodynamic diameter), PM1 (≤1 µm) and air metal components. We determined leukocyte DNA methylation of NOS3 (nitric-oxide-synthase-3) and EDN1 (endothelin-1) through bisulfite-pyrosequencing and we measured ETP as a global coagulation-activation test after standardised triggers.. ETP increased in association with PM10 (β=20.0, 95% CI 3.0 to 37.0), PM1 (β=80.8 95% CI 14.9 to 146.7) and zinc (β=51.3, 95% CI 0.01 to 111.1) exposures. NOS3 methylation was negatively associated with PM10 (β=-0.2, 95% CI -0.4 to -0.03), PM1 (β=-0.8, 95% CI -1.4 to -0.1), zinc (β=-0.9, 95% CI -1.4 to -0.3) and iron (β=-0.7, 95% CI -1.4 to -0.01) exposures. Zinc exposure was negatively associated with EDN1 (β=-0.3, 95% CI -0.8 to -0.1) methylation. Lower NOS3 (β=-42.3; p<0.001) and EDN1 (β=-14.5; p=0.05) were associated with higher ETP. Statistical mediation analysis formally confirmed NOS3 and EDN1 hypomethylation as intermediate mechanisms for PM-related coagulation effects.. Our study showed for the first time, that gene hypomethylation contributes to environmentally induced hypercoagulability.

Topics: Adult; Air Pollutants; Blood Coagulation; Blood Coagulation Disorders; Confidence Intervals; DNA Methylation; Endothelin-1; Gene Expression Regulation; Humans; Industry; Inflammation; Inhalation Exposure; Leukocytes; Male; Middle Aged; Nitric Oxide Synthase Type III; Occupational Diseases; Occupational Exposure; Particulate Matter; Thrombosis; Zinc

Transgenic mice with endothelium-specific endothelin-1 (ET-1) overexpression exhibit endothelial dysfunction and vascular remodeling, oxidative stress, and inflammation. We previously observed that monocytes/macrophages play a role in angiotensin II, aldosterone, and deoxycorticosterone acetate/salt-induced vascular remodeling, oxidative stress, and inflammation using a model with reduced monocytes/macrophages, the osteopetrotic (Op) mouse, which has a mutation in the macrophage colony stimulating factor (Csf1) gene. However, it is unknown whether monocytes/macrophages are implicated in adverse vascular effects of ET-1. We hypothesized that reduction in monocytes/macrophages would blunt ET-1-induced vascular injury. We performed a study on 4- to 6-month-old male mice with endothelium-specific ET-1 overexpression (eET-1), reduction in CSF1 (Csf1(Op/+)), or both (eET-1/Csf1(Op/+)), and their wild-type littermate control mice. There was no difference in systolic blood pressure between groups. Endothelial function and vascular structure were determined on a pressurized myograph. Endothelium-dependent relaxation in response to acetylcholine was similar in eET-1 and eET-1/Csf1(Op/+) mice. Media:lumen ratio and media cross-sectional area were ≈1.5-fold greater in eET-1 than in wild-type mice (P<0.05), which was not observed in mice deficient in CSF1. ET-1-induced oxidative stress measured by dihydroethidium staining (P<0.05) and NADPH oxidase activity assessed with lucigenin chemiluminescence (P<0.05) were blunted by CSF1 deficiency. ET-1 caused a 2.5-fold increase in monocyte/macrophage infiltration compared with wild-type mice (P<0.001), which was blunted in the mice deficient in CSF1. Reduction of monocyte/macrophage-dependent inflammation in mice overexpressing ET-1 in endothelium results in reduced vascular remodeling and oxidative stress, providing evidence for a role of monocytes/macrophages and innate immunity in ET-1-induced vascular injury.

Topics: Animals; Disease Models, Animal; DNA; Endothelin-1; Endothelium, Vascular; Gene Expression Regulation; Inflammation; Macrophage Colony-Stimulating Factor; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Polymerase Chain Reaction; Vascular System Injuries

To investigate cardiorespiratory and inflammatory responses in male workers following exposure to welding fumes and airborne particles in actual workplace conditions.. We measured blood leukocytes and their differential counts, platelet count, hemoglobin, sensitive C-reactive protein, fibrinogen, E-selectin, IL-(interleukin)1β, IL-6, IL-8, tumor necrosis factor alpha (TNF-α) and endothelin-1 in blood samples of twenty workers before and after their working day. We also studied peak expiratory flow (PEF), forced expiratory volume in one second (FEV1), and exhaled nitric oxide (NO). We assessed heart rate variability (HRV) by obtaining 24-hour ambulatory electrocardiograms.. The total blood leukocytes and neutrophils increased after the work shift, whereas IL-1β and E-selectin decreased significantly. There were no statistically significant changes in exhaled NO, FEV1, PEF or HRV.. Occupational exposure to welding fumes and particles caused a slight, acute inflammatory effect estimated based on the increased values of leukocytes and neutrophils in blood and a decrease in the interleukin 1β and E-selectin values, but no changes in the pulmonary function (exhaled NO, FEV1, PEF) or HRV during the working day were observed.

Topics: Adult; Air Pollutants, Occupational; Breath Tests; C-Reactive Protein; E-Selectin; Endothelin-1; Fibrinogen; Forced Expiratory Volume; Gases; Heart Rate; Hemoglobins; Humans; Inflammation; Inhalation Exposure; Interleukins; Leukocyte Count; Male; Middle Aged; Nitric Oxide; Occupational Exposure; Particulate Matter; Peak Expiratory Flow Rate; Platelet Count; Tumor Necrosis Factor-alpha; Welding

To analyze the systemic manifestations of vascular endothelial damage, the activation of hemostatic and inflammatory responses in patients with an infectious inflammation-dependent exacerbation of chronic obstructive pulmonary disease (COPD).. The paper provides the data of examinations of 111 patients with the clinical signs of an infectious inflammation-dependent exacerbation of COPD who had 2 or 3 positive criteria elaborated by N. Anthonisen et al. (1987). The patients were divided into 2 phenotypically different subgroups: 1) 92 (82.9%) COPD patients without clinical manifestations of bronchoectasis; 2) 19 (17.1%) patients with COPD concurrent with documented bronchiectasis. The patient subgroups were matched for smoking status and the characteristics of COPD and respiratory failure. The investigators assessed the time course of changes in the serum level of endothelin-1 (ET-1), the aggregation function of platelets, and the plasma concentrations of D-dimers and homocysteine in patients with COPD compared to healthy, never smokers (n = 35) and smokers (n = 27).. An increase in the levels of the endothelial dysfunction markers ET-1 and homocysteine was found in patients with COPD, which was comparable with the changes in these indicators in the group of smokers. In both subgroups, the rise in plasma D-dimer levels was more pronounced in the patients with a COPD exacerbation than in the smokers. Its therapy with systemic and inhaled glucocorticosteroids reduced C-reactive protein and ET-1 levels in both patient subgroups and in D-dimers in subgroup 1. Elevated D-dimer levels remained when achieving remission, which points to the risk of thrombogenic and thromboembolic events in the patients with an infectious inflammation-dependent exacerbation of COPD and concomitant circulatory system diseases.. The patients with an infectious inflammation-dependent exacerbation of COPD are observed to have elevated peripheral blood markers of endothelial dysfunction and thrombinemia. These changes are pathogenetically caused by smoking or neutrophilic inflammation and associated with a higher risk of thrombogenic events.

Topics: Adult; Biomarkers; Bronchiectasis; Endothelin-1; Endothelium, Vascular; Female; Hemostasis; Homocysteine; Humans; Inflammation; Male; Pulmonary Disease, Chronic Obstructive; Smoking

We investigated the effects of treatment with tempol (an antioxidant) on vascular and metabolic dysfunction induced by a high-fat high-sucrose (HFHS) diet. Rats were randomized to receive an HFHS or chow diet with or without tempol treatment (1.5 mmol·(kg body mass)(-1)·day(-1)) for 4 weeks. Blood pressure, heart rate, and blood flow were measured in the rats by using intravascular catheters and Doppler flow probes. Insulin sensitivity and vascular responses to insulin were assessed during a euglycemic-hyperinsulinemic clamp. In-vitro studies were performed to evaluate vascular reactivity and endothelial and inducible nitric oxide synthase (eNOS; iNOS) expression in vascular and muscle tissues. Endothelin, nitrotyrosine, and NAD(P)H oxidase expressions were determined in vascular tissues, and glucose transport activity and glucose transporter 4 (GLUT4) expression were examined in muscles. Tempol treatment was found to prevent alterations in insulin sensitivity, glucose transport activity, GLUT4 expression, and vascular reactivity, and to prevent increases in plasma insulin, blood pressure, and heart rate noted in the untreated HFHS-fed rats. These were associated with increased levels of eNOS expression in vascular and muscle tissues, but reductions in nitrotyrosine, endothelin, NAD(P)H oxidase, and iNOS expressions. Therefore, oxidative stress induced by a relatively short-term HFHS diet could contribute to the early development of vascular and metabolic abnormalities in rats.

Topics: Animals; Aorta, Thoracic; Blood Pressure; Body Mass Index; Cyclic N-Oxides; Diet, High-Fat; Dietary Sucrose; Endothelin-1; Endothelins; Endothelium, Vascular; Glucose; Glucose Transporter Type 4; Heart Rate; Hemodynamics; Inflammation; Insulin; Insulin Resistance; Male; Muscle, Skeletal; NADPH Oxidases; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Spin Labels; Tyrosine

Small artery remodeling may involve a shift in the diameter-dependent force generating capacity of smooth muscle cells (SMC). We tested to what extent and under which conditions such contractile plasticity occurs. Rat mesenteric arteries were mounted on isometric myographs. Active diameter-tension relations were determined after application of several stimuli for 16 or 40 h at 40 or 110% of the passive diameter at 100 mm Hg. At 40%, 16-hour incubation with endothelin-1 (ET-1) but not U46619 shifted force capacity towards smaller diameters. Inflammatory cytokines (TNF-α, IL-1β, IFN-γ), TGF-β or serum neither induced such shift nor augmented the effect of ET-1. The ET-1-mediated change was not affected by superoxide dismutase and catalase. Inward matrix remodeling in the presence of ET-1 was slower, occurring after 40 h. Arteries maintained at 110% showed a shift of force capacity to larger diameters, which was prevented by ET-1 but not by U46619. In the active but not the passive state, SMC had altered nuclear lengths after incubation at 40%. These data demonstrate contractile plasticity in small arteries, where chronic strain is an outward drive and specifically ET-1 an inward drive, acting through mechanisms that do not seem to relate to oxidative stress, inflammatory pathways or major reorganization of the SMC.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cell Nucleus; Cytokines; Endothelin-1; Inflammation; Male; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth, Vascular; Oxidative Stress; Rats; Rats, Wistar; Vasoconstrictor Agents

Cardiac tamponade is a medical emergency situation associated with a high rate of life-threatening complications, even after immediate interventions. Our aim was to characterize the acute inflammatory consequences of this event in a clinically relevant large animal model.. Cardiac tamponade was induced for 60 min in anesthetized, ventilated and thoracotomized minipigs by intrapericardial fluid administration, the mean arterial pressure (MAP) being maintained in the interval of 40-45 mm Hg (n = 8). A further group (n = 7) served as sham-operated control. The global macrohemodynamics, including the right- and left-heart end-diastolic volumes (RHEDV and LHEDV), the pulmonary vascular resistance index (PVRI) and the superior mesenteric artery (SMA) flow, were monitored for 240 min, and the intestinal microcirculatory changes (pCO2 gap) were evaluated by indirect tonometry. Blood samples were taken for the determination of cardiac troponin T and vasoactive inflammatory mediators, including histamine, nitrite/nitrate, big-endothelin, superoxide and high-mobility group box protein-1 levels in association with intestinal leukocyte and complement activation.. The cardiac tamponade induced significant decreases in MAP, cardiac output, LHEDV and SMA flow, while the PVRI and the pCO2 gap increased significantly. After the removal of fluid from the pericardial sac, the MAP and the LHEDV were decreased, while the PVRI and the pCO2 gap remained elevated when compared with those in the sham-operated group. In the posttamponade period, the abrupt release of inflammatory mediators was accompanied by a significant splanchnic leukocyte accumulation and complement activation.. The macrocirculatory and splanchnic microcirculatory disturbances were accompanied by a significant proinflammatory reaction; endothelin and the complement system may be significant components of the inflammatory cascade that is activated in this porcine model of pericardial tamponade.

Topics: Animals; Cardiac Tamponade; Complement Activation; Endothelin-1; Female; Hemodynamics; HMGB1 Protein; Inflammation; Male; Nitric Oxide; Swine; Swine, Miniature

Minimally modified low-density lipoprotein (mmLDL) is a risk factor for cardiovascular disease. The present study investigated the effects of mmLDL on the expression of endothelin type A (ET(A)) receptors in coronary arteries. Rat coronary arteries were organ-cultured for 24 h. The contractile responses were recorded using a myographic system. ET(A) receptor mRNA and protein expressions were determined using real-time PCR and western blotting, respectively. The results showed that organ-culturing in the presence of mmLDL enhanced the arterial contractility mediated by the ET(A) receptor in a concentration-dependent and time-dependent manner. Culturing with mmLDL (10  μ g/mL) for 24 h shifted the concentration-contractile curves toward the left significantly with increased E(max) of 228% ± 20% from control of 100% ± 10% and significantly increased ET(A) receptor mRNA and protein levels. Inhibition of the protein kinase C, extracellular signal-related kinases 1 and 2 (ERK1/2), or NF- κ B activities significantly attenuated the effects of mmLDL. The c-Jun N-terminal kinase inhibitor or the p38 pathway inhibitor, however, had no such effects. The results indicate that mmLDL upregulates the ETA receptors in rat coronary arterial smooth muscle cells mainly via activating protein kinase C, ERK1/2, and the downstream transcriptional factor, NF- κ B.

Topics: Animals; Atherosclerosis; Coronary Vessels; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Inflammation; Lipoproteins, LDL; Myocytes, Smooth Muscle; NF-kappa B; Organ Culture Techniques; p38 Mitogen-Activated Protein Kinases; Protein Kinase C; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, Endothelin A; Signal Transduction; Up-Regulation

This study was aimed at determining the serum concentration of homocysteine (Hcy) and big endothelin-1 (big ET-1, the precursor of endothelin) in dogs with chronic kidney disease (CKD) with and without hypertension, proteinuria and inflammation, in order to explore their role as biomarkers of hypertension associated with CKD. Hcy and big ET-1 were measured using an enzyme-linked immunosorbent assay and an enzymatic cyclic reaction, respectively, in dogs with CKD staged, as proposed by the International Renal Interest Society (IRIS), using serum creatinine, urinary protein to creatinine (UPC) ratio and systolic blood pressure, and classified as affected or not by inflammation based on the serum concentration of C-reactive protein (CRP). Serum Hcy was significantly higher in dogs of IRIS stages II, III and IV compared with controls and in proteinuric compared with non-proteinuric dogs. No differences relating to the degree of hypertension or to the CRP concentration were found. Serum big ET-1 significantly increased in dogs of IRIS stage IV compared with controls, in proteinuric compared with non-proteinuric dogs, in dogs with severe hypertension compared with those without hypertension, and in dogs with increased CRP compared to those with normal CRP concentrations. Hcy only correlated with serum creatinine but big ET-1 significantly correlated with serum creatinine, UPC ratio, systolic blood pressure, and increased CRP. In conclusion, both Hcy and big ET-1 increase in dogs with CKD. Although further research is needed, big ET-1, but not Hcy, may also be considered as a biomarker of hypertension.

Topics: Animals; Biomarkers; Blood Pressure; Creatinine; Dog Diseases; Dogs; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Homocysteine; Hypertension; Inflammation; Male; Proteinuria; Renal Insufficiency, Chronic

Chronic anticoagulation is a standard of care in idiopathic pulmonary arterial hypertension (IPAH). However, hemostatic abnormalities in this disease remain poorly understood. Therefore, we aimed to study markers of thrombogenesis and fibrinolysis in patients with IPAH.. We studied 27 consecutive patients (67% female) with IPAH aged 50.0 years (IQR: 41.0-65.0) and 16 controls without pulmonary hypertension. Prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin (TAT) complexes were measured to assess thrombogenesis; tissue-type plasminogen activator (tPA) antigen and plasmin-anti-plasmin complex to characterize activation of fibrinolysis; plasminogen activator inhibitor 1 (PAI-1) to measure inhibition of fibrinolysis; and endothelin-1 (ET-1) and interleukin-6 (IL-6) to assess endothelial activation and systemic inflammation, respectively. In addition, in treatment-naive IPAH patients these markers were assessed after 3 months of PAH-specific therapies.. TPA (10.1[6.8-15.8] vs 5.2[3.3-7.3] ng/ml, p<0.001), plasmin-anti-plasmin (91.5[60.3-94.2] vs 55.8[51.1-64.9] ng/ml, p<0.001), IL-6 (4.9[2.5-7.9] vs 2.1[1.3-3.8] pg/ml, p=0.001) and ET-1 (3.7 [3.3-4.5] vs 3.4[3.1-3.5], p= 0.03) were higher in patients with IPAH than in controls. In IPAH patients plasmin-anti-plasmin and tPA correlated positively with IL-6 (r=0.39, p=0.04 and r=0.63, p<0.001, respectively) and ET-1 (r=0.55, p=0.003 and r=0.59, p=0.001, respectively). No correlation was found between tPA or plasmin-anti-plasmin and markers of thrombogenesis. Plasmin-anti-plasmin decreased after 3 months of PAH specific therapy while the other markers remained unchanged.. In the present study we showed that markers of fibrynolysis were elevated in patients with IPAH however we did not find a clear evidence for increased thrombogenesis in this group of patients. Fibrinolysis, inflammation, and endothelial activation were closely interrelated in IPAH.

Topics: Adult; Aged; Endothelin-1; Endothelium, Vascular; Familial Primary Pulmonary Hypertension; Female; Fibrinolysis; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Prothrombin; Thrombin; Tissue Plasminogen Activator

Neurodegeneration is a hallmark of most of the central nervous system (CNS) disorders including stroke. Recently inflammation has been implicated in pathogenesis of neurodegeneration and neurodegenerative diseases. The aim of this study was analysis of expression of several inflammatory markers and its correlation with development of neurodegeneration during the early stage of experimental stroke. Ischemic stroke model was induced by stereotaxic intracerebral injection of vasoconstricting agent endothelin-1 (ET-1). It was observed that neurodegeneration appears very early in that model and correlates well with migration of inflammatory lymphocytes and macrophages to the brain. Although the expression of several studied chemotactic cytokines (chemokines) was significantly increased at the early phase of ET-1 induced stroke model, no clear correlation of this expression with neurodegeneration was observed. These data may indicate that chemokines do not induce neurodegeneration directly. Upregulated in the ischemic brain chemokines may be a potential target for future therapies reducing inflammatory cell migration to the brain in early stroke. Inhibition of inflammatory cell accumulation in the brain at the early stage of stroke may lead to amelioration of ischemic neurodegeneration.

Topics: Animals; Brain; Brain Ischemia; Chemokine CCL2; Chemokine CCL3; Chemokine CCL5; Chemokine CXCL2; Chemokines; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Profiling; Gene Expression Regulation; Inflammation; Lymphocytes; Macrophages; Mice; Neurodegenerative Diseases; Real-Time Polymerase Chain Reaction; Stroke

Although many obese individuals are normoglycemic and asymptomatic of cardiometabolic complications, this apparent healthy state may be a misnomer. Since heart failure is a major cause of mortality in obesity, we investigated the effects of heme-oxygenase (HO) on heart failure and cardiometabolic complications in obese normoglycemic Zucker-fatty rats (ZFs). Treatment with the HO-inducer, hemin, reduced markers of heart failure, such as osteopontin and osteoprotegerin, abated left-ventricular (LV) hypertrophy/fibrosis, extracellular matrix/profibrotic proteins including collagen IV, fibronectin, TGF-β1, and reduced cardiac lesions. Furthermore, hemin suppressed inflammation by abating macrophage chemoattractant protein-1, macrophage-inflammatory protein-1 alpha, TNF-α, IL-6, and IL-1β but enhanced adiponectin, atrial-natriuretic peptide (ANP), HO activity, insulin sensitivity, and glucose metabolism. Correspondingly, hemin improved several hemodynamic/echocardiographic parameters including LV-diastolic wall thickness, LV-systolic wall thickness, mean-arterial pressure, arterial-systolic pressure, arterial-diastolic pressure, LV-developed pressure, +dP/dt, and cardiac output. Contrarily, the HO-inhibitor, stannous mesoporphyrin nullified the hemin effect, exacerbating inflammatory/oxidative insults and aggravated insulin resistance (HOMA-index). We conclude that perturbations in insulin signaling and cardiac function may be forerunners to overt hyperglycemia and heart failure in obesity. Importantly, hemin improves cardiac function by suppressing markers of heart failure, LV hypertrophy, cardiac lesions, extracellular matrix/profibrotic proteins, and inflammatory/oxidative mediators, while concomitantly enhancing the HO-adiponectin-ANP axis.

Topics: Adiponectin; Animals; Atrial Natriuretic Factor; Blood Glucose; Chemokine CCL2; Dinoprost; Endothelin-1; Heart Failure; Heart Function Tests; Heart Ventricles; Heme Oxygenase (Decyclizing); Hemin; Hemodynamics; Inflammation; Insulin; Insulin Resistance; Macrophage Inflammatory Proteins; Macrophages; Metalloporphyrins; Myocytes, Cardiac; Obesity; Rats; Rats, Zucker; Risk Factors; Tumor Necrosis Factor-alpha; Ultrasonography; Up-Regulation

This study investigated the effects of cortisol and insulin, hormones that affect both glycaemic status and vascular function, on the in vitro contractility of isolated healthy equine small laminar veins. Small veins (150-500 μm) draining the digital laminae from healthy horses or ponies were investigated by wire myography. Concentration response curves were constructed for noradrenaline (NA), phenylephrine (PE), endothelin-1 (ET-1) and 5-hydroxytryptamine (5-HT) in the presence of either cortisol (10(-6 ) m) or insulin (1000 μIU/mL). Cortisol significantly increased the maximum contractility of laminar veins to the vasoconstrictors NA and 5-HT but decreased the maximal contraction to ET-1. Insulin decreased the contractility of vessels to PE and ET-1. It is possible that short-term cortisol excess could enhance venoconstrictor responses to 5-HT and NA in laminar veins in vivo, thereby predisposing to laminitis. Additionally, a reduction in the ability of insulin to counteract alpha-adrenoreceptor and ET-1-mediated contraction, likely to occur in subjects with insulin resistance, may further exacerbate venoconstriction in animals prone to laminitis. These mechanisms may also predispose horses with disorders such as equine Cushing's disease and equine metabolic syndrome to laminitis.

Topics: Animals; Endothelin-1; Hoof and Claw; Horse Diseases; Horses; Hydrocortisone; Inflammation; Insulin; Norepinephrine; Phenylephrine; Serotonin; Vasoconstriction; Veins

Chronic inflammation is a salient feature of sickle cell disease (SCD) and transgenic-knockout sickle (BERK) mice. Inflammation is implicated in the activation of hypoxia-inducible factor-1α (HIF-1α) under normoxic conditions. We hypothesize that, in SCD, inflammation coupled with nitric oxide (NO) depletion will induce expression of HIF-1α, a transcription factor with wide-ranging effects including activation of genes for vasoactive molecules. To this end, we have examined the expression of HIF-1α in normoxic BERK mice expressing exclusively human α- and β(S)- globins, and evaluated the effect of fetal hemoglobin (HbF) in BERK mice (i.e., <1.0%, 20%, and 40% HbF). HbF exerts antisickling and anti-inflammatory effects. Here, we show that HIF-1α is expressed in BERK mice under normoxic conditions, accompanied by increased expression of its vasoactive biomarkers such as VEGF, heme oxygenase-1 (HO-1), and serum ET-1 levels. In BERK mice expressing HbF, HIF-1α expression decreases concomitantly with increasing HbF, commensurately with increased NO bioavailability, and shows a strong inverse correlation with plasma NO metabolites (NOx) levels. Reduced HIF-1α expression is associated with decreased HO-1, VEGF, and ET-1. Notably, arteriolar dilation, enhanced volumetric blood flow, and low blood pressure in normoxic BERK mice all show a trend toward normalization with the introduction of HbF. Also, arginine treatment reduced HIF-1α, as well as VEGF expression in normoxic BERK mice, supporting a role of NO bioavailability in HIF-1α activation. Thus HIF-1α expression in normoxic sickle mice is likely a consequence of chronic inflammation, and HbF exerts an ameliorating effect by decreasing sickling, increasing NO bioavailability, and reducing inflammation.

Topics: alpha-Globins; Anemia, Sickle Cell; Animals; Arginine; Arterioles; beta-Globins; Blood Pressure; Disease Models, Animal; Down-Regulation; Endothelin-1; Fetal Hemoglobin; Heme Oxygenase-1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microcirculation; Nitric Oxide; Regional Blood Flow; Vascular Endothelial Growth Factor A; Vasodilation

We aimed to investigate whether atrial natriuretic peptide (ANP) attenuates angiotensin II (Ang II)-induced myocardial remodeling and to clarify the possible molecular mechanisms involved. Thirty-five 8-week-old male Wistar-Kyoto rats were divided into control, Ang II, Ang II + ANP, and ANP groups. The Ang II and Ang II + ANP rats received 1 μg/kg/min Ang II for 14 days. The Ang II + ANP and ANP rats also received 0.1 μg/kg/min ANP intravenously. The Ang II and Ang II + ANP rats showed comparable blood pressure. Left ventricular fractional shortening and ejection fraction were lower in the Ang II rats than in controls; these indices were higher (P < 0.001) in the Ang II + ANP rats than in the Ang II rats. In the Ang II rats, the peak velocity of mitral early inflow and its ratio to atrial contraction-related peak flow velocity were lower, and the deceleration time of mitral early inflow was significantly prolonged; these changes were decreased by ANP. Percent fibrosis was higher (P < 0.001) and average myocyte diameters greater (P < 0.01) in the Ang II rats than in controls. ANP decreased both myocardial fibrosis (P < 0.01) and myocyte hypertrophy (P < 0.01). Macrophage infiltration, expression of mRNA levels of collagen types I and III, monocyte chemotactic protein-1, and a profibrotic/proinflammatory molecule, tenascin-C (TN-C) were increased in the Ang II rats; ANP significantly decreased these changes. In vitro, Ang II increased expression of TN-C and endothelin-1 (ET-1) in cardiac fibroblasts, which were reduced by ANP. ET-1 upregulated TN-C expression via endothelin type A receptor. These results suggest that ANP may protect the heart from Ang II-induced remodeling by attenuating inflammation, at least partly through endothelin 1/endothelin receptor A cascade.

Topics: Angiotensin II; Animals; Anti-Inflammatory Agents; Atrial Natriuretic Factor; Cardiomegaly; Cells, Cultured; Disease Models, Animal; Endothelin-1; Fibrillar Collagens; Fibroblasts; Fibrosis; Heart Diseases; Inflammation; Inflammation Mediators; Infusions, Intravenous; Macrophages; Male; Mitral Valve; Myocardial Contraction; Myocardium; Rats; Rats, Inbred WKY; Receptor, Endothelin A; Signal Transduction; Stroke Volume; Time Factors; Ventricular Function, Left; Ventricular Remodeling

IL-33 signals through ST2 receptors and induces adaptive and innate inflammation. IL-33/ST2 is involved in adaptive inflammation-induced pain. Here, we have investigated the contribution of IL-33/ST2-triggered mechanisms to carrageenin-induced innate inflammation.. Carrageenin- and IL-33-induced inflammatory responses were assessed in BALB/c- (WT) and ST2-deficient ((-/-) ) mice as follows: oedema (plethysmometer), myeloperoxidase activity (colorimetric assay), mechanical hyperalgesia (electronic version of von Frey filaments), cytokine levels (ELISA), PGE2 (RIA), mRNA expression (quantitative PCR), drug treatments targeting leukocyte recruitment (fucoidin), TNF-α (infliximab), CXCL1 (antibody to CXCL1), IL-1 (IL-1ra), endothelin ETA (clazosentan) and ETB (BQ788) receptors and COX (indomethacin).. Carrageenin injection increased ST2 and IL-33 mRNA expression and IL-33 production in paw skin samples. Carrageenin-induced paw oedema, hyperalgesia and myeloperoxidase activity were reduced in ST2(-/-) compared with WT mice, effects mimicked by IL-33 injection in the paw. Furthermore, IL-33-induced hyperalgesia was reduced by fucoidin suggesting a role for recruited leukocytes in its hyperalgesic effect. IL-33-induced hyperalgesia in naïve mice was reduced by treatments targeting TNF, CXCL1, IL-1, endothelin receptors and COX while carrageenin-induced ST2-dependent TNF-α, CXCL1, IL-1β, IL-10 and PGE2 production and preproET-1 mRNA expression. Combining IL-33 and carrageenin at doses that were ineffective as single treatment induced significant hyperalgesia, oedema, myeloperoxidase activity and cytokine production in a ST2-dependent manner.. IL-33/ST2 signalling triggers the production of inflammatory mediators contributing to carrageenin-induced inflammation. These data reinforces the importance of IL-33/ST2 signalling as a target in innate inflammation and inflammatory pain.

Topics: Animals; Carrageenan; Cytokines; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Female; Inflammation; Inflammation Mediators; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Interleukins; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Pain; Receptors, Interleukin; RNA, Messenger; Signal Transduction

Independent studies in experimental models of Trypanosoma cruzi appointed different roles for endothelin-1 (ET-1) and bradykinin (BK) in the immunopathogenesis of Chagas disease. Here, we addressed the hypothesis that pathogenic outcome is influenced by functional interplay between endothelin receptors (ET(A)R and ET(B)R) and bradykinin B(2) receptors (B(2)R).. Intravital microscopy was used to determine whether ETR/B(2)R drives the accumulation of rhodamine-labelled leucocytes in the hamster cheek pouch (HCP). Inflammatory oedema was measured in the infected BALB/c paw of mice. Parasite invasion was assessed in CHO over-expressing ETRs, mouse cardiomyocytes, endothelium (human umbilical vein endothelial cells) or smooth muscle cells (HSMCs), in the presence/absence of antagonists of B(2)R (HOE-140), ET(A)R (BQ-123) and ET(B)R (BQ-788), specific IgG antibodies to each GPCRs; cholesterol or calcium-depleting drugs. RNA interference (ET(A)R or ET(B)R genes) in parasite infectivity was investigated in HSMCs.. BQ-123, BQ-788 and HOE-140 reduced leucocyte accumulation in HCP topically exposed to trypomastigotes and blocked inflammatory oedema in infected mice. Acting synergistically, ET(A)R and ET(B)R antagonists reduced parasite invasion of HSMCs to the same extent as HOE-140. Exogenous ET-1 potentiated T. cruzi uptake by HSMCs via ETRs/B(2)R, whereas RNA interference of ET(A)R and ET(B)R genes conversely reduced parasite internalization. ETRs/B(2)R-driven infection in HSMCs was reduced in HSMC pretreated with methyl-β-cyclodextrin, a cholesterol-depleting drug, or in thapsigargin- or verapamil-treated target cells.. Our findings suggest that plasma leakage, a neutrophil-driven inflammatory response evoked by trypomastigotes via the kinin/endothelin pathways, may offer a window of opportunity for enhanced parasite invasion of cardiovascular cells.

Topics: Animals; Bradykinin B2 Receptor Antagonists; Calcium; Cells, Cultured; Chagas Disease; CHO Cells; Cricetinae; Edema; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Kinins; Mice; Mice, Inbred BALB C; Myocytes, Cardiac; Myocytes, Smooth Muscle; Receptor, Bradykinin B2; Receptor, Endothelin A; Receptor, Endothelin B; Trypanosoma cruzi

One of the most significant responses to fetal cardiac bypass is severe placental dysfunction characterized by increased vascular resistance. We tested the hypothesis that fetal cardiac bypass triggers the activation of nuclear factor kappa-B (NF-KB), a major regulator of inflammatory response, and that pharmacologic inhibition of NF-KB activation by pyrrolidine dithiocarbamate alleviates fetal cardiac bypass-induced placental dysfunction.. Fifteen pregnant goats at 120 to 140 days' gestation were equally divided into the control group with a sham procedure of fetal sternotomy and cannulation (CG), the fetal bypass group (FB), and the fetal bypass group with 300 mg pyrrolidine dithiocarbamate before sternotomy (FP). Fetal cardiac bypass was performed for 30 minutes. Umbilical arterial flow rate was measured by ultrasonic flowmeter and placental vascular resistance was calculated. Fetal plasma levels of nitric oxide (NO), endothlin-1 (ET-1), 6-keto-prostaglandin F1α (6-K), thromboxane B(2) (TXB2), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were assayed. IL-6 and TNF-α mRNA were analyzed by real-time polymerase chain reaction. NF-KB activation was evaluated by electrophoretic mobility shift assay.. Placental vascular resistance significantly increased in the FB and FP groups compared with the CG group. Increases in plasma levels of NO were observed in all 3 groups. Plasma levels of ET-1 rose significantly in the FB and FP groups without noticeable difference between them. Plasma levels of 6-K, TXB(2), IL-6, and TNF-α increased significantly in the FB group compared with the CG and FP groups. The transcription levels of IL-6 and TNF-α mRNA in the placental tissues of the FB group were significantly higher than in the FP and CG groups. The amount of activated NF-KB in the placental tissues of the FB group was also significantly higher than that in the FP and CG groups.. Fetal cardiac bypass-induced inflammatory response possibly mediated by NF-KB caused placental dysfunction. Pharmacologic inhibition of NF-KB activation and decrease in the inflammatory response did not alleviate the placental dysfunction.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Cardiac Surgical Procedures; Electrophoretic Mobility Shift Assay; Endothelin-1; Female; Fetal Blood; Fetal Heart; Gestational Age; Goats; Inflammation; Inflammation Mediators; Interleukin-6; NF-kappa B; Nitric Oxide; Placenta; Placenta Diseases; Placental Circulation; Pregnancy; Pyrrolidines; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiocarbamates; Thromboxane B2; Tumor Necrosis Factor-alpha; Vascular Resistance

With the increasing awareness of Peyronie's disease (PD), the interest in new concept medications to treat the disorder is escalating. Profibrogenic factors such as transforming growth factor (TGF)-beta1, endothelin (ET-1), connective tissue growth factor (CTGF), angiotensin (Ang) II and platelet derived growth factor (PDGF), all appear to be involved in the pathogenesis of PD. β-Thymosins, pirfenidone, nitric oxide (NO) donors, phosphodiesterase (PDE)-5 inhibitors, matrix metalloproteinases (MMPs)/anti-tissue inhibitor of metalloproteinases (TIMP)-1 reduce collagen synthesis, while decorin, follistatin, and Smad 7 exert antifibrotic effects; all have been proposed for the treatment of PD. Alternative and/or novel approaches for the treatment of PD are needed in part because of the recognized multifactorial etiology of this complex disorder. A comprehensive approach for translating available experimental information into clinically effective drug trials for the treatment of PD is needed. We propose a multi-faceted approach for drug development to generate novel drug products for the treatment of PD.

Topics: Adult; Angiotensin II; Animals; Connective Tissue Growth Factor; Disease Models, Animal; Drug Design; Drug Therapy; Endothelin-1; Fibrosis; Humans; Inflammation; Male; Middle Aged; Penile Induration; Platelet-Derived Growth Factor; Transforming Growth Factor beta1; Wound Healing

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by proximal pulmonary vascular obstruction by thrombo-fibrotic material, the origin of which has not been elucidated. Enhanced inflammation could contribute to persistent obstruction by impairing pulmonary vascular cell function in CTEPH. We investigated C-reactive protein (CRP) effects on pulmonary vascular cell function in vitro. Primary cultures of proximal pulmonary endothelial cells (ECs) and smooth muscle cells (SMCs) from CTEPH and nonthromboembolic pulmonary hypertension (PH) patients were established. Recombinant CRP effects on mitogenic activity, adhesion capacity, endothelin-1 and von Willebrand factor (vWF) secretion and intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule-1 expression were investigated in ECs and/or SMCs. Expression of the CRP receptor, lectin-like oxidised low-density lipoprotein receptor (LOX)-1, was evaluated in proximal pulmonary arterial tissue and cells by Western blotting and immunofluorescence. CRP increased CTEPH-SMC proliferation by 250%. CRP increased adhesion capacity, endothelin-1 and vWF secretion by CTEPH-ECs by 37%, 129% and 694%, respectively. CRP-induced adhesion of CTEPH-ECs to monocytes was mediated by ICAM-1. CRP had no effect on cells from nonthromboembolic PH patients, probably because of overexpression of LOX-1 in CTEPH. Local expression of CRP was detected in ECs and SMCs within pulmonary arterial tissue. CRP may contribute to persistent obstruction of proximal pulmonary arteries in CTEPH by promoting vascular remodelling, endothelial dysfunction and in situ thrombosis.

Topics: Adult; Aged; C-Reactive Protein; Case-Control Studies; Cell Adhesion; Cell Proliferation; Cells, Cultured; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertension, Pulmonary; Inflammation; Intercellular Adhesion Molecule-1; Male; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pulmonary Artery; Receptors, Immunologic; Scavenger Receptors, Class E; Thromboembolism; von Willebrand Factor

Endothelin mediates neutrophil recruitment during innate inflammation. Herein we address whether endothelin-1 (ET-1) is involved in neutrophil recruitment in adaptive inflammation in mice, and its mechanisms. Pharmacological treatments were used to determine the role of endothelin in neutrophil recruitment to the peritoneal cavity of mice challenged with antigen (ovalbumin) or ET-1. Levels of ET-1, tumour necrosis factor α (TNFα), and CXC chemokine ligand 1 (CXCL1) were determined by enzyme-linked immunosorbent assay. Neutrophil migration and flow cytometry analyses were performed 4 h after the intraperitoneal stimulus. ET-1 induced dose-dependent neutrophil recruitment to the peritoneal cavity. Treatment with the non-selective ET(A)/ET(B) receptor antagonist bosentan, and selective ET(A) or ET(B) receptor antagonists BQ-123 or BQ-788, respectively, inhibited ET-1- and ovalbumin-induced neutrophil migration to the peritoneal cavity. In agreement with the above, the antigen challenge significantly increased levels of ET-1 in peritoneal exudates. The ET-1- and ovalbumin-induced neutrophil recruitment were reduced in TNFR1 deficient mice, and by treatments targeting CXCL1 or CXC chemokine receptor 2 (CXCR2); further, treatment with bosentan, BQ-123, or BQ-788 inhibited ET-1- and antigen-induced production of TNFα and CXCL1. Furthermore, ET-1 and ovalbumin challenge induced an increase in the number of cells expressing the Gr1(+) markers in the granulocyte gate, CD11c(+) markers in the monocyte gate, and CD4(+) and CD45(+) (B220) markers in the lymphocyte gate in an ET(A)- and ET(B)-dependent manner, as determined by flow cytometry analysis, suggesting that ET-1 might be involved in the recruitment of neutrophils and other cells in adaptive inflammation. Therefore, the present study demonstrates that ET-1 is an important mediator for neutrophil recruitment in adaptive inflammation via TNFα and CXCL1/CXCR2-dependent mechanism.

Topics: Adaptive Immunity; Animals; Chemokine CXCL1; Chemotaxis, Leukocyte; Disease Models, Animal; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Inflammation; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Ovalbumin; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Interleukin-8B; Receptors, Tumor Necrosis Factor, Type I; Time Factors; Tumor Necrosis Factor-alpha

Epidemiological studies suggest that particulate matter (PM(10)) inhalation was associated with adverse effects on brain-related health, however, existing experimental data lacked relevant evidences. In this study, we treated Wistar rats with PM(10) at different concentrations (0.3, 1, 3 and 10 mg/kg body weight (bw)), and investigated endothelial dysfunction and inflammatory responses in the brain. The results indicate that mild pathological abnormal occurred after 15-day exposure (five times with 3 days each), followed by the changes of endothelial mediators (ET-1 and eNOS) and inflammatory markers (IL-1β, TNF-α, COX-2, iNOS and ICAM-1). Also, the sample up-regulated bax/bcl-2 ratio and p53 expression, and induced neuronal apoptosis. It implicates that PM(10) exerted injuries to mammals' brain, and the mechanisms might be involved in endothelial dysfunction and inflammatory responses.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Brain; Coloring Agents; Cytokines; Endothelin-1; Endothelium, Vascular; In Situ Nick-End Labeling; Inflammation; Male; Nitric Oxide Synthase Type III; Particle Size; Particulate Matter; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA

To assess the relationship between endothelial dysfunction, endothelin 1 (ET-1) plasma levels and subclinical inflammation in primary open angle glaucoma (POAG) patients.. We enrolled 40 POAG patients with progressive visual field damage, although well controlled intraocular pressure (IOP) and compared to age and sex matched healthxy subjects. Each patient underwent an ophthalmological examination, a standard achromatic perimetry (SAP), blood sampling to assess ET-1 plasma levels, an objective assessment of cellularity within the anterior chamber (FLARE) and measurement of flow mediated dilation (FMD) with high resolution 2-dimensional ultrasonographic imaging of the brachial artery.. At baseline, POAG patients, compared to healthy controls, showed an increase of ET-1 plasma levels: 2.83 ± 0.28 pg/ml vs. 1.75 ± 0.25 pg/ml (p<0.001), lower FMD values 4.46 ± 1.28% vs. 13.18 ± 2.80% (p<0.001) and increased FLARE values 9.98 ± 0.97 photons/ms vs. 5.87 ± 0.64 photons/ms (p<0.001). A follow up after 1 year revealed a further increase of ET-1 plasma levels (to 3.68 ± 0.60; p<0.001) and decrease of FMD (3.52 ± 1.28; p>0.001).. The increase of ET-1 in POAG patients is related to vascular dysfunction (r=0.942; p=0.001) and vascular dysfunction is related to sub-clinical intraocular inflammation (r=0.968; p=0.001). Thus ET-1 and vascular dysfunction related to sub-clinical inflammation may play a key role in determining a progressive visual field damage in POAG patients who present a well-controlled IOP.

Topics: Adult; Brachial Artery; Case-Control Studies; Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Follow-Up Studies; Glaucoma, Open-Angle; Humans; Inflammation; Intraocular Pressure; Male; Middle Aged; Ultrasonography; Vasodilation; Visual Field Tests; Visual Fields

Small airway narrowing is an important pathology which impacts lung function in chronic obstructive pulmonary disease (COPD). The accumulation of fibroblasts and myofibroblasts contribute to inflammation, remodeling and fibrosis by production and release of mediators such as cytokines, profibrotic factors and extracellular matrix proteins. This study investigated the effects of the phosphodiesterase 4 inhibitor roflumilast, combined with the long acting β2 adrenergic agonist indacaterol, both approved therapeutics for COPD, on fibroblast functions that contribute to inflammation and airway fibrosis.. The effects of roflumilast and indacaterol treatment were characterized on transforming growth factor β1 (TGFβ1)-treated normal human lung fibroblasts (NHLF). NHLF were evaluated for expression of the profibrotic mediators endothelin-1 (ET-1) and connective tissue growth factor (CTGF), expression of the myofibroblast marker alpha smooth muscle actin, and fibronectin (FN) secretion. Tumor necrosis factor-α (TNF-α) was used to induce secretion of chemokine C-X-C motif ligand 10 (CXCL10), chemokine C-C motif ligand 5 (CCL5) and granulocyte macrophage colony-stimulating factor (GM-CSF) from NHLF and drug inhibition was assessed.. Evaluation of roflumilast (1-10 μM) showed no significant inhibition alone on TGFβ1-induced ET-1 and CTGF mRNA transcripts, ET-1 and FN protein production, alpha smooth muscle expression, or TNF-α-induced secretion of CXCL10, CCL5 and GM-CSF. A concentration-dependent inhibition of ET-1 and CTGF was shown with indacaterol treatment, and a submaximal concentration was chosen for combination studies. When indacaterol (0.1 nM) was added to roflumilast, significant inhibition was seen on all inflammatory and fibrotic mediators evaluated, which was superior to the inhibition seen with either drug alone. Roflumilast plus indacaterol combination treatment resulted in significantly elevated phosphorylation of the transcription factor cAMP response element-binding protein (CREB), an effect that was protein kinase A-dependent. Inhibition of protein kinase A was also found to reverse the inhibition of indacaterol and roflumilast on CTGF.. These results demonstrate that addition of roflumilast to a LABA inhibits primary fibroblast/myofibroblast function and therapeutically this may impact lung fibroblast proinflammatory and profibrotic mediator release which contributes to small airway remodeling and airway obstruction in COPD.

Topics: Actins; Adrenergic beta-2 Receptor Agonists; Aminopyridines; Benzamides; Cells, Cultured; Chemokine CCL5; Chemokine CXCL10; Connective Tissue Growth Factor; Cyclopropanes; Endothelin-1; Fibroblasts; Fibronectins; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Indans; Inflammation; Lung; Phosphodiesterase 4 Inhibitors; Pulmonary Fibrosis; Quinolones; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Aortic valve stenosis (AS) is an actively regulated pathobiological process which has an inflammation origin, and manifests as an accumulation of lipids and, ultimately, calcification of the aortic valve tissue. Increased plasma levels of the proinflammatory factor endothelin-1 (ET-1) have been reported in AS. Moreover, increased tissue levels of ET-1 and its ET(A) receptor, which mediates the fibrotic and proliferative effects of ET-1, have been reported in stenotic aortic valves. The study aim was to determine whether endothelin receptor antagonism has an effect on the supposed receptor-mediated uptake of ET-1 to aortic valves when ET-1 may be involved in the pathogenesis of AS.. By using valve tissue explants in culture, it was determined whether the ET(A)-ET(B) receptor antagonist tezosentan was capable of reducing the uptake of 125I-labeled ET-1 to human aortic valves. Aortic valves were obtained from 16 patients (11 males, five females; mean age 71 +/- 11.2 years) and from two donors without AS (as controls) at the time of aortic valve or aortic root surgery. Valve tissue samples were cultured in ET-1 (10 nmol/l), in the presence or absence of tezosentan (10 nmol/l).. ET-1 uptake was found to be pronounced in the calcified areas of the valve, and tezosentan markedly reduced the receptor-mediated uptake of 125I-labeled ET-1. The inhibitory effect was most evident in the well-calcified part of the valve. The gene expression levels of the ET receptors ET(A) and ET(B) were unaltered in human aortic valves during a four-day exposure to the antagonist.. The ability of the ET(A)-ET(B) receptor antagonist tezosentan to inhibit ET-1 uptake in valve tissue suggests that continuous ET antagonist therapy might serve as new strategy to slow down the pathophysiological processes of AS.

Topics: Aged; Aged, 80 and over; Aortic Valve; Aortic Valve Stenosis; Calcinosis; Cells, Cultured; Drug Repositioning; Endothelin A Receptor Antagonists; Endothelin-1; Female; Humans; Inflammation; Lipid Metabolism; Male; Middle Aged; Pyridines; Receptor, Endothelin A; Tetrazoles; Vasodilator Agents

Endothelin-1 (ET-1) has been suggested to be involved in different types of pain due to its neuromodulatory nature. However, its role in inflammatory pain processing, specifically the origin-specific effect, has not yet been clearly defined. Therefore, the aim of this study is to determine the role of cell-type specific ET-1 induction in the modulation of inflammatory pain processing.. The current study assesses the effects of ET-1 over-expression specifically targeted to astrocytes (GET-1) or endothelial cells (TET-1) on the expression of pain-like behaviors induced by a model of inflammatory pain, consisting of a formalin injection into the hind paw.. The baseline sensitivity thresholds of GET-1 and TET-1 mice to the response elicited by tactile and radiant heat stimulation were similar to those observed in age-matched non-transgenic (NTg) controls. Relative to the NTg controls, GET-1 mice displayed a marked decrease in pain-like behavioral responses during the second phase of formalin-induced pain (i.e., 15-20 min after injection), whereas the responses elicited in TET-1 mice were unaltered. The levels of mRNA encoding adrenomedullin, calcitonin gene-related peptide and calcitonin-like receptor were elevated in the spinal cord of saline-injected GET-1 mice compared to those of NTg mice.. The current results support a suppressor role for astrocyte-derived ET-1 in inflammatory pain and suggest that the study of GET-1 mice might provide mechanistic insights for improving the treatment of inflammatory pain.

Topics: Adrenomedullin; Animals; Astrocytes; Behavior, Animal; Calcitonin Gene-Related Peptide; Calcitonin Receptor-Like Protein; Disease Models, Animal; Endothelial Cells; Endothelin-1; Formaldehyde; Gene Expression Regulation; Inflammation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pain; RNA, Messenger; Spinal Cord

Presented herein are the findings of examination of 176 people. Of these, 128 were found to suffer lower limb atherosclerosis (LLA) and 48 were apparently healthy people constituting a control group. Amongst the 128 patients, 74 (58%) had atherosclerotic lesions of the iliac arteries, 54 (42%) subjects had lesions of the femoral and popliteal arteries. The average age of the patients amounted to 62.4±4.3 years. There were ten (8%) women and 118 (92%) men. The control group consisted of 42 (89%) men and six (11%) women. The mean age of the control group patients was 58.9±3.2 years. All underwent functional and laboratory examinations including angiography, duplex scanning and dopplerography of lower limb arteries, as well as determining blood serum markers of inflammation (hs-CRP and IL-6), as well as endothelial lesion markers (ET-1 and VWF). The comparative analysis revealed that patients with LLA had signs of chronic vascular inflammation accompanied in the majority of cases by hyperhomocysteinemia with endothelial dysfunction, as well as direct association between the degree of the vascular inflammatory reaction and severity of clinical manifestations of lower limb ischaemia.

Topics: Aged; Angiography; Biomarkers; C-Reactive Protein; Endothelin-1; Endothelium, Vascular; Female; Femoral Artery; Homocysteine; Humans; Inflammation; Interleukin-6; Lower Extremity; Male; Middle Aged; Peripheral Arterial Disease; Popliteal Artery; Severity of Illness Index; Statistics as Topic; Ultrasonography, Doppler, Duplex; von Willebrand Factor

The problems associated with small-for-size liver grafts (ie, high mortality rates, postoperative complications, and acute rejection) remain critical issues in partial orthotopic liver transplantation (OLT). In association with partial OLT, splenectomy (SP) is a procedure used to reduce the portal pressure. However, the precise effects of SP on partial OLT have been unclear. In this study, using small-for-size liver grafts in rats, we examined the cytoprotective effects of SP on OLT. Liver grafts were assigned to 2 groups: a control group (OLT alone) and an SP group (OLT after SP). SP significantly increased animal survival and decreased liver damage. SP exerted the following cytoprotective effects: (1) it improved hepatic microcirculation and prevented increases in the portal pressure after OLT, (2) it suppressed the hepatic infiltration of neutrophils and macrophages through the direct elimination of splenic inflammatory cells before OLT, (3) it decreased the hepatic expression of tumor necrosis factor α and interleukin-6, (4) it attenuated sinusoidal endothelial injury, (5) it decreased plasma endothelin 1 levels and increased hepatic heme oxygenase 1 expression, (6) it suppressed hepatocellular apoptosis through the down-regulation of hepatic caspase-3 and caspase-8 activity, and (7) it increased hepatic regeneration. In conclusion, SP for small-for-size grafts exerts dual cytoprotective effects by preventing excessive portal vein hepatic inflow and eliminating splenic inflammatory cell recruitment into the liver; this in turn inhibits hepatocellular apoptosis and improves liver regeneration.

Topics: Animals; Caspase 3; Caspase 8; Cytoprotection; Endothelin-1; Gene Expression Regulation; Inflammation; Interleukin-6; Liver; Liver Transplantation; Macrophages; Male; Neutrophils; Peroxidase; Portal Vein; Rats; Rats, Wistar; Splenectomy

Exposure to particulate matter (PM) increases the incidence of cardiovascular disease, but the underlying mechanisms remain unclear. To characterise ambient PM collected from a coach station in an urban area, particulate polycyclic aromatic hydrocarbons (PAHs) and trace metals were evaluated, and diagnostic ratios were then used to determine the sources based on the PAHs identified in PM. To elucidate the mechanism of PM-induced vascular toxicology, human coronary artery endothelial cells (HCAECs) were exposed to PM, PM-free supernatant and residual PM, and the associations between PAHs and trace metals, nitric oxide (NO), endothelin-1 (ET-1) and interleukin-6 (IL-6) were investigated. Petrogenic-related particulate emissions, such as vehicle exhaust, accounted for 68.75% and 75.00% of mass in the 0.1-1-μm PM (PM(0.1-1)) and <0.1-μm PM (PM(0.1)) size fractions, respectively. Vehicle exhaust particles (VEPs) caused significant NO suppression and increase in ET-1 and IL-6, whereas residual PM caused an increase in NO, ET-1 and IL-6 compared with the effects of the corresponding supernatants. PAHs in PM, particularly those with 4-6 rings, were associated with NO suppression, and ET-1 and IL-6 were positively correlated with the amount of trace metal compounds. These findings suggest that chemical components affect the regulation of vasoactive function and inflammation.

Topics: Cardiovascular Diseases; Cell Line; Dose-Response Relationship, Drug; Endothelial Cells; Endothelin-1; Humans; Inflammation; Interleukin-6; Nitric Oxide; Particulate Matter; Polycyclic Aromatic Hydrocarbons; Statistics, Nonparametric; Trace Elements; Vehicle Emissions

Our aim was to develop a large animal model of sepsis induced by fecal peritonitis, which reproduces the characteristic macrohemodynamic, microcirculatory and inflammatory changes seen in human sepsis.. Anesthetized minipigs were subjected to fecal peritonitis (n = 9; 0.5 g/kg i.p. autofeces) or sham-operation (i.p. saline, n = 6). Invasive hemodynamic monitoring was started with regular blood gas analyses between the 15-24 hr of the insult. Sublingual microcirculation was characterized by red blood cell velocity changes (with orthogonal polarization spectral imaging), and the extravascular lung water index (EVLWI) was measured. The plasma levels of big-endothelin (big-ET) and high-mobility group box protein-1 (HMGB1) were determined from venous blood samples.. The mean arterial pressure gradually decreased below 70 mmHg in septic animals, while the heart rate and cardiac output increased constantly. In spite of the hyperdynamic reaction, significant elevation of the EVLWI was observed, while the sublingual microcirculation deteriorated, as compared with the control group. The big-ET and HMGB1 plasma concentrations were significantly elevated between 6-24 hr of peritonitis.. The in vivo data suggest that our fecal peritonitis-induced experimental sepsis model is of clinical relevance, and may play useful roles in the development of novel, sepsis-related therapies.

Topics: Animals; Arterial Pressure; Biomarkers; Blood Flow Velocity; Cardiac Output; Disease Models, Animal; Endothelin-1; Feces; Heart Rate; Hemodynamics; HMGB1 Protein; Inflammation; Microcirculation; Peritonitis; Sepsis; Swine; Swine, Miniature; Time Factors

To investigate the roles of vascular dysregulation and inflammation in normal-tension glaucoma (NTG), we determined the plasma levels of endothelin-1 (ET-1), matrix metalloproteinase-9 (MMP-9), macrophage chemoattractant protein-1 (MCP-1), and high-sensitivity C-reactive protein (hs-CRP).. Forty-five patients with NTG and age-matched 35 healthy controls were enrolled in this study. Blood samples from all subjects were assayed for ET-1, MMP-9, MCP-1, and hs-CRP concentrations and other systemic factors.. There were no significant differences in hemoglobin, hematocrit, RBC count, WBC count, platelet count, fasting glucose, HbA1c, total cholesterol, triglyceride, LDL, and HDL between the NTG and control groups. The systemic levels of ET-1 and MCP-1 were significantly higher in the NTG group than in the control group (p = 0.05 and 0.02, respectively). The MMP-9 and hs-CRP levels were not significantly different between the NTG and control groups.. After excluding patients with cardiovascular and other systemic diseases, plasma ET-1 and MCP-1 levels were elevated in patients with NTG. The MMP-9 and hs-CRP levels were not significantly different in NTG. Increased ET-1 and MCP-1 levels suggest that ischemia/inflammation may play a role in the pathogenesis of NTG.

Topics: C-Reactive Protein; Case-Control Studies; Chemokine CCL2; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation; Intraocular Pressure; Ischemia; Low Tension Glaucoma; Male; Matrix Metalloproteinase 9; Middle Aged; Prospective Studies

Chronic hypoxia (CH) induces an inflammatory response in rat carotid body that is characterized by immune cell invasion and the expression of pro-inflammatory cytokines. In the present study, we have investigated the role of type-A endothelin (ET-A) receptors in the development of CH-induced inflammation. After 7 days of CH (380 Torr), double-label immunofluorescence studies demonstrated elevated levels of ET-A receptor and tyrosine hydroxylase (TH) in O(2)-sensitive type I cells. Following CH, ET-A receptors were also expressed on resident and invasive CD45+ immune cells distributed in tissue surrounding chemosensory cell lobules. Immnofluorescence and quantitative PCR studies showed that concurrent treatment with the ET-A/B receptor antagonist, bosentan (200 mg/kg/day), blocked CH-induced ED-1+ macrophage invasion and the upregulation of cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and monocyte chemoattractant protein-1 (MCP-1). Moreover, bosentan treatment blocked the CH-induced increases in expression of acid-sensitive ion channels (ASICs) in chemoafferent neurons in the petrosal ganglion (PG). Our findings are consistent with the hypothesis that CH-induced inflammation involves the upregulation and release of ET-1 from type I cells. ET-1 may act in an autocrine/paracrine mechanism via ET-A receptors on chemosensory type I cells and immune cells to promote an inflammatory response.

Topics: Acid Sensing Ion Channels; Adaptation, Physiological; Animals; Antihypertensive Agents; Bosentan; Carotid Body; Cell Movement; Chemokine CCL2; Chemoreceptor Cells; Chronic Disease; Endothelin-1; Gene Expression; Hypoxia; Inflammation; Interleukin-1; Interleukin-1beta; Leukocyte Common Antigens; Macrophages; Rats; Receptor, Endothelin A; Sulfonamides; Tumor Necrosis Factor-alpha; Tyrosine 3-Monooxygenase

Pre-eclampsia is new onset hypertension during pregnancy with proteinuria. The initiating event in pre-eclampsia is postulated to involve reduced placental perfusion, which leads to widespread dysfunction of the maternal vascular endothelium. Cytokines also appear to contribute to the development of the pathological condition. The aim of this study was to evaluate the role of cytokines in pre-eclampsia and to study the relationship between endothelin-1 and cytokines with the severity of the disease.. This cross-sectional study included 300 women with pre-eclampsia and 200 healthy pregnant women. Their blood samples were analyzed for endothelin-1 and inflammatory cytokines.. Increased endothelin-1 and cytokines [tumor necrosis factor-α, interleukin-2 (IL-2) and γ-interferon (IFN-γ)] levels were found in pre-eclampsia (P < 0.001). Significant positive correlation was seen between endothelin-1 and cytokine level (IL-2 and IFNγ) in the pre-eclamptic group (P = 0.001).. We conclude that pre-eclampsia is associated with increased levels of both endothelin-1 and circulating inflammatory cytokines, which points toward the role of endothelial and inflammatory components.

Topics: Adult; Cross-Sectional Studies; Cytokines; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Humans; India; Inflammation; Interferon-gamma; Interleukin-2; Pilot Projects; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha

In this study we investigate the effects of adrenomedullin on myocardial injury after ischemia-reperfusion (I/R) after abdominal aortic surgery.. Thirty-two Wistar rats were randomized into 4 groups (n = 8) as follows: control group (sham laparotomy), the aortic I/R group, aortic I/R plus adrenomedullin group (underwent aortic I/R periods, and received a bolus intravenous injection of .05 μg/kg/min adrenomedullin), and the control plus adrenomedullin group.. Biochemical analysis showed that aortic I/R significantly increased (P < .05) the plasma levels of troponin-I and tumor necrosis factor-α, and the myocardial tissue levels of malondialdehyde, superoxide dismutase, catalase, and angiotensin II, whereas aortic I/R plus adrenomedullin significantly decreased these same factors (P < .05). Aortic I/R significantly increased (P < .05) myocardial tissue levels of nitric oxide whereas aortic I/R plus adrenomedullin significantly increased the same factor (P < .05).. These results indicate that adrenomedullin has protective effects against myocardial injury induced by abdominal aortic I/R in rats.

Topics: Adrenomedullin; Angiotensin II; Animals; Aorta; Apoptosis; Biomarkers; Caspase 3; Catalase; Constriction; Endothelin-1; Immunohistochemistry; Inflammation; Lipid Peroxidation; Male; Malondialdehyde; Myocardial Reperfusion Injury; Myocytes, Cardiac; Nitric Oxide; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Superoxide Dismutase; Troponin I; Tumor Necrosis Factor-alpha

Rats fed a high fat diet develop increased adiposity and oxidative stress leading to impaired vasodilation. The purpose of the present study was to examine the effects of high fat-induced increases in adiposity and oxidative stress on vasoconstrictor reactivity of isolated mesenteric arteries. We hypothesized that rats with more adiposity would develop oxidative stress-potentiated increases in iNOS-derived nitric oxide leading to diminished vasoconstriction. Male Sprague-Dawley rats were fed either a control (Chow) or high fat diet for 6 weeks. The roles of oxidative stress and iNOS in the impaired vasoconstrictor responses to endothelin-1 were characterized in small mesenteric arteries. Rats fed the HFD developed significantly more adiposity compared to Chow rats. Plasma levels of nitric oxide and the inflammatory factor tumor necrosis factor α were significantly higher in high fat fed rats compared to Chow rats (nitric oxide: 95.36±19.3 vs. 38.96±6.7 μM; tumor necrosis factor α: 598±111.4 vs. 292±71.8 pg/ml, respectively). Despite exhibiting elevated systolic blood pressure compared to Chow rats (153.5±2.4 vs. 137.5±2.7 mm Hg), endothelin-1 mediated vasoconstriction was impaired in isolated mesenteric arteries from high fat fed rats but was normalized by individual or combined inhibition of nitric oxide synthase, iNOS, or oxidative stress. Therefore, oxidative stress and iNOS are involved in the attenuation of endothelin-1 mediated vasoconstriction observed in isolated mesenteric arteries from high fat fed rats.

Topics: Adiposity; Animals; Blood Pressure; Dietary Fats; Endothelin-1; Feeding Behavior; In Vitro Techniques; Inflammation; Male; Mesenteric Arteries; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type II; Nitrites; Oxidative Stress; Rats; Rats, Sprague-Dawley; Vasoconstriction; Weight Gain

Endothelin (ET)-1, a potent renal vasoconstrictor with mitogenic properties, is upregulated by ischemia and has been shown to induce renal injury via the ET-A receptor. The potential role of ET-A blockade in chronic renovascular disease (RVD) has not, to our knowledge, been previously reported. We hypothesized that chronic ET-A receptor blockade would preserve renal hemodynamics and slow the progression of injury of the stenotic kidney in experimental RVD. Renal artery stenosis, a major cause of chronic RVD, was induced in 14 pigs and observed for 6 wk. In half of the pigs, chronic ET-A blockade was initiated (RVD+ET-A, 0.75 mg·kg(-1)·day(-1)) at the onset of RVD. Single-kidney renal blood flow, glomerular filtration rate, and perfusion were quantified in vivo after 6 wk using multidetector computer tomography. Renal microvascular density was quantified ex vivo using three-dimensional microcomputer tomography, and growth factors, inflammation, apoptosis, and fibrosis were determined in renal tissue. The degree of stenosis and increase in blood pressure were similar in RVD and RVD+ET-A pigs. Renal hemodynamics, function, and microvascular density were decreased in the stenotic kidney but preserved by ET-A blockade, accompanied by increased renal expression of vascular endothelial growth factor, hepatocyte growth factor, and downstream mediators such as phosphorilated-Akt, angiopoietins, and endothelial nitric oxide synthase. ET-A blockade also reduced renal apoptosis, inflammation, and glomerulosclerosis. This study shows that ET-A blockade slows the progression of renal injury in experimental RVD and preserves renal hemodynamics, function, and microvascular density in the stenotic kidney. These results support a role for ET-1/ET-A as a potential therapeutic target in chronic RVD.

Topics: Angiography; Animals; Apoptosis; Blood Pressure; Disease Progression; Endothelin A Receptor Antagonists; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Fibrosis; Hepatocyte Growth Factor; In Situ Nick-End Labeling; Inflammation; Kidney; Kidney Function Tests; Renal Artery Obstruction; Renal Circulation; Signal Transduction; Swine; Tomography; Vascular Endothelial Growth Factor A

The enhanced carotid body (CB) chemosensory response to hypoxia induced by chronic intermittent hypoxia (CIH) has been attributed to oxidative stress, which is expected to increase the expression of chemosensory modulators including chemoexcitatory pro-inflammatory cytokines in the CB. Accordingly, we studied the time-course of the changes in the immunohistological expression of TNF-α, IL-1β, IL-6, ET-1, iNOS, eNOS and 3-nitrotyrosine in the CB, along with the progression of enhanced CB chemosensory responses to acute hypoxia in male Sprague-Dawley rats exposed to CIH (5%O₂, 12 times/h per 8h) for 7, 14 and 21 days. Exposure to CIH for 7 days resulted in a sustained potentiation of CB chemosensory responses to acute hypoxia, which persisted until 21 days of CIH. The chemosensory potentiation was paralleled by an increased 3-nitrotyrosine expression in the CB. On the contrary, CIH produced a transient 2-fold increase of ET-1 immunoreactivity at 7 days, a decrease in eNOS immunoreactivity, and a delayed but progressive increase of TNF-α, IL-1β and iNOS immunoreactivity, which was not associated with changes in systemic plasma levels or immune cell invasion within the CB. Thus, present results suggest that the local expression of chemosensory modulators and pro-inflammatory cytokines in the CB may have different temporal contribution to the CB chemosensory potentiation induced by CIH.

Topics: Animals; Carotid Body; Cytokines; Disease Models, Animal; Endothelin-1; Hypoxia, Brain; Inflammation; Inflammation Mediators; Male; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Time Factors; Up-Regulation

Nephrotic syndrome induced by adriamycin (ADR) is an experimental model of glomerulosclerosis in humans. The AT(1) receptor for angiotensin II (Ang II) is involved in the renal expression of the nuclear factor-kappa B (NF-ΚB) during this nephrosis. NF-ΚB is a transcription factor for proinflammatory effects of Ang II; however, there is no information about the role of this receptor in the renal proinflammatory events in ADR nephrosis.. To determine the role of Ang II in ADR nephrosis, Sprague-Dawley rats were treated with ADR (6 mg/kg iv). One ADR group received oral losartan treatment (15 mg/kg gavage) 3 days before ADR injection and then daily for 4 weeks, and the other group water. Animals were sacrificed at week 4 and renal macrophage infiltration, ICAM-1, superoxide anion (O(2(-))) and Ang II expressions were analysed by indirect immunofluorescence and histochemical techniques.. ADR rats showed increased expression of ICAM-1, Ang II, O(2(-)) and macrophage infiltration, events that were diminished by losartan treatment. Ang II expression remained unaltered after antagonist treatment. Proteinuria was reduced after 3 weeks of treatment.. These data suggest that Ang II plays a role in the inflammatory events during ADR-induced nephrosis, probably mediated by AT(1) receptors.

Topics: Angiotensin II; Animals; Cholesterol; Disease Models, Animal; Doxorubicin; Endothelin-1; Fluorescent Antibody Technique; Inflammation; Inflammation Mediators; Kidney; Losartan; Male; Nephrosis; Proteinuria; Rats; Rats, Sprague-Dawley; Time Factors; Triglycerides; Weight Gain

Autoimmune associated congenital heart block (CHB) may result from pathogenic cross-talk between inflammatory and profibrosing pathways. Incubation of macrophages with immune complexes (IC) composed of Ro60, a target of the pathologic maternal autoantibodies necessary for CHB, hY3 ssRNA, and affinity-purified anti-Ro60 antibody induces the Toll-like receptor 7 (TLR7)-dependent generation of supernatants that provoke a fibrosing phenotype in human fetal cardiac fibroblasts. We show herein that these cells are a major source of TGFβ and that endothelin-1 (ET-1) is one of the key components responsible for the profibrosing effects generated by stimulated macrophages. Supernatants from macrophages incubated with IC induced the fibroblast secretion of TGFβ, which was inhibited by treating the macrophages with an antagonist of TLR7. Under the same conditions, the induced fibroblast secretion of TGFβ was decreased by inhibitors of the ET-1 receptors ETa or ETb or by an anti-ET-1 antibody but not by an isotype control. Exogenous ET-1 induced a profibrosing phenotype, whereas fibroblasts transfected with either ETa or ETb siRNA were unresponsive to the profibrosing effects of the IC-generated macrophage supernatants. Immunohistochemistry of the hearts from two fetuses dying with CHB revealed the presence of ET-1-producing mononuclear cells in the septal region in areas of calcification and fibrosis. In conclusion, these data support a novel role of ET-1 in linking TLR7 inflammatory signaling to subsequent fibrosis and provide new insight in considering therapeutics for CHB.

Topics: Antibodies; Autoimmunity; Endothelin-1; Female; Fibroblasts; Fibrosis; Flow Cytometry; Heart Block; Humans; Inflammation; Leukocytes, Mononuclear; Macrophages; Ribonucleoproteins; Toll-Like Receptor 7; Transforming Growth Factor beta

Topics: Angioplasty, Balloon, Coronary; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Artery Disease; Endothelin-1; Female; Humans; Inflammation; Inflammation Mediators; Male; Myocardial Infarction; Ventricular Function, Left

Chronic obstructive pulmonary disease (COPD) is characterized by the presence of a low-grade systemic inflammation that is implicated in the pathogenesis of numerous extrapulmonary manifestations, such as hypogonadism. Endothelin-1 (ET-1) is a molecule that demonstrates pro-inflammatory properties and can augment the airway and systemic inflammation. Single nucleotide polymorphisms (SNPs) of the ET-1 gene that increase ET-1 serum levels are an important area of investigation. We examined the alterations in inflammatory markers [C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)] and in the levels of testosterone, free testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) in a group of male COPD smokers when compared to their age-matched controls and how these alterations relate to the presence of a functional ET-1 SNP, the adenine insertion SNP +138 insA/delA.. In this case control study, 80 male control smokers and 82 male COPD smokers were recruited for comparison. Among the male COPD smokers, 37 were carriers of the +138 insA/delA SNP. Two COPD subgroups according to genotype were formed: (1) A group of 45 males homozygous for the wild type allele (3A/3A) and (2) a group of 37 males heterozygous for the mutant allele (3A/4A).. Levels of testosterone and free testosterone were lower in the COPD group and even lower in the 3A/4A COPD group. CRP and ESR levels were higher in both COPD groups, but their elevation was statistically significant only for the 3A/4A COPD group. Testosterone and free testosterone levels correlated positively with PaO2 for both COPD groups. An inverse correlation between testosterone and CRP was demonstrated for the 3A/4A COPD subgroup.. Levels of testosterone correlated to FEV1, hypoxemia and weakly to CRP. The synchronous presence of the +138 insA/delA SNP resulted in even greater sex hormone level decline probably due to the presence of a more intense systemic inflammation.

Topics: C-Reactive Protein; Case-Control Studies; Endothelin-1; Follicle Stimulating Hormone; Forced Expiratory Volume; Genotype; Gonadal Steroid Hormones; Humans; Inflammation; Luteinizing Hormone; Male; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Smoking

The levels of C-reactive protein (CRP), tumor necrosis factor (TNF)-α, brain natriuretic peptide (BNP) and endothelin-1 (ET-1) were investigated to analyze the systemic inflammation in chronic obstructive pulmonary disease (COPD) patients with and without pulmonary hypertension.. From January 2006 to December 2010, 89 patients with COPD were enrolled in our hospital. There were 67 males and 22 females, with a mean age of (70 ± 7) and a mean FEV(1) of (47 ± 13)%. Pulmonary pressure was assessed by Doppler echocardiography. The levels of plasma BNP, TNF-α and ET-1 were measured by enzyme-linked immunosorbent assay kits. High-sensitivity plasma CRP level was assessed by chemiluminescent immunoassay.. Forty-two patients were classified as COPD with pulmonary hypertension group and 47 patients as COPD without pulmonary hypertension group. The level of CRP [51.4 mg/L (20.1 - 92.0) mg/L], ET-1 [5.9 ng/L (3.7 - 10.4) ng/L] and BNP [303.2 ng/L (112.5 - 824.7) ng/L] in patients with pulmonary hypertension were significantly higher than in that in patients without hypertension, CRP [26.7 mg/L (11.5 - 62.9) mg/L], ET-1 [2.1 ng/L (1.3 - 4.7) ng/L] and BNP [143.7 ng/L (85.5 - 306.7) ng/L]. The level of TNF-α showed no difference between the 2 groups [8.5 ng/L (4.8 - 13.7) ng/L and 6.7 ng/L (3.2 - 10.3) ng/L], respectively. Multivariate analysis showed that PaO₂ (P < 0.05), CRP (P < 0.05) and BNP (P < 0.05) could predict pulmonary hypertension independently.. The level of CRP, ET-1 and BNP were related to pulmonary hypertension in COPD patients, suggesting that systemic inflammation play a role in the pathogenesis of pulmonary hypertension in COPD.

Topics: Aged; C-Reactive Protein; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Inflammation; Inflammation Mediators; Male; Middle Aged; Natriuretic Peptide, Brain; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

Endotoxemia and/or systemic inflammation may lead to disturbances in the cardiac autonomic nervous system and consequent arrhythmia. The underlying mechanism remains unclear. Therefore, we investigated the expression of nerve growth factor (NGF) and its association with cardiac sympathovagal balance in a rodent model of self-limited peritonitis. Male Wistar rats were randomized into the following groups: normal control, sham, gastric perforation (GP), and GP treated with methylprednisolone. Cardiac expression of NGF, growth-associated protein 43 (GAP43), along with other nerve markers were evaluated at several time points (6 h to 2 weeks) after GP. An autoregressive process was performed on each detrended electrocardiogram to calculate the heart rate power spectrum. Compared with the normal control and sham groups, expression of NGF was significantly elevated for 1 week after GP. We also found the up-regulated GAP43 and tyrosine hydroxylase protein levels in the GP group, which persisted after recovery from peritonitis. Gastric perforation caused a biphasic change in the ratio of low-frequency to high-frequency power (an index of sympathovagal balance), with an initial decrease followed by recovery at 24 h. Increased NGF and cardiac sympathetic marker expression were temporally associated with the restoration of the cardiac sympathovagal balance. Methylprednisolone abrogated the NGF up-regulation induced by GP and delayed the resumption of sympathovagal balance. We conclude that GP resulted in up-regulation of cardiac NGF, GAP43, and tyrosine hydroxylase expression that coincided with recovery of cardiac sympathovagal balance. Moreover, methylprednisolone can effectively block GP-induced NGF up-regulation.

Topics: Animals; Anti-Inflammatory Agents; Autonomic Pathways; Blotting, Western; C-Reactive Protein; Endothelin-1; Enzyme-Linked Immunosorbent Assay; GAP-43 Protein; Heart Rate; Inflammation; Interleukin-6; Male; Methylprednisolone; Nerve Growth Factor; Peritonitis; Polymerase Chain Reaction; Random Allocation; Rats; Rats, Wistar

The related inflammatory cytokines, interleukin- (IL-) 1beta and IL-33, are both implicated in the response of the heart to injury. They also activate mitogen-activated protein kinases (MAPKs) in cardiac myocytes. The hypertrophic Gq protein-coupled receptor agonist endothelin-1 is a potentially cardioprotective peptide and may modulate the inflammatory response. Endothelin-1 also stimulates (MAPKs) in cardiac myocytes and promotes rapid changes in expression of mRNAs encoding intercellular and intracellular signalling components including receptors for IL-33 (ST2) and phosphoprotein phosphatases. Prior exposure to endothelin-1 may specifically modulate the response to IL-33 and, more globally, influence MAPK activation by different stimuli. Neonatal rat ventricular myocytes were exposed to IL-1beta or IL-33 with or without pre-exposure to endothelin-1 (5h) and MAPK activation assessed. IL-33 activated ERK1/2, JNKs and p38-MAPK, but to a lesser degree than IL-1beta. Endothelin-1 increased expression of soluble IL-33 receptors (sST2 receptors) which may prevent binding of IL-33 to the cell-surface receptors. However, pretreatment with endothelin-1 only inhibited activation of p38-MAPK by IL-33 with no significant influence on ERK1/2 and a small increase in activation of JNKs. Inhibition of p38-MAPK signalling following pretreatment with endothelin-1 was also detected with IL-1beta, H(2)O(2) or tumour necrosis factor alpha (TNFalpha) indicating an effect intrinsic to the signalling pathway. Endothelin-1 pretreatment suppressed the increase in expression of IL-6 mRNA induced by IL-1beta and decreased the duration of expression of TNFalpha mRNA. Coupled with the general decrease in p38-MAPK signalling, we conclude that endothelin-1 attenuates the cardiac myocyte inflammatory response, potentially to confer cardioprotection.

Topics: Animals; Endothelin-1; Enzyme Activation; Gene Expression Regulation; In Vitro Techniques; Inflammation; Interleukins; Myocytes, Cardiac; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction

In this study, we evaluated the potential anti-fibrotic property of neferine, a bisbenzylisoquinline alkaloid extracted from the seed embryo of Nelumbo mucifera Gaertn. Intratracheal bleomycin administration resulted in pulmonary fibrosis 14 and 21 days posttreatment, as evidenced by increased hydroxyproline content in bleomycin group (255.77+/-97.17 microg/lung and 269.74+/-40.92 microg/lung) compared to sham group (170.78+/-76.46 microg/lung and 191.24+/-60.45 microg/lung), and the hydroxyproline was significantly suppressed (193.07+/-39.55 microg/lung and 201.08+/-71.74 microg/lung) by neferine administration (20mg/kg, b.i.d). The attenuated-fibrosis condition was also validated by histological observations. Biochemical measurements revealed that bleomycin caused a significant decrease in lung superoxidae dismutase (SOD) activity, which was accompanied with a significant increase in malondialdehyde (MDA) levels and myeloperoxidase (MPO) activity on the 7th and 14th days. However, neferine reversed the decrease in SOD activity as well as the increase in MDA and MPO activity. Enzyme-linked immunosorbent assay and radio-immunity assay showed that treatment with neferine alleviated bleomycin-induced increase of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and endothelin-1 in plasma or in tissue. Additionally, neferine blocked bleomycin-induced increases of NF-kappaB in nuclear extracts and TGF-beta(1) in total protein extracts of murine RAW264.7 macrophages. In summary, neferine attenuates bleomycin-induced pulmonary fibrosis in vitro and in vivo. The beneficial effect of neferine might be associated with its activities of anti-inflammation, antioxidation, cytokine and NF-kappaB inhibition.

Topics: Animals; Benzylisoquinolines; Bleomycin; Cell Line; Cell Proliferation; Cytokines; Endothelin-1; Gene Expression Regulation; Hydroxyproline; Inflammation; Interleukin-6; Mice; NF-kappa B; Oxidative Stress; Pulmonary Fibrosis; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Placenta growth factor (PlGF) is released by immature erythrocytes and is elevated in sickle cell disease (SCD). Previous data generated in vitro suggest that PlGF may play a role in the pathophysiology of SCD-associated pulmonary hypertension (PHT) by inducing the release of the vasoconstrictor, endothelin-1. In this cross-sectional study of 74 patients with SCD, we confirm that PlGF is significantly elevated in SCD compared with healthy control subjects. We found significantly higher levels of PlGF in SCD patients with PHT but observed no association of PlGF with the frequency of acute pain episodes or history of acute chest syndrome. The observed correlation between PlGF and various measures of red cell destruction suggests that hemolysis, and the resultant erythropoietic response, results in the up-regulation of PlGF. Although relatively specific, PlGF, as well as N-terminal pro-brain natriuretic peptide and soluble vascular cell adhesion molecule, has low predictive accuracy for the presence of PHT. Prospective studies are required to conclusively define the contribution of PlGF to the pathogenesis of PHT and other hemolytic complications in SCD.

Topics: Adult; Anemia, Sickle Cell; Case-Control Studies; Cross-Sectional Studies; Endothelin-1; Female; Hemolysis; Humans; Hypertension, Pulmonary; Inflammation; Male; Middle Aged; Placenta Growth Factor; Predictive Value of Tests; Pregnancy Proteins; Prognosis; Young Adult

Hypertensive disorders of pregnancy are characterized by systemic and placental inflammation; however, treatment for these conditions has remained elusive. We tested whether administration of the anti-inflammatory cytokine interleukin-10 (IL-10) during pregnancy would attenuate the hypertension, endothelial dysfunction, proteinuria, and inflammation seen in pregnant DOCA/saline-treated (PDS) rats. Normal pregnant (NP) rats and PDS were given daily intraperitoneal injections of recombinant IL-10 from gestational day 13 until death on day 20. Systolic blood pressure, aortic endothelium-dependent relaxation responses, and urinary protein excretion were measured on days 13 and 20 of gestation. Fetal number and development, plasma endothelin-1 levels, serum and placental levels of IFNgamma and IL-10, and aortic and placental levels of platelet endothelial cell adhesion molecule (PECAM) were assessed on gestational day 20. Systolic blood pressure, aortic endothelial dysfunction, and urinary protein excretion were significantly increased at gestational day 13 in PDS rats. However, all of these were restored to NP levels following IL-10 treatment in PDS rats. IL-10 treatment also significantly increased the number of pups per litter in PDS rats and did not further affect fetal development. The beneficial effects of IL-10 in PDS rats were likely mediated by the decreased plasma levels of endothelin-1, decreased levels of circulating and placental IFNgamma, as well as decreased aortic and placental expression of PECAM. These data demonstrate that exogenous IL-10 can normalize blood pressure and endothelial function in pregnancy-induced hypertensive rats and may be beneficial in women with hypertensive disorders of pregnancy.

Topics: Animals; Aorta; Blood Pressure; Congenital Abnormalities; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Female; Hypertension, Pregnancy-Induced; Inflammation; Interferon-gamma; Interleukin-10; Litter Size; Male; Placenta; Platelet Endothelial Cell Adhesion Molecule-1; Pre-Eclampsia; Pregnancy; Proteinuria; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Animal and clinical studies have suggested that polyphenols in fruits, red wine, and tea may delay the development of atherosclerosis through their antioxidant and anti-inflammatory properties. We investigated whether individual dietary polyphenols representing different polyphenolic classes, namely quercetin (flavonol), (-)-epicatechin (flavan-3-ol), theaflavin (dimeric catechin), sesamin (lignan), or chlorogenic acid (phenolic acid), reduce atherosclerotic lesion formation in the apolipoprotein E (ApoE)(-/-) gene-knockout mouse.. Quercetin and theaflavin (64-mg/kg body mass daily) significantly attenuated atherosclerotic lesion size in the aortic sinus and thoracic aorta (P<0.05 versus ApoE(-/-) control mice). Quercetin significantly reduced aortic F(2)-isoprostane, vascular superoxide, vascular leukotriene B(4), and plasma-sP-selectin concentrations; and augmented vascular endothelial NO synthase activity, heme oxygenase-1 protein, and urinary nitrate excretion (P<0.05 versus control ApoE(-/-) mice). Theaflavin showed similar, although less extensive, significant effects. Although (-)-epicatechin significantly reduced F(2)-isoprostane, superoxide, and endothelin-1 production (P<0.05 versus control ApoE(-/-) mice), it had no significant effect on lesion size. Sesamin and chlorogenic acid treatments exerted no significant effects. Quercetin, but not (-)-epicatechin, significantly increased the expression of heme oxygenase-1 protein in lesions versus ApoE(-/-) controls.. Specific dietary polyphenols, in particular quercetin and theaflavin, may attenuate atherosclerosis in ApoE(-/-) gene-knockout mice by alleviating inflammation, improving NO bioavailability, and inducing heme oxygenase-1. These data suggest that the cardiovascular protection associated with diets rich in fruits, vegetables, and some beverages may in part be the result of flavonoids, such as quercetin.

Topics: Animals; Anti-Inflammatory Agents; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Biflavonoids; Biomarkers; Catechin; Chlorogenic Acid; Cholesterol; Diet; Dioxoles; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; F2-Isoprostanes; Fatty Acids; Flavonoids; Heme Oxygenase-1; Inflammation; Leukotriene B4; Lignans; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type III; Nitrites; Oxidative Stress; P-Selectin; Phenols; Polyphenols; Quercetin; Superoxides

Although Nox5 (Nox2 homolog) has been identified in the vasculature, its regulation and functional significance remain unclear.. We sought to test whether vasoactive agents regulate Nox5 through Ca(2+)/calmodulin-dependent processes and whether Ca(2+)-sensitive Nox5, associated with Rac-1, generates superoxide (O(2)(*-)) and activates growth and inflammatory responses via mitogen-activated protein kinases in human endothelial cells (ECs).. Cultured ECs, exposed to angiotensin II (Ang II) and endothelin (ET)-1 in the absence and presence of diltiazem (Ca(2+) channel blocker), calmidazolium (calmodulin inhibitor), and EHT1864 (Rac-1 inhibitor), were studied. Nox5 was downregulated with small interfering RNA. Ang II and ET-1 increased Nox5 expression (mRNA and protein). Effects were inhibited by actinomycin D and cycloheximide and blunted by diltiazem, calmidazolium and low extracellular Ca(2+) ([Ca(2+)](e)). Ang II and ET-1 activated NADPH oxidase, an effect blocked by low [Ca(2+)](e), but not by EHT1864. Nox5 knockdown abrogated agonist-stimulated O(2)(*-) production and inhibited phosphorylation of extracellular signal-regulated kinase (ERK)1/2, but not p38 MAPK (mitogen-activated protein kinase) or SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal kinase). Nox5 small interfering RNA blunted Ang II-induced, but not ET-1-induced, upregulation of proliferating-cell nuclear antigen and vascular cell adhesion molecule-1, important in growth and inflammation.. Human ECs possess functionally active Nox5, regulated by Ang II and ET-1 through Ca(2+)/calmodulin-dependent, Rac-1-independent mechanisms. Nox5 activation by Ang II and ET-1 induces ROS generation and ERK1/2 phosphorylation. Nox5 is involved in ERK1/2-regulated growth and inflammatory signaling by Ang II but not by ET-1. We elucidate novel mechanisms whereby vasoactive peptides regulate Nox5 in human ECs and demonstrate differential Nox5-mediated functional responses by Ang II and ET-1. Such phenomena link Ca(2+)/calmodulin to Nox5 signaling, potentially important in the regulation of endothelial function by Ang II and ET-1.

Topics: Angiotensin II; Calcium; Calcium Channel Blockers; Calmodulin; Cells, Cultured; Diltiazem; Endothelial Cells; Endothelin-1; Enzyme Activation; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Humans; Imidazoles; Inflammation; JNK Mitogen-Activated Protein Kinases; Membrane Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NADPH Oxidase 5; NADPH Oxidases; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proliferating Cell Nuclear Antigen; Pyrones; Quinolines; rac1 GTP-Binding Protein; RNA Interference; RNA, Messenger; Signal Transduction; Superoxides; Time Factors; Vascular Cell Adhesion Molecule-1

Several new biomarkers are related to mortality in community-acquired pneumonia (CAP).. Aim of this study was to compare new biomarkers for the prediction of short- and long-term all-cause mortality in CAP.. We enrolled 728 patients (59.0 ± 18.2 yr) with CAP. Midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), proarginin-vasopressin (copeptin), proendothelin-1 (CT-proET-1), procalcitonin (PCT), C-reactive protein, white blood cell (WBC) count, and clinical confusion, respiratory rate, blood pressure, and age over 65 years (CRB-65) score were determined on admission. Patients were followed up for 180 days.. In patients who died of any cause within 28 and 180 days (2.5 and 5.1%, respectively), MR-proADM, MR-proANP, copeptin, CT-proET-1 and PCT as well as CRB-65 were significantly higher compared with survivors. MR-proADM had the best performance for 28 days (HR 3.67) and 180 days (HR 2.84) survival. The C index of MR-proADM for 28-day survival (0.85) was superior to MR-proANP (0.81), copeptin (0.78), CT-proET-1 (0.79), and CRB-65 (0.72) for the prediction of mortality. For prediction of mortality at 180 days, the C index of MR-proADM (0.78) was higher than that for MR-proANP (0.74), copeptin (0.73), CT-proET-1 (0.76), PCT, C-reactive protein, and white blood cells. MR-proADM was independent of CRB-65, and added prognostic information for short- and long-term mortality. MR-proADM was an independent and strong predictor of short- and long-term mortality.. All new biomarkers were good predictors of short- and long-term all-cause mortality, superior to inflammatory markers, and at least comparable to CRB-65 score. MR-proADM showed the best performance. A combination of CRB-65 with MR-proADM might be the best predictor for mortality.

Topics: Adolescent; Adrenomedullin; Adult; Age Distribution; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Community-Acquired Infections; Comorbidity; Endothelin-1; Female; Germany; Humans; Inflammation; Leukocyte Count; Male; Middle Aged; Pneumonia; Predictive Value of Tests; Protein Precursors; Respiratory Rate; Survival Analysis; Vasopressins; Young Adult

Endothelin (ET) 1 is a potent vasoactive peptide implicated in the pathogenesis of hypertension and renal disease. The aim of the current study was to test the hypotheses that ET-1 increases albumin permeability of glomeruli isolated from normal rats and that chronic ET-1 infusion will increase glomerular permeability and inflammation independent of blood pressure. Glomerular permeability to albumin was determined from the change in glomerular volume induced by exposing isolated glomeruli to oncotic gradients. Incubation of glomeruli taken from normal rats with ET-1 at a concentration that did not produce direct glomerular contraction (1 nmol/L) significantly increased glomerular permeability to albumin, reaching a maximum after 4 hours. Chronic ET-1 infusion for 2 weeks in Sprague-Dawley rats significantly increased glomerular permeability to albumin and nephrin excretion rate, effects that were attenuated in rats given an ET(A) receptor antagonist (ABT-627, 5 mg/kg per day). Urinary protein and albumin excretion and mean arterial pressure (telemetry) were not changed by ET-1 infusion. Acute incubation of glomeruli isolated from ET-1-infused rats with the selective ET(A) antagonist significantly reduced glomerular permeability to albumin, an effect not observed with acute treatment with a selective ET(B) antagonist. Chronic ET-1 infusion increased glomerular and plasma soluble intercellular adhesion molecule 1 and monocyte chemoattractant protein 1 and elevated the number of macrophages and lymphocytes in renal cortices (ED-1 and CD3-positive staining, respectively). These effects were all attenuated in rats given an ET(A) selective antagonist. These data support the hypothesis that ET-1 directly increases glomerular permeability to albumin and renal inflammation via ET(A) receptor activation independent of changes in arterial pressure.

Topics: Analysis of Variance; Animals; Atrasentan; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Immunoassay; Immunohistochemistry; Inflammation; Kidney Glomerulus; Male; Permeability; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Endothelin

Clinical data has shown that stroke exacerbates dementia in Alzheimer's disease (AD) patients. Previous work, combining rat models of AD and stroke have shown that neuroinflammation may be the common mediator between AD and stroke toxicity. This study examined the effects of triflusal (2-acetoxy-4-trifluoromethylbenzoic acid) in APP(23) transgenic mice receiving strokes. Six month-old APP(23) mice over-expressing mutant human amyloid precursor protein (APP) were used to model AD in this study. Unilateral injections of a potent vasoconstrictor, endothelin-1, into the striatum were used to mimic small lacunar infarcts. Immunohistochemical analysis was performed to examine AD-like pathology and inflammatory correlates of stroke and AD. APP(23) mice showed increases in AD-like pathology and inflammatory markers of AD in the cortex and hippocampus. Endothelin-induced ischemia triggered an inflammatory response along with increases in AD pathological markers in the region of the infarct. Triflusal reduced inflammation surrounding the endothelin-induced infarct only. At the dose used, anti-inflammatory treatment may be beneficial in reducing the AD and inflammatory correlates of stroke in a combined AD-stroke mouse model.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antigens, CD; Brain Ischemia; Disease Models, Animal; Endothelin-1; Humans; Inflammation; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B; Platelet Aggregation Inhibitors; Salicylates; Stroke; tau Proteins; Tumor Necrosis Factor-alpha

Patients with sickle cell disease (SCD) exhibit a chronic inflammatory state manifested by leukocytosis and increased circulating levels of proinflammatory cytochemokines. Our studies show that placenta growth factor levels are high in SCD, and placental growth factor induces the release of the vasoconstrictor endothelin-1 (ET-1) from pulmonary microvascular endothelial cells. In this study, we observed that ET-1 increased the expression of the chemokines MIP-1β or CCL4. ET-1-induced MIP-1β mRNA expression in THP-1 cells and human peripheral blood monocytes occurred via the activation of PI3K, NADPH oxidase, p38 MAPK, and JNK-1 but not JNK-2. ET-1-induced MIP-1β expression involved hypoxia-inducible factor-1α (HIF-1α), independent of hypoxia, as demonstrated by silencing with HIF-1α small interfering RNA, EMSA, and chromatin immunoprecipitation analysis. ET-1-induced MIP-1β promoter luciferase activity was attenuated when any of the five hypoxia-response elements, AP-1, or NF-κB binding motifs in the proximal MIP-1β promoter (-1053/+43 bp) were mutated. Furthermore, ET-1 significantly downregulated the expression of a key microRNA, microRNA-195a, which showed a complementary binding site in the 3' untranslated region of MIP-1β mRNA. Moreover, ET-1-induced MIP-1β mRNA expression in either THP-1 cells or peripheral blood monocytes was reduced upon expression of microRNA-195a. Conversely, transfection of monocytes with anti-microRNA-195a oligonucleotide augmented several-fold ET-1-induced MIP-1β expression. Taken together, these studies showed that ET-1-mediated MIP-1β gene expression is regulated via hypoxia-response elements, AP-1, and NF-κB cis-binding elements in its promoter and negatively regulated by microRNA-195, which targets the 3' untranslated region of MIP-1β RNA. These studies provide what we believe are new avenues, based on targets of HIF-1α and microRNAs, for ameliorating inflammation in SCD.

Topics: 3' Untranslated Regions; Anemia, Sickle Cell; Blotting, Western; Cell Line; Chemokine CCL4; Chromatin Immunoprecipitation; Electrophoretic Mobility Shift Assay; Endothelin-1; Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; MicroRNAs; Monocytes; Mutagenesis, Site-Directed; NF-kappa B; Promoter Regions, Genetic; RNA, Small Interfering; Transcription Factor AP-1; Transfection

The adipocytokines leptin and adiponectin represent a critical link between metabolism, immunity and chronic inflammation. A chronic vascular inflammatory state plays an important role in the pathophysiology of thalassaemia. We aimed to analyze the levels of these adipocytokines and determine any possible correlations with disease severity or vascular inflammation markers in beta-thalassaemia.. Serum leptin, adiponectin, high-sensitivity C-reactive protein, endothelins, vascular adhesion molecule-1, intracellular adhesion molecule-1 and L- and E-selectin were measured in 28 beta-thalassaemia patients and compared with levels in healthy controls.. Leptin was significantly lower in patients compared to controls (2.23 ± 1.8 vs. 10.24 ± 5.78 μg/l; p = 0.0018), whereas adiponectin was elevated (11.75 ± 5.67 vs. 6.83 ± 2.75 μg/l; p = 0.009). For both adipocytokines, no correlations were found with characteristics such as age, gender, type of chelation, body mass index z score or haemoglobin. Leptin, but not adiponectin, was negatively correlated with ferritin (p = 0.032, r = -0.61). No correlations were found between leptin and the inflammation markers. However, adiponectin was positively correlated with endothelin-1 (p = 0.022, r = 0.63).. Serum leptin is low in beta-thalassaemia, perhaps due to the toxic effect of iron overload on adipose tissue. Paradoxically, adiponectin levels are high and positively correlated with endothelin-1, raising questions about the pro- or anti-inflammatory role of this adipocytokine in beta-thalassaemia.

Topics: Adipokines; Adiponectin; Adolescent; Adult; Aging; beta-Thalassemia; Biomarkers; Blood Transfusion; Body Mass Index; C-Reactive Protein; Chelating Agents; Child; Endothelin-1; Endothelin-3; Female; Ferritins; Humans; Inflammation; Intercellular Adhesion Molecule-1; Leptin; Male; Middle Aged; Vascular Cell Adhesion Molecule-1

Endothelin may contribute to the development of inflammatory events such as leukocyte recruitment and nociception. Herein, we investigated whether endothelin-mediated mechanical hypernociception (decreased nociceptive threshold, evaluated by electronic pressure-meter) and neutrophil migration (myeloperoxidase activity) are inter-dependent in antigen challenge-induced Th1-driven hind-paw inflammation. In antigen challenge-induced inflammation, endothelin (ET) ET(A) and ET(B) receptor antagonism inhibited both hypernociception and neutrophil migration. Interestingly, ET-1 peptide-induced hypernociception was not altered by inhibiting neutrophil migration or endothelin ET(B) receptor antagonism, but rather by endothelin ET(A) receptor antagonism. Furthermore, endothelin ET(A), but not ET(B), receptor antagonism inhibited antigen-induced PGE(2) production, whereas either selective or combined blockade of endothelin ET(A) and/or ET(B) receptors reduced hypernociception and neutrophil recruitment caused by antigen challenge. Concluding, this study advances knowledge into the role for endothelin in inflammatory mechanisms and further supports the potential of endothelin receptor antagonists in controlling inflammation.

Topics: Animals; Chemotaxis, Leukocyte; Dinoprostone; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hyperalgesia; Inflammation; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; Pain Measurement; Pressure; Skin

The objective of this study was to evaluate traditional risk factors for cardiovascular disease (CVD) and endothelin-1 (ET-1) levels in Takayasu arteritis (TA) patients. Twenty-two TA patients and 37 controls were evaluated. TA patients had a higher prevalence of hypertension (63.6% vs. 21.6%, p=0.001) and higher levels of triglycerides (129.5 mg/dL+/-70.8 vs. 88.4 mg/dL+/-60.8, p=0.017) than controls. Mean number of CVD risk factors was 1.64+/-1.22 in TA patients and 1.03+/-1.44 among controls, p=0.030. More TA patients presented at least one CVD risk factor when compared to controls (77.2% vs. 51.3%, p=0.048). ET-1 levels were higher in patients than in controls (1.49 pg/mL+/-0.45 vs. 1.27 pg/mL+/-0.32, p=0.034), however no significant difference was found between patients with active and inactive disease. In this study, TA patients presented a higher prevalence of hypertension, higher levels of triglycerides, and ET-1 than controls.

Topics: Adult; Atherosclerosis; Cardiovascular Diseases; Endothelin-1; Female; Humans; Hypertension; Inflammation; Male; Middle Aged; Risk Factors; Takayasu Arteritis; Treatment Outcome; Triglycerides

Although endothelin-1 (ET-1) has been suggested to contribute to the pathogenesis of neointima formation and atherosclerosis, the individual roles of ET-1 derived from certain cell types in this disease remain unclear. In this study, we determined the role of vascular endothelial ET-1 on vascular inflammation and neointima formation using vascular endothelial ET-1-knockout [ET-1(f/f); Tie2-Cre (+)] mice.. Intimal hyperplasia was induced by complete ligation of the left carotid artery in 12-week-old male ET-1(f/f);Tie2-Cre (+) mice (n = 35) and the wild-type (WT) littermates (n = 34). Following this intervention, neointima formation was reduced in ET-1(f/f);Tie2-Cre (+) mice compared with the WT mice, independent of the difference in blood pressure. This reduction was associated with a decrease in inflammatory cell recruitment to the vessel wall, which was accompanied by reduced expression levels of endothelial adhesion molecules as well as chemokines and a decrease in vascular smooth muscle cell proliferation.. The results of our study provide direct evidence for the role of vascular endothelial ET-1 in mediating vascular inflammation and neointima formation following vascular injury in addition to promoting vasoconstriction and cell proliferation. Furthermore, this study suggests a strategy for the efficient design of ET receptor antagonists with targeted inhibition of ET-1 signalling in vascular endothelial cells.

Topics: Animals; Blood Pressure; Carotid Arteries; Carotid Artery Injuries; Cell Adhesion Molecules; Cell Proliferation; Chemotaxis, Leukocyte; Disease Models, Animal; Endothelial Cells; Endothelin-1; Heart Rate; Hyperplasia; Inflammation; Integrases; Ligation; Macrophages; Male; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Receptor, TIE-2; Receptors, Endothelin; Regional Blood Flow; Time Factors; Tunica Intima

The literature shows an increase in endothelin-1 with increased levels of erythrocytes. There are also indications that inflammation and elevated endothelin-1 levels interact with erythropoiesis. In this study, the association of erythrocytes and endothelin-1 in women of different ethnicities was investigated. Blood pressure, vascular resistance, and C-reactive protein (P = 0.09) were significantly higher in the African women (n = 102) compared to the Caucasian women (n = 115), while arterial compliance was significantly lower in the African women with no significant differences for endothelin-1. In single, partial, and multiple regression analyses, there was a significant positive correlation between the red blood cell count and log endothelin-1 in the Caucasians while in the Africans there was a weak negative correlation. This is an indication that endothelin-1 might interfere with erythrocyte production in Africans with higher levels of inflammation.

Topics: Adult; Black People; Blood Pressure; C-Reactive Protein; Endothelin-1; Erythrocyte Count; Female; Humans; Inflammation; South Africa; Vascular Resistance; White People

Adrenomedullin (ADM) and endothelin-1 (ET-1) are novel promising peptide biomarkers in chronic heart failure (CHF). According to recent studies among their pleiotropic effect they play roles in the regulation of inflammation. The aim of the study was to measure the above mentioned two vasoactive peptides in parallel in a well characterized population of patients with CHF, and study their associations with inflammatory markers.. A total of 186 patients (138 male, 48 female) with <45% left ventricular ejection fraction (LVEF), and without acute inflammatory disease, were enrolled. Plasma midregional-proADM (MR-proADM) and C-terminal-proET-1 (CT-proET-1) were determined by a novel sandwich immunoluminometric assay.. Increased MR-proADM and CT-proET-1 plasma levels were measured in patients with severe CHF (NYHA III-IV) as compared to the group of NYHA I-II (p<0.0001). MR-proADM and CT-proET-1 levels showed significant negative correlation with serum albumin and prealbumin levels (p

Topics: Adrenomedullin; Aged; Biomarkers; Chronic Disease; Cross-Sectional Studies; Endothelin-1; Female; Heart Failure; Humans; Inflammation; Male; Middle Aged; Ventricular Dysfunction, Left

Chronic inflammation contributes to the development and progression of chronic kidney disease (CKD). Identifying renal inflammation early is important. There are currently no specific markers of renal inflammation. Endothelin-1 (ET-1) is implicated in the pathogenesis of CKD. Thus, we investigated the impact of progressive renal dysfunction and renal inflammation on plasma and urinary ET-1 concentrations. In a prospective study, plasma and urinary ET-1 were measured in 132 subjects with CKD stages 1 to 5, and fractional excretion of ET-1 (FeET-1) was calculated. FeET-1, serum C-reactive protein (CRP), urinary ET-1:creatinine ratio, and urinary albumin:creatinine ratio were also measured in 29 healthy volunteers, 85 subjects with different degrees of inflammatory renal disease but normal renal function, and in 10 subjects with rheumatoid arthritis without renal involvement (RA). In subjects with nephritis associated with systemic lupus erythematosus (SLE), measurements were done before and after 6 mo of treatment. In subjects with CKD, plasma ET-1 increased linearly as renal function declined, whereas FeET-1 rose exponentially. In subjects with normal renal function, FeET-1 and urinary ET-1:creatinine ratio were higher in SLE subjects than in other groups (7.7 +/- 2.7%, 10.0 +/- 3.0 pg/mumol, both P < 0.001), and correlated with CRP, and significantly higher than in RA subjects (both P < 0.01) with similar CRP concentrations. In SLE patients, following treatment, FeET-1 fell to 3.6 +/- 1.4% (P < 0.01). Renal ET-1 production increases as renal function declines. In subjects with SLE, urinary ET-1 may be a useful measure of renal inflammatory disease activity while measured renal function is still normal.

Topics: Adult; Aged; Biomarkers; Endothelin-1; Female; Humans; Inflammation; Kidney Failure, Chronic; Lupus Nephritis; Male; Middle Aged; Young Adult

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia and dyslipidemia. The abnormalities in nutrient metabolism and elevated inflammatory mediators resulting from DM lead to impairment of wound healing and vulnerability to infection and foot ulcers. Diabetic lower limb ischemia often leads to limb necrosis. Lower extremity bypass surgery (LEBS) is indicated to prevent limb loss in patients with critical leg ischemia. This study investigated the alteration of inflammatory and endothelium dysfunction markers before and after LEBS in DM patients. Twenty one type 2 DM patients with LEBS were included. Blood was drawn before and at 1 day and 7 days after surgery in the patients. Plasma soluble cellular adhesion molecule levels and blood leukocyte integrin expressions were measured. Also, plasma concentrations of endothelin-1 and nitric oxide were analyzed to evaluate the vascular endothelial function. The results showed that there were no significant differences in plasma cellular adhesion molecules, endothelin-1 and nitric oxide levels, nor did any differences in leukocyte integrin expressions before and after the operation. These results suggest that the efficacy of LEBS on alleviating inflammatory reaction and improving endothelial function in DM patients was not obvious.

Topics: Aged; Biomarkers; Cell Adhesion Molecules; Diabetes Mellitus, Type 2; Endothelin-1; Endothelium, Vascular; Female; Humans; Inflammation; Integrins; Ischemia; Leg; Leukocytes; Male; Middle Aged; Nitric Oxide; Postoperative Period

Sub-Saharan Africa is afflicted by high hypertension prevalence that is expected to rise even further along with increasing obesity rates. The present study aimed to investigate the role of visfatin in obesity and to explore associations of visfatin with markers of endothelial function and hemodynamics in African women compared to a well-matched white sample. The present study involved urban African (n = 102) and white (n = 115) women from South Africa, individually matched for age and BMI. We measured blood pressure, cardiac output, and arterial compliance noninvasively, and analyzed visfatin as well as circulating markers of vascular function and inflammation in serum. Serum visfatin concentration did not differ between African and white women. Visfatin was unrelated to obesity in African women but positive associations for total and abdominal obesity were found in white women. Age- and obesity-adjusted univariate and multivariate analyses revealed significant positive associations of visfatin with endothelin-1 and fibrinogen in African women. Identical analyses in white women indicated a positive association of visfatin with C-reactive protein and von Willebrand factor. Our findings suggest a possible role of visfatin in the cardiovascular system that seems to be independent of obesity in the African women.

Topics: Adult; Biomarkers; Black People; C-Reactive Protein; Endothelin-1; Endothelium, Vascular; Female; Fibrinogen; Humans; Inflammation; Nicotinamide Phosphoribosyltransferase; Obesity; Obesity, Abdominal; South Africa; von Willebrand Factor; White People; Young Adult

Ghrelin is a newly discovered peptide as an endogenous ligand for the growth hormone secretagogue receptor, and has been demonstrated to exert beneficial effect in the cardiovascular system. In the present study, we investigated whether ghrelin administration could inhibit cardiac neural remodeling and sympathetic hyperinnervation after myocardial infarction. Sprague-Dawley rats underwent coronary ligation to induce myocardial infarction and receiving ghrelin chronically (100 microg/kg s.c., twice daily) or saline control for 4 weeks after onset of ischemia. Four weeks after treatment, rats were sacrificed. We examined the expression of nerve growth factor and never markers as well as the mRNA expressions of inflammatory mediators in the infarcted border and non-infarcted left ventricular free wall. We also examined the NF-kappaBp65 protein and I-kappaBalpha protein levels by Western blot analysis. Compared to the control group, ghrelin administration significantly decreased the density of nerve fibers with positive immunostaining for GAP43 and TH, and decreased NGF mRNA and protein levels in the infarcted border and the non-infarcted area. Ghrelin also significantly suppressed interleukin-1beta, tumor necrosis factor-alpha, and endothelin-l mRNA expression, and inhibited NF-kappaB activation. In conclusion, treatment with ghrelin inhibited neural remodeling and sympathetic hyperinnervation, the process that may be associated with the inhibition of proinflammatory response and NGF signaling.

Topics: Animals; Endothelin-1; Gene Expression Regulation; Ghrelin; Inflammation; Interleukin-1beta; Male; Myocardial Infarction; Nerve Growth Factor; NF-kappa B; Protein Transport; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Sympathetic Nervous System; Tumor Necrosis Factor-alpha

ATP-driven efflux transport proteins at the blood-brain barrier protect the healthy brain but impede pharmacotherapy of the disordered CNS. To investigate the question how ATP-binding cassette (ABC)-transporters are regulated during inflammation or infection we analysed the effects of the cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) on the expression of brain multidrug resistance proteins in primary cultures of porcine brain capillary endothelial cells. We found that TNF-alpha and IL-1beta rapidly decrease Abcg2 (BMDP/BCRP) mRNA expression within 6 h. After 24 and 48 h the mRNA level came back to control values. The mRNA reduction at 6 h was counter-regulated by the anti-inflammatory glucocorticoid hydrocortisone. Abcg2 protein levels were suppressed at prolonged stimulations but not after 6 h of stimulation which correlates with Abcg2 specific substrate uptake measurements. Abcb1 (p-glycoprotein) protein expression was transiently increased after TNF-alpha addition within 6 h of incubation followed by a reduction after 24 and 48 h whereas the Abcb1 mRNA levels were not changed. IL-1beta caused a continuous decrease in protein expression of both ABC-transporters. Long-term treatment with an assumed TNF-alpha-downstream agent, the vasoconstrictor endothelin-1, induced Abcg2 protein expression but suppressed Abcb1. Other efflux pumps like multidrug resistance-associated proteins/Abcc were rarely affected. The present results imply a complex regulation of the two most abundant ABC-transporters at the blood-brain barrier during early inflammation stages suggesting that Abcb1 (p-glycoprotein) is an early target of TNF-alpha-signalling counterbalanced by Abcg2.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents; ATP-Binding Cassette Transporters; Blood-Brain Barrier; Brain; Cells, Cultured; Electric Impedance; Endothelial Cells; Endothelin-1; Gene Expression Regulation; Hydrocortisone; Inflammation; Interleukin-1beta; Swine; Time Factors; Tumor Necrosis Factor-alpha

To observe the effect of Wenyang Yiqi Pingchuan Recipe (WYPR) on the pathomorphology of lung and its regulation on lung tissue contents of nitric oxide (NO) and endothelin-1 (ET-1) in rats with bronchial asthma.. Sixty SD rats were randomly divided into 6 groups: the normal group, the model group, and the four treated groups treated with high dose WYPR, low dose WYPR, Guilong Kechuanning Capsule and aminophylline, respectively, 10 in each group. Except those in the normal group, all rats of bronchial asthma model were established by egg protein sensitization and provocated by inhalation. The treatments were given via gastrogavage every day starting from the first provocation (the 3rd week of modeling) to the execution. Rats were sacrificed after 4-week treatment, their lung was taken for determining the contents of NO and ET-1, and histopathological changes in lung were observed as well.. Compared with the normal group, the contents of NO and ET-1 in the lung tissue, the thickness of bronchus wall and bronchus smooth muscle, the number of eosinophil granulocytes increased in the model group and the low dose WYPR group, showing statistical significance (P < 0. 01). As compared with the model group, all the above-mentioned indices were lower in all the 4 treated groups (P < 0.05 or P < 0.01), but the lowering in the WYPR treated groups (either high or low dose) was more significant than in the Guilong Kechuanning treated group (P < 0.05 or P < 0.01); while compared with the aminophylline treated group, the high dose WYPR group was superior in reducing eosinophile granulocytes (P < 0.01), but no significance between them was shown in NO and ET-1 levels (P > 0.05).. WYPR could reduce the eosinophilic infiltration, decrease the contents of NO and ET-1 in the lung tissue, restrain the air passage inflammation and inhibit the pathological process as airway remodeling.

Topics: Animals; Asthma; Drugs, Chinese Herbal; Endothelin-1; Inflammation; Lung; Nitric Oxide; Rats; Rats, Sprague-Dawley

Necrotizing enterocolitis (NEC) has high morbidity in premature infants. Hypoxia-ischemia, infection, and enteral feeding are risk factors associated with NEC, whereas feeding human milk is protective. Vasoactive and inflammatory mediators in NEC remain elusive. Gangliosides are found in human milk and enterocyte membranes. An infant bowel model of NEC was developed to test the hypothesis that gangliosides modulate the inflammatory response to infection and hypoxia.. Viable, noninflamed bowel was obtained from 9 infants between 26 and 40 weeks' gestational age. Infant bowel was treated in culture with Escherichia coli lipopolysaccharide (LPS) and hypoxia in the presence or absence of preexposure to gangliosides. Bowel necrosis and production of nitric oxide, endothelin-1, serotonin, eicosanoids, hydrogen peroxide, and proinflammatory cytokines were measured.. Ganglioside preexposure reduced bowel necrosis and endothelin-1 production in response to LPS. Gangliosides suppressed infant bowel production of nitric oxide, leukotriene B4, prostaglandin E2, hydrogen peroxide, interleukin-1beta, interleukin-6, and interleukin-8 in response to LPS exposure and hypoxia.. A bowel protective effect of gangliosides is indicated by modulation of vasoactive mediators and proinflammatory signal suppression.

Topics: Animals; Anti-Inflammatory Agents; Colon; Endothelin-1; Enterocolitis, Necrotizing; Escherichia coli; Gangliosides; Humans; Hypoxia; In Vitro Techniques; Infant, Newborn; Inflammation; Inflammation Mediators; Lipopolysaccharides; Milk; Necrosis

We recently demonstrated that endothelin-1 (ET-1) was strongly expressed in inflamed gingival tissues, but the biological role of ET-1 in gingival tissue remains unknown. This study focused on the relationship between ET-1 and interleukin-1beta (IL-1beta), an important cytokine during the periodontal inflammatory process. We determined the protein levels of ET-1 and IL-1beta in gingival tissues from patients and examined whether ET-1 could regulate the expression of the IL-1beta gene and protein in oral epithelial cells and fibroblasts in vitro. There was a significant correlation between the levels of ET-1 and IL-1beta in 26 gingival tissues, as determined by ELISA. Following the confirmation of two specific ET-1 receptors (ETA and ETB receptors) on the cultured cells, the effects of ET-1 stimulation on IL-1beta mRNA and protein expression were evaluated by RT-PCR and ELISA, respectively. The IL-1beta mRNA and protein levels were enhanced by ET-1 stimulation in a dose-dependent manner, and the enhancement of IL-1beta was inhibited by ETA or ETB receptor antagonists. These findings indicate that ET-1 is involved in the regulation of IL-1beta expression in gingival tissues and suggest that ET-1 signaling to the cells may be a therapeutic target for treating IL-1beta-dependent inflammatory responses.

Topics: Adult; Cells, Cultured; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Fibroblasts; Gene Expression Regulation; Gingiva; Humans; Inflammation; Interleukin-1beta; Male; Young Adult

Premature delivery occurs in 12% of all births and accounts for nearly half of long-term morbidity. Current therapeutic approaches to preterm delivery are ineffective and present serious risks to both mother and fetus. The single most common cause of preterm birth is infection. Previous in vitro investigations have shown that endothelin-1 (ET-1) is induced by inflammatory cytokines and that it increases myometrial smooth muscle tone. Furthermore, we have previously shown that both the endothelin-converting enzyme-1 (ECE-1) inhibitor, phosphoramidon, as well as a novel ET-1 receptor A antagonist synthesized by our group, control premature delivery in a mouse model of inflammation-associated preterm delivery. In the current work, we show that levels of both ET-1 and ECE-1 are increased in gestational tissues in E16.5 mice induced to deliver prematurely after lipopolysaccharide administration. We also show that premature delivery is controlled by treatment with the selective endothelin receptor A antagonist BQ-123 in a dose-dependent manner. Finally, we show here for the first time that premature delivery can be controlled using RNA silencing, by hydrodynamic transfection of E15 mice with ECE-1 RNAi. Taken together, these data support a critical role for the ECE-1/ET-1 system in inflammation-associated premature delivery. The ability to control premature delivery by antagonizing or silencing the ECE-1/ET-1 system offers a novel approach to an unmet clinical need.

Topics: Animals; Aspartic Acid Endopeptidases; Endothelin A Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Female; Immunohistochemistry; Inflammation; Lipopolysaccharides; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Models, Animal; Obstetric Labor, Premature; Peptides, Cyclic; Placenta; Pregnancy; Premature Birth; RNA, Small Interfering; Uterus

Endothelins are well known as modulators of inflammation in the periphery, but little is known about their possible role in brain inflammation. Stimulation of astrocyte prostaglandin, an inflammatory mediator, synthesis was shown so far only by endothelin 3 (ET-3). By contrast, several studies showed no change or slight decrease of basal nitric oxide synthesis after treatment of astrocytes with endothelin 1 (ET-1) and ET-3. However, a significant increase in astrocytic and microglial nitric oxide synthase (NOS) was observed after exposure to ET-1 and ET-3 in a model of forebrain ischaemia. Here we demonstrate that all three endothelins (ET-1, ET-2, ET-3) significantly enhanced the synthesis of prostaglandin E(2) and nitric oxide in glial cells. Each of the selective antagonists for ETA and ETB receptors (BQ123 and BQ788 respectively), significantly inhibited endothelins-induced production of both nitric oxide and prostaglandin E(2). These results suggest a regulatory mechanism of endothelins, interacting with both endothelin receptors, on glial inflammation. Therefore, inhibition of endothelin receptors may have a therapeutic potential in pathological conditions of the brain, when an uncontrolled inflammatory response is involved.

Topics: Animals; Astrocytes; Cells, Cultured; Dinoprostone; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelin-3; Inflammation; Neuroglia; Nitric Oxide; Nitric Oxide Synthase; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Receptor, Endothelin A; Receptor, Endothelin B

During the inflammatory response, activation of G-protein coupled receptors (GPCRs) by inflammatory mediators rapidly leads to inhibition of gap junction intercellular communication (GJIC); however, the steps that lead to this inhibition are not known. Combining high-resolution fluorescence microscopy and functional assays, we found that activation of the GPCRs PAR-1 and ET(A/B) by their natural inflammatory mediator agonists, thrombin and endothelin-1, resulted in rapid and acute internalization of gap junctions (GJs) that coincided with the inhibition of GJIC followed by increased vascular permeability. The endocytosis protein clathrin and the scaffold protein ZO-1 appeared to be involved in GJ internalization, and ZO-1 was partially displaced from GJs during the internalization process. These findings demonstrate that GJ internalization is an efficient mechanism for modulating GJIC in inflammatory response.

Topics: Clathrin; Endocytosis; Endothelin-1; Endothelium, Vascular; Gap Junctions; HeLa Cells; Humans; Inflammation; Membrane Proteins; Permeability; Phosphoproteins; Receptor, Endothelin A; Receptor, Endothelin B; Receptor, PAR-1; Receptors, G-Protein-Coupled; Thrombin; Zonula Occludens-1 Protein

To explore a novel nonspecific immunomodulation for the treatment of allergic airway inflammation by RNA interference for endothelin converting enzyme (ECE) using 12-alkylated chitosans/plasmid-encoding antisense ECE complex nanoparticles.. Forty BALB/c mice were randomly divided into Group N (normal control), Group NM (OVA + 12-ACSs/antisense-ECE plasmid), Group As (OVA) and Group DNA (OVA + antisense-ECE plasmid), and sensitized by intraperitoneal injection of OVA at day 1 and day 14, followed by challenge with aerosol of 1% OVA at day 24, 25 and 26, but with saline as a control (N). Supernatants from cultured splenocytes and lung homogenates were subjected to detection of the levels of interleukin-4, 5, 10, 13 (IL-4, 5, 10, 13), interferon-gamma (IFN-gamma) and endothelin-1 (ET-1) by using ELISA. Lung tissues were embedded, sliced and HE stained for histopathologic examination. The cultured splenocytes were subjected to flow cytometry detection (IL-4, IL-10 and IFN-gamma).. Mice in group NM showed a lower level of cell count than that in either group AS or group DNA. Compared with N group, the lung tissues taken from the mice in As and DNA groups displayed allergic inflammation with eosinophil infiltration, while the pulmonary inflammation was decreased significantly in group NM. The levels of ET-1, IL-4, IL-13 and IL-5 were down regulated in group NM compared to As and DNA groups (P < 0.05 or P < 0.01). After stimulation by OVA, the splenocytes from the mice in NM group produced a higher level of IL-10 than that from As and DNA groups (P < 0.05 or P < 0.01). The number of Th2 lymphocytes (CD(4)(+) T cells with IL-4 expression) was significantly elevated in the mice of As, DNA and NM groups respectively, while the number of Th2 lymphocytes was lower in the mice of group NM than in the mice of group As or group DNA. The number of CD(4)(+)CD(25)(+) cells with IL-10 expression was up-regulated in the mice of As, DNA and NM groups respectively compared to the control. The percentage of T regulating cells was higher in the mice of group NM compared with that in the mice of group As or group DNA. No detectable difference in the level of Th1 cells (CD(4)(+) T cells with IFN-gamma expression) was found among the 4 groups.. 12-ACSs can encapsulate and deliver antisense-ECE expression plasmid into bronchial epithelial cells in vitro and 12-ACSs/antisense ECE plasmid complex nanoparticles have the capability to down regulate the synthesis of ET-1 and thus decrease the allergic airway inflammation in OVA-sensitized mice.

Topics: Animals; Aspartic Acid Endopeptidases; Chitosan; Endothelin-1; Endothelin-Converting Enzymes; Female; Inflammation; Metalloendopeptidases; Mice; Mice, Inbred BALB C; Nanoparticles; Plasmids; Pneumonia; Respiratory Hypersensitivity

Antenatal infections are associated with an increased risk of perinatal morbidity and mortality. Systemic application of endotoxins to the fetus results in an increase in placental vascular resistance and chronic reduction in umbilical blood flow. We studied morphological alterations of the placenta in response to fetal inflammation in the preterm sheep.. Therefore, 14 fetal sheep were chronically instrumented at a mean gestational age of 107+/-1 days (term is 147 days). Four days after surgery fetuses received 100 ng lipopolysaccharide (LPS; n=8) or saline (control; n=6) intravenously. Fetal heart rate and arterial blood pressure were monitored continuously while blood gases and acid-base balance were measured at time points 0, +1, +3, +6, +12, +24, +48 and +72 h. Three days after LPS application placental cotyledons were analyzed by immunohistochemistry and morphometry. Different primary antibodies like AE 1 and AE 3 against cytokeratins were used. Secondary antibodies were visualized with 3-amino-9-ethylcarbazole (AEC) or using the Vectastain kit (Vector Laboratories, Burlingame, CA). Double staining was carried out first by utilizing Vectastain kit (black), followed by AEC staining (red). Counterstaining was performed with haematoxylin.. Fetal tachycardia and hypertension were induced transiently during the first 12h after LPS application. Fetuses suffered from mild hypoxaemia while acidemia was absent. Morphometry revealed a non-significant shift in the relation of maternal and fetal placental compartments towards the maternal parts in response to LPS treatment. Endotoxin induced an increased proliferation in both compartments of the placenta with a 3.2-fold increase on the maternal and a 1.8-fold increase on the fetal side.. Systemic endotoxin exposure of the preterm fetal sheep leads to a change in the gross organization of the placenta and changes in the proliferation patterns in both placental compartments. These rearrangements inside the placenta may disturb its organ function and subsequently lead to fetal morbidity associated with the fetal inflammatory response syndrome and chronic placental dysfunction, respectively.

Topics: Acid-Base Equilibrium; Animals; Blood Pressure; Endothelin-1; Female; Fetus; Heart Rate, Fetal; Inflammation; Lipopolysaccharides; Placenta; Pregnancy; Sheep

Studies suggest that the inflammatory cytokine TNF-alpha plays a role in the prognosis of end-stage renal diseases. We previously showed that TNF-alpha inhibition slowed the progression of hypertension and renal damage in angiotensin II salt-sensitive hypertension. Thus, we hypothesize that TNF-alpha contributes to renal inflammation in a model of mineralocorticoid-induced hypertension. Four groups of rats (n = 5 or 6) were studied for 3 wk with the following treatments: 1) placebo, 2) placebo + TNF-alpha inhibitor etanercept (1.25 mg.kg(-1).day(-1) sc), 3) deoxycorticosterone acetate + 0.9% NaCl to drink (DOCA-salt), or 4) DOCA-salt + etanercept. Mean arterial blood pressure (MAP) measured by telemetry increased in DOCA-salt rats compared with baseline (177 +/- 4 vs. 107 +/- 3 mmHg; P < 0.05), and TNF-alpha inhibition had no effect in the elevation of MAP in these rats (177 +/- 8 mmHg). Urinary protein excretion significantly increased in DOCA-salt rats compared with placebo (703 +/- 76 vs. 198 +/- 5 mg/day); etanercept lowered the proteinuria (514 +/- 64 mg/day; P < 0.05 vs. DOCA-salt alone). Urinary albumin excretion followed a similar pattern in each group. Urinary monocyte chemoattractant protein (MCP)-1 and endothelin (ET)-1 excretion were also increased in DOCA-salt rats compared with placebo (MCP-1: 939 +/- 104 vs. 43 +/- 7 ng/day, ET-1: 3.30 +/- 0.29 vs. 1.07 +/- 0.03 fmol/day; both P < 0.05); TNF-alpha inhibition significantly decreased both MCP-1 and ET-1 excretion (409 +/- 138 ng/day and 2.42 +/- 0.22 fmol/day, respectively; both P < 0.05 vs. DOCA-salt alone). Renal cortical NF-kappaB activity also increased in DOCA-salt hypertensive rats, and etanercept treatment significantly reduced this effect. These data support the hypothesis that TNF-alpha contributes to the increase in renal inflammation in DOCA-salt rats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Chemokine CCL2; Desoxycorticosterone; Disease Models, Animal; Endothelin-1; Etanercept; Hypertension; Immunoglobulin G; Inflammation; Kidney; Kidney Diseases; Male; Mineralocorticoids; NF-kappa B; Rats; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

Discovery of treatments to protect axonal function of neurons and prevent permanent disability associated with progressive multiple sclerosis (MS) has faced the uphill challenge of assessing relatively small changes in accumulated axon damage within a background environment that is disorganized by CNS inflammation. We hypothesized that transient immunosuppression after initiation of MS-like autoimmune mechanisms would disassociate development of MS-like myelinated axon pathology from development of CNS inflammation in a rat model of autoimmune optic neuritis (AON). A rat model of myelin oligodendrocyte glycoprotein peptide-induced AON was transiently treated (on days 3-7 after antigen exposure) with 5-(4-phenylbutoxy)psoralen (PAP-1), an immunomodulatory drug previously shown specifically to suppress proliferation of effector memory T-cells and immunoglobulin class-switched B-cells. Thirteen days after antigen exposure, optic nerves were harvested for quantitative assessment of 12 MS-associated pathologies using microfluorimetry. With one exception, the immunoreactivities (-ir) for eight markers of MS-like neuroinflammation and immune infiltration were significantly reduced (P < 0.05) by transient PAP-1 treatment, often to levels significantly below those detected in normal control rat optic nerves. With one exception, four immunoreactive markers of MS-like myelinated axon pathology were detected at levels indicating increased axon/myelin pathology compared with vehicle-treated rats with AON (P < 0.05). These data suggest the conclusion that early causative mechanisms in CNS autoimmunity initiate signaling mechanisms that diverge into two separate pathways, one that is strongly associated with inflammatory responses and one that is associated predominantly with disturbed axon-myelin interactions and impaired fast axonal transport.

Topics: Animals; Autoimmune Diseases; Endothelin-1; Female; Ficusin; Inflammation; Interleukin-1; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Optic Neuritis; Pancreatitis-Associated Proteins; Rats; Rats, Inbred BN

Accumulation of neutrophils in brain after transient focal stroke remains controversial with some studies showing neutrophils to be deleterious, whereas others suggest neutrophils do not contribute to ischemic injury. Myeloperoxidase (MPO) has been used extensively as a marker for quantifying neutrophil accumulation, but is an indirect method and does not detect neutrophils alone. To elucidate the interaction of macrophages in the neutrophil inflammatory response, we conducted double-label immunofluorescence in brain sections at 0, 1, 2, 3, 7, and 15 days after ischemia. Each of these results was obtained from the same animal to determine correlations between neutrophil infiltration and ischemic damage. It was found that MPO activity increased up to 3 days after cerebral ischemia. Dual-staining revealed that macrophages engulf neutrophils in the brain and that this engulfment of neutrophils increased with time, with 50% of neutrophils in the brain engulfed at 3 days and approximately 85% at 15 days (N=5, P<0.05). Interestingly, at 7 days the amount of dual-staining was decreased to 20% (N=5, P<0.05). Neutrophil infiltration was positively correlated with ischemic damage in both the cortex and striatum (r(2)=0.86 and 0.80, respectively, P<0.01). The results of this study indicate that the MPO from neutrophils phagocytized by macrophages may continue to contribute to the overall MPO activity, and that previous assessments that have utilized this marker to measure neutrophil accumulation may have mis-calculated the number of neutrophils within the ischemic territory and hence their contribution to the evolution of the infarct at later time points. Thus any biphasic infiltration of neutrophils may have been masked by the accumulation of macrophages.

Topics: Animals; Brain Ischemia; Endothelin-1; Fluorescent Antibody Technique; Immunohistochemistry; Infarction, Middle Cerebral Artery; Inflammation; Macrophages; Male; Microscopy, Confocal; Middle Cerebral Artery; Neutrophil Infiltration; Peroxidase; Rats; Rats, Long-Evans; Stereotaxic Techniques

Several inflammatory biomarkers are linked to cardiovascular risk. In order to investigate their coexistence and relative responses, several established and two novel markers (lactoferrin and the terminal complement complex), representing infection and central components of inflammation, were measured simultaneously in patients undergoing first-time coronary angiography.. Blood samples from patients with (n=131) or without (n=103) significant coronary artery stenosis were analyzed for plasma markers representing endothelium, platelets, neutrophils, monocytes, and complement, C-reactive protein, and antibodies against the infectious agents Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus. In multivariate logistic regression analysis, hypercholesterolemia (p<0.001), increased concentrations of the neutrophil activation marker lactoferrin (p<0.001) and the monocyte activation marker neopterin (p=0.012), lower concentrations of the terminal complement complex (p<0.001), and antibodies against C. pneumoniae (p=0.023) were variables linked to coronary artery stenosis. In univariate analysis additional relationships were found to current smoking (p<0.001), increased plasma concentrations of vascular cell adhesion molecule-1 (p=0.015), E-selectin (p<0.01), myeloperoxidase (p=0.051) and endothelin-1 (p=0.053), as well as diabetes (p=0.039).. Activation of multiple inflammatory pathways and C. pneumoniae infection may influence the inflammatory response in atherosclerosis. These pilot data provide an indication of the relative usefulness of various inflammatory biomarkers, indicating that the novel markers lactoferrin and the terminal complement complex warrant further investigation.

Topics: Analysis of Variance; C-Reactive Protein; Chi-Square Distribution; Complement Membrane Attack Complex; Coronary Angiography; Coronary Artery Disease; E-Selectin; Endothelin-1; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Lactoferrin; Logistic Models; Male; Middle Aged; Neopterin; Peroxidase; Risk Factors; Vascular Cell Adhesion Molecule-1

Ischemic preconditioning may provide a systemic organ protection, evident as the phenomenon known as remote preconditioning. Unstable angina may be a clinical analogue to ischemic preconditioning. Vein graft harvesting induces inflammation of the graft wall. We hypothesized that preoperative unstable angina preconditions vein grafts and reduces the inflammatory response to graft harvesting. Consecutive patients with stable or unstable angina undergoing open heart surgery (n = 12 in each group) were studied. Saphenous vein biopsies were collected at the start of graft harvesting, and when the last proximal anastomosis to the aorta was finished (average 112 minutes later). Gene expression of inflammatory mediators (tumor necrosis factor alpha, interleukin-1beta (IL-1beta), E-selectin (CD62E), intercellular leukocyte adhesion molecule 1, inducible nitric oxide synthase, endothelin-1) increased after surgical handling (semiquantitative RT-PCR). In vein grafts from unstable patients the increase was attenuated for Il-1beta (p < 0.004) and CD62E (p < 0.001). In stable patients the protein expression of IkappaBalpha and heat shock protein72 was reduced by surgical handling (p < 0.04), but was not influenced in unstable patients (immunoblotting). In vitro relaxation to acetylcholine was enhanced, and contractions to phenylephrine and endothelin-1 were attenuated in veins rings from unstable patients (p < 0.003). In conclusion, surgical handling of vein grafts induces inflammation of the vessel wall. This response was reduced in grafts from patients with unstable angina, indicating a possible systemic preconditioning-like effect of acute coronary syndromes.

Topics: Aged; Angina Pectoris; Angina, Unstable; Cell Adhesion Molecules; E-Selectin; Endothelin-1; Female; Gene Expression; Gene Expression Regulation; HSP72 Heat-Shock Proteins; Humans; I-kappa B Proteins; Inflammation; Interleukin-1beta; Ischemic Preconditioning; Male; Middle Aged; Nitric Oxide Synthase; Reverse Transcriptase Polymerase Chain Reaction; Saphenous Vein; Tumor Necrosis Factor-alpha; Ventricular Remodeling

The aim of this study was to investigate the effect of lycopene on the vascular endothelial function and the expression of inflammatory agents in hyperhomocysteinemic rats. Fifty male Sprague-Dawley rats weighed 145- 155g were on a commercial rat chow diet for seven days, and then were randomized into five groups: normal control group (NC) fed with AOAC diet and four hyperhomocysteinemic groups fed with AOAC diet plus 3% L-methionine. Four hyperhomocysteinemic groups were daily supplemented with 0 (HC), 10 mg/kg (HL1), 15 mg/kg (HL2), 20 mg/kg (HL3) lycopene dissolved in corn oil respectively by intragastric administration for 12 weeks. At the end of experiment, their blood and abdominal aortas were collected after etherization. Serum levels of Hcy were determined by HPLC, nitric oxide (NO) and nitric oxide synthase (NOS) by chromatometry, endothelin- 1 (ET-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) by ELISA. Hematoxylin and eosin staining and oil red staining were used to analyze abdominal aortas histologically. Moderate hyperhomocysteinemia was induced in hyperhomocysteinemic groups. Serum level of NO was lower and ET-1 was higher in HC rats than in NC, NL2 and NL3 rats (p<0.01). There was no difference of serum NOS activity among five groups. There were some foam cells and depositions of lipochondria in aortic tunica intima in HC and HL1 rats, which were not found in HL2 and HL3 rats. Serum levels of VCAM-1, MCP-1, IL-8 were higher in HC rats than in NC, NL1, NL2 and NL3 rats (p<0.01). The present study indicated that lycopene exerts an antiatherogenic effect by inhibiting the expression of inflammatory agents in hyperhomocysteninemic rats.

Topics: Animals; Antioxidants; Aorta, Abdominal; Carotenoids; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Hyperhomocysteinemia; Inflammation; Lycopene; Male; Methionine; Nitric Oxide; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; Vascular Cell Adhesion Molecule-1

Feeding high fructose (Frc) to rats induces a moderate increase in blood pressure, which is associated with insulin resistance. The present study was designed to evaluate the effect of the methanol extract of Sorbus commixta cortex (MSC) on vascular inflammation in a rat model of the metabolic syndrome induced by a high Frc-diet. Male Sprague-Dawley rats were divided into 4 groups and treated for 7 weeks as follows: 1) control, 2) high Frc-diet group, 3) Frc/MSC1 group; high Frc-diet group treated with MSC (100 mg/kg/day), and 4) Frc/MSC2 group; high Frc-diet group treated with MSC (200 mg/kg/day). High Frc-induced decreases of the expression level of aortic endothelial nitric oxide synthase (ecNOS) while the production of cyclic GMP (cGMP) was restored by treatment with MSC. On the contrary, increases of the expression level of endothelin-1 (ET-1) in the aorta, the transcription factor, the cytokine related with vascular inflammation, and the adhesion molecules were suppressed by MSC treatment. Moreover, MSC treatment was shown to lessen the thickening noted in the aortic intima and media of the high Frc-diet group. Our findings suggest that MSC may have an anti-vascular inflammatory effect on rats with a high Frc-induced metabolic syndrome.

Topics: Animals; Aorta, Thoracic; Cell Adhesion Molecules; Cyclic GMP; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Fructose; Guanosine Monophosphate; Inflammation; Male; Metabolic Syndrome; Methanol; NF-kappa B; Nitrites; Plant Extracts; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sorbus; Sweetening Agents; Triglycerides; Tunica Intima; Tunica Media

Endothelin-1 (ET-1) is a major transcriptional activator of renal proximal tubule cells acting in an autocrine and paracrine manner. In animal studies, ET-1 has been implicated in progressive renal interstitial fibrosis by promoting gene expression, possibly via the inflammatory NF-kappaB signal pathway. While ET-1-dependent mechanisms of signal transduction have been studied mainly in tumor cell lines, we analyzed the mechanism of ET-1-induced, NF-kappaB-mediated target gene activation in proximal tubule cells.. Human renal proximal tubule cells were stimulated with ET-1 and gene expression analyzed by protein microarray, Western blot, non-radioactive electromobility shift assay, and quantitative real-time polymerase chain reaction.. Activation of NF-kappaB occurs only via an ET-1-specific type A receptor (not type B as in animals). Induction can be blocked by bosentan, and endothelin-A but not endothelin-B receptor-specific antagonists. Protein microarray screening shows activation of two independent cascades (via the endothelin-A receptor, or via diacylglycerol) leading to NF-kappaB induction. The independent induction is also reflected by target gene expression such as the vascular cell adhesion molecule-1, interleukin-6, and fractalkine at different time points.. Thus prohibiting ET-1-mediated gene transcription necessitates blocking of NF-kappaB and diacylglycerol signal transduction in proximal tubule cells.

Topics: Cells, Cultured; Diglycerides; Endothelin-1; Epithelial Cells; Gene Expression; Gene Expression Profiling; Humans; Inflammation; Kidney Tubules, Proximal; NF-kappa B; Receptor, Endothelin A; Receptor, Endothelin B; Signal Transduction

Bronchial asthma is a chronic inflammatory disease of the respiratory tract where variety of cells plays a role, particularly mast cells, eosinophils (Eo), and T lymphocytes. At present, there is no clear-cut clinical or laboratory parameter to monitor the activity of this disease. Our study was designed to examine and compare serum eosinophilic cationic protein (S-ECP) levels, plasma ET-1 (P-ET) levels and percentage of eosinophils with CD44 (EoCD44) in paediatric asthmatic patients.. In our study, a group of 97 atopic children with persisting mild asthma, had a detailed analysis of their personal history. In addition, S-ECP, P-ET, EoCD44, eosinophil blood count (Eo) and serum levels of IgE(S-IgE) in peripheral blood were determined. Subsequently, children were treated with montelukast (singular), a leukotriene receptor antagonist for a period of three weeks (montelukast tablets in a dose of 5 mg once a day). A second S-ECP, P-ET, EoCD44 were determined in the interval of 3 months from the first collection. In 97 asthmatic children a correlation between P-ET and EoCD44 (p=0.002; r= -0.5) were found.. Our follow-up study surprisingly confirmed a correlation between P-ET and EoCD44. The lower percentage of EoCD44 in peripheral blood in asthmatic children is due to Eo inflammation activity and attests the massive Eo invasion into the airways. The determination of combination - S-ECP, P-ET, EoCD44 - provides an indirect evidence of the multiple features of Eo inflammation.

Topics: Adolescent; Asthma; Child; Child, Preschool; Endothelin-1; Eosinophil Cationic Protein; Eosinophils; Female; Humans; Hyaluronan Receptors; Inflammation; Male

Endothelin-1 (ET-1), a potent vasoconstrictor peptide, is involved in several functions of eye pathophysiology, such as regulation of intraocular tension and retinal reactive vasoconstriction. As ET-1 pro-inflammatory and fibrosing activity is emerging in different fields of pathology, we investigated the expression of ET-1 and endothelin-converting enzyme-1 (ECE-1) in chalazia, granulomatous lesions of the eyelid. ET-1 and ECE-1 were analyzed by immunohistochemistry (IHC) in twenty surgically removed chalazia, with regard to expression in eyelid structures and inflammatory infiltrate. Phenotype of ET-1 expressing inflammatory cells was established by double immunofluorescence. The cellular localization of prepro-ET-1 (pp-ET-1) mRNA and ECE-1 mRNA was studied by nonisotopic in situ hybridization (ISH). Neutrophils (PMNs), macrophages and T-lymphocytes were scattered in stroma, around alveoli and grouped in lipogranulomas. PMNs, macrophages, basal epithelium of meibomian adenomers and central ducts immunostained for ET-1. ECE-1 protein was found in meibomian adenomers, conjunctival epithelium, tarsal mucous glands and in inflammatory cells. Hybridization signals for pp-ET-1 mRNA and ECE-1 mRNA were recognized in healthy and degenerating meibomian ducts, adenomers, inflammatory cells, as well as in vessel walls. ECE-1 mRNA was also present in conjunctival epithelium and Henle's crypts. Our findings suggest that the multifunctional peptide ET-1 may have a role in molecular genesis of tissue damage in chalazia. ET-1 cytokine activity is likely to support the migration of inflammatory cells and the setting of lipogranulomas; ET-1 stimulation might contribute to proliferation of fibroblasts and collagen synthesis. ET-1 upregulation on meibomian adenomers and ducts may further enhance granulomas formation by stimulating lipid release.

Topics: Adolescent; Adult; Aged; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Eyelids; Female; Gene Expression Regulation; Granuloma; Humans; Immunohistochemistry; In Situ Hybridization; Inflammation; Male; Metalloendopeptidases; Middle Aged

To examine prospectively whether inflammatory biomarkers and endothelin (ET)-1 are increased in patients with renal artery stenosis (RAS), and to investigate how treatment with percutaneous transluminal renal angioplasty (PTRA) affects these variables during the first month after intervention.. One hundred patients with suspected RAS undergoing renal angiography were included. PTRA was performed if the trans-stenotic mean arterial pressure gradient was>or=10 mmHg. High-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha), neopterin, CD40 ligand (CD40L) and endothelin-1 (ET-1) were measured before, and 1 day and 1 month after PTRA (n=61) or diagnostic angiography only (n=39).. At baseline there were no significant differences in inflammatory biomarkers or ET-1 levels between patients subsequently undergoing PTRA or angiography only. After angiography, IL-6 and hs-CRP had increased in both groups compared to baseline (P<0.001). At this time point hs-CRP (10.90+/-1.48 versus 6.37+/-1.61 mg/l; P<0.05) and IL-6 (13.70+/-0.94 versus 13.00+/-0.17 pg/ml; P<0.01) were higher in the PTRA group than in patients subjected to angiography only. One month after PTRA, systolic blood pressure and levels of IL-6 and ET-1 were lower than before intervention (P<0.05), whereas CD40L had increased compared to baseline (P<0.01).. In patients with RAS, PTRA triggers rapid transient increases in hs-CRP and IL-6; however, 1 month after PTRA, both IL-6 and ET-1 had decreased compared to before intervention, indicating beneficial effects of PTRA on inflammation and the endothelin system.

Topics: Aged; Angioplasty; Biomarkers; Blood Pressure; Endothelin-1; Female; Humans; Inflammation; Interleukin-6; Kidney; Male; Middle Aged

Inflammatory response, axonal damage and demyelination are important components of the pathophysiology of acute neurodegenerative diseases. We have investigated the outcome of these pathological events following an excitotoxic or an ischemic damage to the spinal nucleus of adult rats at 1 and 7 days postinjury. Microinjections of 80 nmol of NMDA or 40 pmol of endothelin-1 into the rat spinal nucleus induced differential histopathological events. NMDA injection induced intense tissue loss in the gray matter (GM) without significant tissue loss in the white matter (WM). There was a mild inflammatory response, with recruitment of a few neutrophils and macrophages. Axonal damage was present in the GM following NMDA injection, with negligible axonal damage in the WM. Myelin impairment was apparent at 7 days. Microinjections of endothelin-1 into the same region induced lesser tissue loss than NMDA injections, concomitant with an intense inflammatory response characterized by recruitment of macrophages, but not of neutrophils. There were more axonal damage and early myelin impairment after endothelin-1 injection. These results were confirmed by quantitative analysis. Microcysts were present in the WM of the trigeminothalamic tract at 7 days following injection of endothelin-1. These results show that an ischemic damage to the spinal nucleus affects both GM and WM with more bystander inflammation, axonal damage and myelin impairment, while excitotoxic damage induces effects more restricted to the GM. These pathological events may occur following acute damage to the human brain stem and can be an important contributing factor to the underlying functional deficits.

Topics: Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Axons; Brain Ischemia; Cell Count; Demyelinating Diseases; Ectodysplasins; Endothelin-1; Inflammation; Male; Myelin Basic Protein; N-Methylaspartate; Neurotoxins; Rats; Rats, Wistar; Time Factors; Trigeminal Nucleus, Spinal

A complex network of regulatory neuropeptides controls airway inflammation reaction, in which airway epithelial cells adhering to and activating leukocytes is a critical step. To study the effect of intrapulmonary regulatory peptides on adhesion of polymorphonuclear leukocytes (PMNs) to bronchial epithelial cells (BECs) and its mechanism, several regulatory peptides including vasoactive intestinal peptide (VIP), epidermal growth factor (EGF), endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP), were investigated. The results demonstrated that VIP and EGF showed inhibitory effects both on the secretion of IL-1, IL-8 and the adhesion of PMNs to BECs, whereas ET-1 and CGRP had the opposite effect. Anti-intercellular adhesion molecule-1 (ICAM-1) antibody could block the adhesion of PMNs to ozone-stressed BECs. Using immunocytochemistry and reverse transcription-polymerase chain reaction (RT-PCR), it was shown that VIP and EGF down-regulated the expression of ICAM-1 in BECs, while ET-1 and CGRP up-regulated ICAM-1 expression. NF-kappaB inhibitor MG132 blocked ICAM-1 expression induced by ET-1 and CGRP. Furthermore, in electric mobility shift assay (EMSA), VIP and EGF restrained the binding activity of NF-kappaB to the NF-kappaB binding site within the ICAM-1 promoter in ozone-stressed BECs, while CGRP and ET-1 promoted this binding activity. IkappaB degradation was consistent with NF-kappaB activation. These observations indicate that VIP and EGF inhibit inflammation, while ET-1 and CGRP enhance the inflammation reaction.

Topics: Animals; Base Sequence; Bronchi; Calcitonin Gene-Related Peptide; Cell Adhesion; Cells, Cultured; Endothelin-1; Epidermal Growth Factor; Epithelial Cells; I-kappa B Kinase; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-8; Interleukins; Neutrophils; NF-kappa B; Peptides; Rabbits; Time Factors; Vasoactive Intestinal Peptide

Ischemic preconditioning (IP) and intermittent inflow occlusion (IO) have provided beneficial outcomes in hepatic resection. However, comparison of these two procedures against warm hepatic ischemia-reperfusion injury has not been studied enough.. Pigs that had undergone 65% hepatectomy were subjected to Control (120 min continuous ischemia, n = 6), IP (10 min ischemia and 10 min reperfusion, followed by 120 min continuous ischemia, n = 6), and IO (120 min ischemia in the form of eight successive periods of 15 min ischemia and 5 min reperfusion, n = 6). We evaluated hepatocyte injury by aspartate aminotransferase, lactate dehydrogenase and hepaplastin test, hepatic microcirculation by hepatic tissue blood flow (HTBF) and endothelin (ET)-1, inflammatory response by tumor necrosis factor-alpha (TNF-alpha), and histopathology after reperfusion.. IP prevented hepatocyte injury, HTBF disturbance, and hepatocyte necrosis in histopathology as well as IO. These two groups showed significantly better outcomes than Control. IP produced significantly less ET-1 and TNF-alpha than IO.. IP ameliorated hepatic warm ischemia-reperfusion injury. Furthermore, IP gained more advantages in preventing chemokine production such as ET-1 and inflammatory response over IO. IP could take the place of IO for hepatectomy.

Topics: Animals; Aspartate Aminotransferases; Blood Flow Velocity; Endothelin-1; Hepatectomy; Inflammation; Ischemic Preconditioning; L-Lactate Dehydrogenase; Liver; Male; Microcirculation; Necrosis; Postoperative Complications; Reperfusion Injury; Specific Pathogen-Free Organisms; Swine; Time Factors; Tumor Necrosis Factor-alpha

Inhalation of endothelin (ET)-A receptor antagonists has been shown to improve gas exchange in experimental acute lung injury (ALI) but may induce side effects by increasing circulating ET-1 levels. We investigated whether the inhaled ET(A) receptor antagonist, LU-135252, at low doses, improves gas exchange without affecting ET-1 plasma concentrations and lung injury in an animal model of ALI. Twenty-two piglets were examined in a prospective, randomized, controlled study. In anesthetized animals, ALI was induced by surfactant depletion. Animals received either LU-135252 at a dose of 0.3 mg/kg during 20 mins (LU group; n = 11), or nebulization of saline buffer (control group; n = 11). The Mann-Whitney U test was used to compare groups (P < 0.05). In the LU group, arterial partial pressure of oxygen (PaO2) and mean pulmonary artery pressure (MPAP) improved compared with the control group (PaO2, 319 +/- 44 mm Hg vs. 57 +/- 3 mm Hg; MPAP, 32 +/- 2 mm Hg vs. 41 +/- 2 mm Hg; values at 6 hrs after induction of ALI; P < 0.05). Mean arterial pressure and cardiac output were not different between groups. ET-1 plasma concentrations increased from 0.96 +/- 0.06 fmol/ml after induction of ALI to a maximum of 1.17 +/- 0.09 fmol/ml at 3 hrs after ALI onset in the LU group and did not differ significantly from the control group (1.21 +/- 0.08 fmol/ml, not significant). On histologic examination, we found no differences in total lung injury score between groups. However, the LU group revealed significantly reduced interstitial inflammation and hemorrhage (P < 0.05 vs. control group). In this animal model of ALI, inhalation of LU-135252 at a dose of 0.3 mg/kg induced a significant and sustained improvement in gas exchange, whereas there were no changes in ET-1 plasma concentrations. Furthermore, our data indicate a trend toward decreased pulmonary inflammation in the group receiving the inhaled ET(A) receptor antagonist.

Topics: Acute Disease; Administration, Inhalation; Animals; Blood Pressure; Cardiac Output; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin-1; Inflammation; Lung Diseases; Phenylpropionates; Prospective Studies; Pulmonary Gas Exchange; Pyrimidines; Random Allocation; Swine

Endothelin-1 (ET-1) is increasingly recognized as a proinflammatory mediator in various diseases, such as atherosclerosis and acute respiratory distress syndrome (ARDS). Angiopoietin-1 (Ang-1), a ligand of the endothelial receptor Tie2, inhibits endothelial apoptosis, reduces vascular leakage, and suppresses the induction of inflammatory markers, indicating that it has diverse vasoprotective, anti-inflammatory actions. Thus, we examined the effects of Ang-1 on ET-1 production in vitro and in vivo and investigated cell-based gene transfer of Ang-1 in a rat model of lipopolysaccharide (LPS)-induced ARDS. Cultured human endothelial cells were treated with recombinant Ang-1 with or without tumor necrosis factor-alpha (TNF-alpha) (100 U/ml). ET-1 release into the culture medium after 24 hrs was determined by enzyme-linked immunosorbent assay. Levels of preproendothelin-1 (ppET-1) mRNA were measured by quantitative reverse transcription-polymerase chain reaction. Fisher344 rats were subjected to cell-based gene transfer to the lung circulation by injecting syngeneic fibroblasts transfected with Ang-1 cDNA or a null plasmid vector. After 24 hrs, LPS (100 microg/kg body wt) was instilled intratracheally to induce pulmonary inflammation. Bronchoalveolar lavage was performed 6 hrs later, and lungs were harvested for histologic and molecular analyses. ET-1 release from cultured endothelial cells was dose-dependently reduced by Ang-1, which also prevented induction of ET-1 release by TNF-alpha (P < 0.05). RNA expression of ppET-1 was similarly reduced. In LPS-challenged lungs, ppET-1 RNA was induced 3.4-fold, and ET-1 protein in lavage fluid was increased 5.6-fold (P < 0.05). Ang-1 gene transfer attenuated the LPS-induced increases in ppET-1 RNA and lavage ET-1 protein by 34% and 33%, respectively (P < 0.05). The downregulation of ET-1 correlated with the amelioration of pulmonary inflammation, as indicated by reductions in leukocyte infiltration (by 43%) and intra-alveolar septal thickening (by 40%). These results show that ET-1 transcript and protein levels are downregulated by Ang-1 in both in vitro and in vivo systems and that cell-based Ang-1 gene transfer markedly ameliorated inflammation in vivo in an experimental model of ARDS. Thus, cell-based gene transfer of Ang-1 may provide a novel treatment strategy for ARDS by attenuating vascular inflammation via suppression of ET-1.

Topics: Angiopoietin-1; Animals; Cells, Cultured; Culture Media; Dose-Response Relationship, Drug; Down-Regulation; Endothelin-1; Endothelium, Vascular; Fibroblasts; Gene Expression Regulation; Gene Transfer Techniques; Inflammation; Lung Diseases; Male; Random Allocation; Rats; Rats, Inbred F344; Skin

Endothelin (ET-1) has been shown to crucially contribute to UV-induced skin responses such as tanning. To test whether ET-1 is also involved in early cutaneous reactions to UV, we assessed ET-1 skin levels in UV-irradiated mice. In correlation with the levels of UV-induced skin inflammation, ET-1 concentrations increased substantially and continually. Moreover, blocking of ET-1 receptors (ETA) resulted in significantly decreased cutaneous inflammation following UV irradiation. When we assessed skin responses to ET-1 injections, we observed prominent mast cell degranulation and mast cell-dependent inflammation. Since mast cells also critically contributed to UV-induced inflammation, we determined the ET-1-dependent inflammatory response to UV in the absence and presence of these cells. Interestingly, ETA blockade did not decrease UV-induced inflammation in mast cell-deficient mice, unless these mice had been adoptively transferred with mast cells before irradiation. This indicates that skin inflammation due to UV irradiation is caused in part by ET-1 acting on skin mast cells.

Topics: Animals; Cell Degranulation; Dermatitis; Dose-Response Relationship, Radiation; Endothelin A Receptor Antagonists; Endothelin-1; Inflammation; Mast Cells; Mice; Mice, Transgenic; Receptor, Endothelin A; Ultraviolet Rays

Following transient focal stroke, rapid accumulation and activation of neutrophils in the ischaemic region is deleterious due to release of reactive oxygen species and myeloperoxidase (MPO). The purpose of this study was to examine whether AM-36, both a Na+ channel blocker and an antioxidant, afforded neuroprotection by modulating neutrophil accumulation into brain, following endothelin-1 (ET-1) induced middle cerebral artery occlusion (MCAo) in conscious rats.. AM-36 was administered at 3 and 24 h after ET-1-induced MCAo. Functional recovery was determined using grid-walking and cylinder tests. Image analysis of brain sections was used to determine infarct volume. The effect of AM-36 on neutrophil infiltration and their interaction with macrophages was examined in rats at 48 h following MCAo by both an MPO assay and double-label immunofluorescence. Blood brain barrier (BBB) breakdown was measured by the area stained by intravenous Evans Blue.. AM-36 reduced functional deficits in both tests such that no difference existed from pre-ischaemic values at 48 h. Neutrophil infiltration, assessed by MPO activity, and infarct volume were significantly reduced following AM-36 administration by 54 and 60% respectively. Similarly, immunofluorescence revealed that AM-36 reduced neutrophil infiltration by approximately 50% in selected brain regions, when compared to controls, and also modulated macrophage phagocytosis of neutrophils. Breakdown of the BBB was significantly reduced by 60% following AM-36 treatment.. These findings suggest that AM-36 can directly modulate the neutrophil inflammatory response and reduce BBB breakdown following MCAo.

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Endothelin-1; Fluorescent Antibody Technique; Inflammation; Male; Microscopy, Confocal; Neutrophils; Peroxidase; Piperazines; Rats; Rats, Long-Evans

Fresh vehicular emissions potentially represent a ubiquitous environmental concern for cardiovascular health. We compared electrocardiographic effects of fresh gasoline engine emissions with resuspended paved road dust in a mouse model of coronary insufficiency. Apolipoprotein E (ApoE)-/- mice on a high fat diet were exposed by whole-body inhalation to either gasoline emissions at 60 microg/m3 particulate matter (PM), an equivalent atmosphere with particles filtered out of the whole exhaust, or paved road dust at 0.5 and 3.5 mg /m3 for 6 h/d for 3 d. Radiotelemetry recordings of electrocardiogram (ECG) were analyzed for changes in T-wave morphology (QT interval, T-wave amplitude, and T-wave Area). Following exposures, lung lavage and blood samples were obtained to assay for markers of pulmonary and systemic inflammation. No exposure induced significant changes in heart rate and only the high concentration of road dust induced signs of pulmonary inflammation. T-wave area exhibited significant deviation from baseline values during exposure to gasoline exhaust particulates, but not to either concentration of road dust or gasoline emissions sans particulates. Gasoline-exposed mice demonstrated elevated plasma endothelin-1, but did not cause systemic inflammation. These data support the hypothesis that freshly-generated engine emissions, as opposed to resuspended paved road dust, may drive cardiac effects that have been observed at road-sides in the environment. The absence of ECG effects for both very high concentrations of road dust PM and equivalent concentrations of the vapor/gas phase of gasoline engine exhaust further indicate the specific risk conferred by fresh vehicular PM.

Topics: Animals; Apolipoproteins E; Biomarkers; Bronchoalveolar Lavage Fluid; Coronary Disease; Dust; Electrocardiography; Electrophysiology; Endothelin-1; Gasoline; Heart; Inflammation; Male; Mice; Mice, Knockout; Particulate Matter; Pneumonia; Vehicle Emissions

Hepatic ischemia-reperfusion injury is an inevitable consequence during liver surgery. The outcome is particularly poor in cirrhotic livers, which are more prone to hepatic ischemia-reperfusion injury. We aim to study whether FTY720 could attenuate hepatic ischemia-reperfusion injury both in normal and in cirrhotic livers. We applied a 70% liver-ischemia (60 min) model in rats with normal or cirrhotic livers. FTY720 was given 20 min before ischemia and 10 min before reperfusion (1 mg/kg, i.v.). Liver tissues and blood were sampled at 20 min, 60 min, 90 min, 6 h and 24 h after reperfusion for detection of MAPK-Egr-1, Akt pathways and caspase cascade. Hepatic ultrastructure and apoptosis were also compared. FTY720 significantly improved liver function in the rats with normal and cirrhotic livers. Akt pathway was activated at 6 and 24 h after reperfusion. FTY720 significantly down-regulated Egr-1, ET-1, iNOS and MIP-2 accompanied with up-regulation of A20, IL-10, HO-1 and Hsp70. MAPK (Raf-MEK-Erk) pathway was down-regulated. Hepatic ultrastructure was well maintained and fewer apoptotic liver cells were found in the FTY720 groups. In conclusion, FTY720 attenuates ischemia-reperfusion injury in both normal and cirrhotic livers by activation of cell survival Akt signaling and down-regulation of Egr-1 via Raf-MEK-Erk pathway.

Topics: Animals; Apoptosis; Blotting, Western; Chemokine CXCL2; Chemokines, CXC; DNA Primers; Down-Regulation; Endothelin-1; Epidermal Growth Factor; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Fingolimod Hydrochloride; Gene Expression Regulation; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hepatocytes; HSP70 Heat-Shock Proteins; Immunosuppressive Agents; In Situ Nick-End Labeling; Inflammation; Intercellular Signaling Peptides and Proteins; Interleukin-10; Liver; Male; MAP Kinase Signaling System; Microscopy, Electron; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; p38 Mitogen-Activated Protein Kinases; Propylene Glycols; Proteins; raf Kinases; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sphingosine; Time Factors; Up-Regulation

At present it is unclear whether endothelial activation is systematically present in preeclampsia or restricted to specialized vascular beds. Therefore, this study aimed to investigate the presence of generalized proinflammatory endothelial activation in severe, early-onset preeclampsia in vivo.. During caesarean section, biopsies were obtained from abdominal subcutaneous fat, abdominal fascia, and myometrium from 11 severe, early-onset preeclamptic and 19 healthy pregnant women. Prior to caesarean, section plasma levels of von Willebrand Factor (vWF), sVCAM-1, and C-reactive protein (CRP) were measured by ELISA. Consecutive cryostat sections were stained immunohistochemically for CD31, E-selectin, VCAM-1, and ICAM-1. For subcutaneous fat tissue, endothelial gene expression levels of E-selectin, VCAM-1, ICAM-1, endothelin-1 (ET-1), and endothelial nitric oxide synthase (eNOS) were quantified by real-time RT-PCR, using normalization to the endothelium-specific housekeeping genes CD31 and VE-cadherin.. Plasma levels of vWF, sVCAM-1, and CRP were elevated in the preeclampsia group compared to the control group, indicating enhanced endothelial activation and inflammatory response in the severely diseased preeclamptic women. By immunohistochemical analysis, no E-selectin and VCAM-1 expression could be detected in, and no differences in endothelial ICAM-1 staining could be observed between the preeclampsia and the control group for all tissues studied. Endothelial gene expression levels of E-selectin, VCAM-1, ICAM-1, ET-1, and eNOS were comparable between the preeclampsia and control group.. Protein and gene expression analysis of E-selectin, VCAM-1, ICAM-1, ET-1, and eNOS, key mediators involved in pro-inflammatory endothelial activation, could not identify endothelial activation in severe, early-onset preeclampsia in the tissues studied. However, elevated plasma levels of markers of endothelial activation and inflammation were observed. These results may suggest that in severe, early-onset preeclampsia pro-inflammatory endothelial cell activation is not a generalized phenomenon, but is likely restricted to (possibly organ-specific) specialized vascular beds.

Topics: Adult; Biopsy; E-Selectin; Endothelin-1; Endothelium, Vascular; Female; Gene Expression Profiling; Humans; Immunohistochemistry; Inflammation; Intercellular Adhesion Molecule-1; Pre-Eclampsia; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; Severity of Illness Index; Vascular Cell Adhesion Molecule-1

Endothelin receptors have been involved in inflammatory, neuropathic and tumoral pain. In the case of inflammatory hyperalgesia, some previous papers have pointed towards the involvement of ETB receptors, although the stimulation of ETA receptors seems to participate in the development of the inflammatory reaction. We have studied the effect of ETA and ETB receptor antagonists in the thermal and mechanical hyperalgesia induced in a model of acute (induced by carrageenan) and chronic (induced by complete Freund's adjuvant, CFA) inflammation in mice. The i.pl. administration of the selective ETA antagonist BQ-123 (1-10 nmol) antagonized the thermal hyperalgesia detected by the unilateral hot plate test, observed in both inflammatory models, whereas the i.pl. administration of the ETB selective antagonist BQ-788 (17.7 nmol) failed to modify this. In contrast, both BQ-123 (3-17.7 nmol) and BQ-788 (3-17.7 nmol) antagonized the mechanical hyperalgesia, as assessed by the Randall-Selitto test in carrageenan- and CFA-treated mice. Both BQ-123 and BQ-788 were able to antagonize the mechanical hyperalgesia induced by ET-1 (200 pmol; i.pl.) in the same dose range. Thus, ETA receptors are involved in both thermal and mechanical hyperalgesia whereas ETB receptors are only involved in mechanical hyperalgesia in these inflammatory models. In conclusion, the role of ETB receptors in inflammatory pain is further supported and new insights into the participation of ETA receptors in inflammatory hyperalgesia are given.

Topics: Animals; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Freund's Adjuvant; Hot Temperature; Hyperalgesia; Inflammation; Male; Mice; Oligopeptides; Pain Measurement; Peptides, Cyclic; Physical Stimulation; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors

Myocardial expression of endothelin-1 (ET-1) and its receptors ET(A) and ET(B) is increased in heart failure. However, the role of ET-1 and its signaling pathways in the pathogenesis of myocardial diseases is unclear.. Human ET-1 cDNA was placed downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA). This line (ET+) was bred with one harboring cardiac myocyte-restricted expression of tTA (alphaMHC-tTA). Myocardial ET-1 peptide levels were significantly increased in binary transgenic (BT, ET+/tTA+) compared with nonbinary transgenic (NBT, ET+/tTA-; ET-/tTA+; ET-/tTA-) or DOX-treated BT littermates (40.1+/-4.7 versus 2.6+/-1.2 fmol/mL, P<0.003). BT mice demonstrated progressive mortality between 5 and 11 weeks after DOX withdrawal, associated with left ventricular dilatation and contractile dysfunction (peak +dP/dT, 4673+/-468 versus 5585+/-658 mm Hg/s, P<0.05). An interstitial inflammatory infiltrate, including macrophages and T lymphocytes, was evident in the myocardium of BT mice, associated with sequential increases in nuclear factor-kappaB translocation and expression of tumor necrosis factor-alpha, interferon-gamma, interleukin-1 and interleukin-6. Significant prolongation of survival was observed with the combined ET(A)/ET(B) antagonist LU420627 (n=8, P<0.05) in BT mice but not the ET(A)-selective antagonist LU135252 (n=5, P=0.9), consistent with an important role for ET(B) in this model.. These are the first data to demonstrate that cardiac overexpression of ET-1 is sufficient to cause increased expression of inflammatory cytokines and an inflammatory cardiomyopathy leading to heart failure and death.

Topics: Animals; Cardiomyopathy, Dilated; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Humans; Inflammation; Mice; Mice, Transgenic; Myocardium; Phenotype

Leukocyte adhesion to endothelial cells plays a key role in inflammatory processes associated with end-organ injury. Endothelin-1 (ET-1), which stimulates inflammatory processes, contributes to cardiovascular damage in deoxycorticosterone (DOCA)-salt hypertension. We investigated whether ETA receptor blockade modulates in vivo leukocyte-endothelial cell interactions and expression of cell adhesion molecules (CAM) involved in these processes. DOCA-salt and control uninephrectomized rats were treated with the ETA antagonist BMS182874 (40 mg/kg per day) or vehicle. Analysis of CAMs expression by reverse transcription-polymerase chain reaction and immunohistochemistry showed increased cardiac platelet selectin (P-selectin), detected mainly in endothelial cells, and vascular cell adhesion molecule-1 (VCAM-1), but not intercellular adhesion molecule-1 (ICAM-1), in DOCA-salt rats. Cardiac expression of endothelial selectin (E-selectin) was decreased, whereas immunoreactivity to ED-1 and myeloperoxidase (MPO) activity, markers of macrophage and leukocyte infiltration, respectively, were increased in DOCA-salt. Leukocyte-endothelial cell interaction, functionally assessed in venules of internal spermatic fascia by intravital microscopy, was significantly altered in DOCA-salt rats as evidenced by increased leukocyte adhesion and decreased rolling. BMS182874 treatment normalized leukocyte-endothelium interactions, decreased cardiac VCAM-1 expression in DOCA and control groups, and had no effects on ICAM-1 expression. BMS182874 also increased E-selectin and abolished P-selectin expression in DOCA-salt, but not in control rats. The ETA antagonist reduced cardiac ED-1 content and MPO activity and prevented cardiac damage in DOCA-salt rats. These data indicate that ET-1 participates, via activation of ETA receptors, in altered leukocyte-endothelial cell interactions in DOCA-salt rats, possibly by modulating expression of CAMs, and that the inflammatory status is associated with cardiac damage in mineralocorticoid hypertension.

Topics: Animals; Cell Adhesion; Cell Adhesion Molecules; Chemotaxis, Leukocyte; Dansyl Compounds; Desoxycorticosterone; Disease Models, Animal; E-Selectin; Endothelin A Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Gene Expression Regulation; Hypertension; Hypertension, Renovascular; Inflammation; Intercellular Adhesion Molecule-1; Leukocytes; Macrophages; Male; Myocardium; Nephrectomy; P-Selectin; Rats; Rats, Wistar; Receptor, Endothelin A; Reverse Transcriptase Polymerase Chain Reaction; Sodium Chloride, Dietary; Vascular Cell Adhesion Molecule-1

Topics: Animals; Anti-Inflammatory Agents; Blood Pressure; Endothelin-1; Endothelium, Vascular; Humans; Immunohistochemistry; Inflammation; Nitric Oxide; Nitric Oxide Synthase; Receptors, Endothelin

The hypothesis that up-regulation of bronchial constrictor endothelin receptors in airway smooth muscle cells may contribute to hyperreactivity during airway inflammation was tested in the present study by quantitative endothelin receptor mRNA analysis and functional responses in ring segments of rat trachea and bronchi. Real time reverse transcription polymerase chain reaction was used to quantify endothelin receptor expression in rat airway smooth muscle cells following Sephadex-induced inflammation. Compared with controls, Sephadex-induced airway inflammation caused a significant increase (3.9 times P<0.05) of endothelin receptor type B mRNA expression in bronchial smooth muscle cells, but not in tracheal smooth muscle cells. Functional myograph studies of bronchial and tracheal ring segments without epithelium (mechanically denuded) revealed an increase of the maximum contractile effects of endothelin-1 (a dual agonist for both endothelin type A and B receptors) and sarafotoxin 6c (a selective agonist for endothelin B receptors) in bronchial smooth muscle cells in Sephadex-induced inflammation, but not in tracheal smooth muscle cells. The enhanced maximal responses of bronchial smooth muscle cells to endothelin-1 and sarafotoxin 6c in Sephadex-induced inflammation support our molecular findings and hence imply a role for endothelin B receptors in airway hyperreactivity during airway inflammation.

Topics: Animals; Bronchi; Dextrans; Endothelin-1; In Vitro Techniques; Inflammation; Male; Myocytes, Smooth Muscle; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Trachea; Up-Regulation; Viper Venoms

Elevations in endothelin-1 (ET-1) and inflammatory cytokines may impair myocardial reperfusion through the induction of microvascular constriction or obstruction; however, the generation of these factors close to the site of lesion rupture is unknown.. Coronary sinus (CS) and aortic blood was sampled during angioplasty for acute myocardial infarction (AMI) or stable angina to assess the local release of ET-1, interleukin-1beta, interleukin-6, tumor necrosis factor-alpha and C-reactive protein following atherosclerotic plaque rupture. Transthoracic echocardiography documented left ventricular function in AMI. ET-1 levels were higher in CS than in aortic blood in AMI (3.0 +/- 0.3 pmol/L vs 2.6 +/- 0.3 pmol/L, P =.04), but not in stable angina (1.7 +/- 0.2 pmol/L vs 1.5 +/- 0.3 pmol/L, P = NS). CS ET-1 levels were also higher in AMI than in stable angina (3.0 +/- 0.3 pmol/L vs 1.7 +/- 0.2 pmol/L, P =.002), and correlated with left ventricular dysfunction (R(2) = 0.51, P =.02). In contrast, C-reactive protein levels were higher in CS than in aortic blood only in stable angina (2.3 +/- 0.4 mg/L vs 1.8 +/- 0.3 mg/L, P =.01). Similarly, CS tumor necrosis factor-alpha was higher in stable angina than in AMI (6.0 +/- 1.4 pg/mL vs 2.5 +/- 0.9 pg/mL, P =.02).. Local myocardial release of ET-1 is highest in AMI, where it relates to the extent of myocardial dysfunction. Although local inflammation is a component of stable coronary artery disease, it does not appear acutely enhanced in AMI.

Topics: Angina Pectoris; Angioplasty, Balloon, Coronary; C-Reactive Protein; Cytokines; Endothelin-1; Female; Humans; Inflammation; Male; Middle Aged; Myocardial Infarction; Myocardium; Ventricular Function, Left

Endothelin-1 (ET-1) switching in cytokines program and adhesive cascade at atherosclerosis.. 29 patients, suffering from atherosclerosis. The initial ET-1, sCAM: P-, E-selectins, ICAM-1, VCAM-1 levels and IL-1a, IL-1b, IL-6, IL-8 and IL-10 levels and their changes in response to high shear stress (shear rate 100/second, incubation for 6 hours at 37 degrees C) and blood coagulation (incubation at 37 degrees C for 6 hours also) were measured by ELISA kits.. ET-1 level was increased after both tests by unclear mechanisms of its releasing. The increased level of all researched molecules was detected without tests even. After shear stress the sP- and sE-selectins levels were significantly decreased, whereas their levels were strong correlated to ET-1.. We hypothesized that the multiple mechanisms of cell-cell communication were switched on (ET-1 releasing and selctin reinternalization). The ET-1 were closely correlated to proinflammatory cytokines. We postulate that the ET-1 is active participant in cytokine- and sCAM-induced inflammatory repsonse at atherosclerosis.

Topics: Atherosclerosis; Blood Coagulation; Cell Adhesion Molecules; Cytokines; Endothelin-1; Humans; Inflammation; Inflammation Mediators; Stress, Mechanical; Up-Regulation

The hemodynamic and proinflammatory effects of endothelin-1 (ET-1) in proximal (1st/2nd order) and terminal (3rd/4th order) arterioles and venules were examined in small intestine submucosa of anesthetized guinea pigs. Vessel diameter (D), red blood cell velocity, and blood flow (Q) were determined in eight proximal and eight terminal microvessels before and at 20 min of ET-1 suffusion (10(-10), 10(-9), and 10(-8) M) and then with endothelin-A (ET(A))-receptor blockade with BQ-123 (10(-5) M). This protocol was repeated with platelet-activating factor (PAF) inhibition (WEB-2086, 1.0 mg/kg iv; n = 16). The ET-1-mediated microvascular responses were also examined with endothelin-B (ET(B))-receptor blockade using BQ-788 (10(-5) M; n = 11) alone or with ET(A+B)-receptor blockade with BQ-123 + BQ-788 (n = 10). Microvascular permeability was assessed by FITC-albumin (25 mg/kg iv) extravasation in seven series: 1) buffered modified Krebs solution suffusion (n = 6), 2) histamine suffusion (HIS; 10(-3) M, n = 5), 3) ET-1 suffusion (10(-8) M, n = 5), 4) BQ-123 (10(-5) M) plus ET-1 suffusion (n = 5), 5) PAF inhibition before ET-1 suffusion (n = 5), 6) histamine-1 (H1)-receptor blockade (diphenhydramine, 20 mg/kg iv) before ET-1 suffusion (n = 5), and 7) ET(B)-receptor blockade before (BQ-788 10(-5) M; n = 3) or with ET-1 suffusion (n = 3). D and Q decreased at 10(-8) M ET-1 and returned to control values with BQ-123 and BQ-123+BQ788 but not with BQ-788 in proximal microvessels. D did not change in terminal microvessels with ET-1 (10(-8) M) but decreased with BQ-788 and increased with BQ-123. PAF inhibition did not affect the D and Q responses of proximal microvessels to ET-1 but prevented the fall in Q in terminal microvessels with ET-1. ET-1 increased vascular permeability to approximately 1/3 of that with HIS; this response was prevented with BQ-123 and WEB-2086 but not with H1-receptor blockade. This is the first evidence that submucosal terminal microvessel flow is reduced with ET-1 independent of vessel diameter changes and that this response is associated with increased microvascular permeability mediated via ET(A)-receptor stimulation and PAF activation.

Topics: Animals; Azepines; Endothelin Receptor Antagonists; Endothelin-1; Guinea Pigs; Hemodynamics; Inflammation; Intestine, Small; Male; Microcirculation; Peptides, Cyclic; Receptors, Endothelin; Regional Blood Flow; Triazoles; Vasoconstriction

Endothelin-1 (ET-1) exerts many biological effects in airways, including bronchoconstriction, airway mucus secretion, cell proliferation, and inflammation. We investigated the effect of ET-1 on Na absorption and Cl secretion in human bronchial epithelial cells. Addition of 10(-7) M ET-1 had no effect on the inhibition of the short circuit current (Isc) induced by amiloride, a Na channel blocker. Addition of 10(-7) M ET-1 to the apical bath in the presence of amiloride increased Isc in cultured human bronchial epithelial cells studied in Ussing chambers. No effect was observed when ET-1 was added to basolateral bath, indicating that the involved ET-1 receptors are likely present only in the apical membrane of the cells. Use of Cl-free solutions and bumetanide reduced the ET-1-induced increases in Isc, indicating that ET-1 stimulates Cl secretion. The ET-1-induced increase in Isc was prevented by exposure to the ETB receptor antagonist BQ-788 but not to the ETA receptor antagonist BQ-123. ET-1 did not raise intracellular Ca levels, but increased the intracellular concentration of cAMP. These findings indicate that ET-1 is a Cl secretagogue in human airways and acts presumably through apically located ETB receptors and activation of the cAMP pathway.

Topics: Amiloride; Binding Sites; Biological Transport; Bronchi; Bumetanide; Cells, Cultured; Chlorine; Cyclic AMP; Dose-Response Relationship, Drug; Egtazic Acid; Endothelin-1; Epithelium; Humans; Indomethacin; Inflammation; Ions; Prostaglandin-Endoperoxide Synthases; Receptor, Endothelin B; Receptors, Endothelin; Sodium Channels

Topics: Adult; Biomarkers; C-Reactive Protein; Cell Adhesion Molecules; Coronary Disease; Endothelin-1; Endothelium, Vascular; Humans; Hypertriglyceridemia; Inflammation; Interleukin-6; Male; Risk Factors; von Willebrand Factor

Intercellular adhesion molecule-1 (ICAM-1) is an important adhesion molecule leading to adhesion between cells; NF-kappaB, being universally distributed in the organism, is an important nuclear transcription factor leading to a rapid response to the stimuli. Line of evidence have shown that ICAM-1 transcription and NF-kappaB activation is an important step of inflammatory reaction. To testify that intrapulmonary regulatory peptides modulate inflammatory lesion of bronchial epithelial cells (BECs) through their effect on ICAM-1 expression and nuclear factor kappaB (NF-kappaB) activation, we used immunocytochemistry, RT-PCR, and electrophoretic mobility-shift assay (EMSA) to determine the ICAM-1 expression and NF-kappaB activity in BECs. The effects of NF-kappaB inhibitor MG-132 on ICAM-1 expression were also observed. The results showed that vasoactive intestinal peptide (VIP) and epidermal growth factor (EGF) decreased ICAM-1 expression in O(3)-stressed BECs, while endothelin-1 (ET-1) and calcitonin gene-related peptides (CGRP) increased ICAM-1 expression in resting BECs. MG-132 blocked ICAM-1 expression induced by O(3), ET-1 and CGRP. The results obtained by using EMSA confirmed that VIP and EGF restrained the activation of NF-kappaB in O(3)-stressed BECs; CGRP and ET-1 promoted activation of NF-kappaB. These observations indicate that VIP and EGF abated the injury by means of down-regulatory effects on ICAM-1 transcription and NF-kappaB activation, while ET-1 and CGRP enhanced the inflammation reaction by an up-regulatory effect. It is suggested that a developing and intensive airway inflammation correlates closely with a persistent expression of ICAM-1 and repeated activation of NF-kappaB.

Topics: Animals; Bronchi; Cell Adhesion; Cells, Cultured; Endothelin-1; Epithelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; NF-kappa B; Peptides; Rabbits; Vasoactive Intestinal Peptide

We hypothesized that the venous limb of an arteriovenous (AV) fistula would evince up-regulation of genes relevant to vascular remodeling along with neointimal hyperplasia and relevant histological changes. Using the aorto-caval model of an AV fistula model in the rat, we demonstrate marked up-regulation in such proinflammatory genes as monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, and endothelin-1, 2 weeks after the creation of the fistula. Neointimal hyperplasia occurred in variable degrees by 5 weeks after establishing the fistula, and by 16 weeks, such neointimal hyperplasia was progressive and pronounced; at this time point, abundant extracellular matrix was also observed. Smooth muscle cells were present in the hyperplastic neointima as evidenced by staining for alpha-smooth muscle actin; ultrastructurally, smooth muscle cells with a synthetic as well as a contractile phenotype were readily observed. Accumulation of extracellular matrix in the model at 16 weeks was accompanied by increased expression of transforming growth factor-beta1 mRNA, the latter finding contrasting with the suppression of transforming growth factor-beta1 mRNA observed in this model at 2 weeks. In summary, we describe marked up-regulation in proinflammatory genes and progressive neointimal formation in the venous vasculature in an AV fistula model in the rat. We suggest that such alteration in gene expression and histological injury, in conjunction with the relative simplicity of this model, offer a new approach in the study of such timely biological and clinically relevant phenomena as differential gene expression in response to hemodynamic forces, processes involved in vascular remodeling, mechanisms of injury in venous bypass grafts, and mechanisms of dysfunction of AV fistulae used in hemodialysis.

Topics: Animals; Arteriovenous Fistula; Blotting, Northern; Chemokine CCL2; Disease Models, Animal; Endothelin-1; Gene Expression; Hyperplasia; Inflammation; Inflammation Mediators; Microscopy, Electron; Plasminogen Activator Inhibitor 1; Rats; RNA, Messenger; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tunica Intima; Vena Cava, Inferior

To inquire into effects of cytokines and other inflammatory media, and peptide hormones during multiple organ dysfunction syndrome (MODS) subsequent to acute abdominal diseases.. In 19 patients with MODS due to acute abdominal diseases, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), thromboxane B(2) (TXB(2)), 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), endotoxin, gene-related peptide(CGRP), endothelin-1 (ET-1) and substance P (SP) in plasma, and lipid peroxide (LPO) and nitric oxide (NO) in serum were determined dynamically.. Both TNF-alpha and IL-6 at increased significantly in MODS patients; IL-6 on day 0 in patients without treatment of endoscopic retrograde bile duct drainage (ERBD) were higher than that in patients with correspondent treatment, IL-6 in severe acute cholangitis patients was higher than that in patients with acute necrotic pancreatitis, it approached 24,000 ng/L during toxic shock. TNF-alpha and IL-6 during early stage of MODS were higher than that during systemic inflammatory response syndrome (SIRS) respectively. Endotoxin and LPO levels in MODS patients increased significantly. The levels of NO in emergency patients with MODS was elevated, but lowered in patients with acute necrotic pancreatitis, hepatocarcinoma, advanced age's patients with long time fever due to hepatic abscess. TXB(2) and 6-keto-PGF(1alpha) during early stage rose significantly, both decreased after treatment. ET-1 and CGRP during early stage increased significantly, SP peaked on day 0.. The level of IL-6 persistently higher than 300 ng/L suggests the diagnosis of MODS. The levels of IL-6 and TNF-alpha could be taken as an indication of the degree of SIRS. NO maybe either increased or decreased, ET-1, CGRP, TXB(2), 6-keto-PGF(1alpha), endotoxin, and LPO are found to be increased MODS.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Cytokines; Digestive System Diseases; Endothelin-1; Female; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Multiple Organ Failure; Peptide Hormones; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

1. Inflammatory bowel disease (IBD) is a condition that involves proinflammatory cytokines such as interleukins 1beta and 6 (ILs). In this disease, it has been shown that an abnormal microcirculatory system is implicated. 2. Therefore, the effects of in vivo treatment for three days with interleukins 1beta and 6 were investigated on rat isolated mesenteric vascular bed (MVB). 3. A significant concentration-dependent increase in vascular response to noradrenaline (NA) was found, with a significant difference in Emax between control (93.01 +/- 16.78 mmHg) and treated preparations (137.91 +/- 5.20 mmHg). Endothelin-1(ET-1) induced a significantly greater increase of perfusion pressure in treated rats in comparison with control rats at the highest concentration used (0.1 microm). 4. The concentration-dependent decrease of perfusion pressure induced by acetylcholine (ACh) in MVB precontracted with NA was significantly reduced in specimens from treated rats in comparison with control rats, with a significant difference in Emax between control and treated preparations. 5. Perivascular nerve stimulation (PNS) evoked contractions with no difference between treatments. Similarly, no difference in relaxant effect was found after PNS in specimens precontracted with NA, in the presence of guanethidine. 6. These findings indicate that the precocious inflammation acts only at postsynaptic level, facilitating vascular contraction. These data seem to support the hypothesis that vascular dysfunction caused by overproduction of ILs may contribute, among other immunological factors, to vasculitis in IBD that leads to intestinal ischaemia through vasoconstriction.

Topics: Acetylcholine; Animals; Arginine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Electric Stimulation; Endothelin-1; Fever; Guanethidine; Inflammation; Interleukin-1; Interleukin-6; Intestinal Mucosa; Isomerism; Isoproterenol; Male; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Norepinephrine; Perfusion; Rats; Rats, Sprague-Dawley; Sumatriptan; Time Factors; Vascular Resistance; Vasoconstriction; Vasodilation

Topics: Animals; Apoptosis; Endothelin-1; Humans; Inflammation; Lung; Lung Transplantation; Models, Biological; Nitric Oxide; Reactive Oxygen Species

Topics: Animals; Asthma; Biomarkers; Bronchial Spasm; Child; Endothelin-1; Endothelium, Vascular; Epithelial Cells; Fibrosis; Humans; Inflammation; Lung; Mice; Mice, Transgenic

C-reactive protein (CRP) has been suggested to actively participate in the development of atherosclerosis. In the present study, we examined the role of the potent endothelium-derived vasoactive factor endothelin-1 (ET-1) and the inflammatory cytokine interleukin-6 (IL-6) as mediators of CRP-induced proatherogenic processes.. Saphenous vein endothelial cells (HSVECs) were incubated with human recombinant CRP (25 microg/mL, 24 hours) and the expression of vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1), and monocyte chemoattractant chemokine-1 was determined. The effects of CRP on LDL uptake were assessed in macrophages using immunofluorescent labeling of CD32 and CD14. In each study, the effect of endothelin antagonism (bosentan) and IL-6 inhibition (monoclonal anti-IL-6 antibodies) was examined. The effects of CRP on the secretion of ET-1 and IL-6 from HSVECs were also evaluated. Incubation of HSVECs with recombinant human CRP resulted in a marked increase in ICAM-1 and VCAM-1 expression (P<0.001). Likewise, CRP caused a significant increase in monocyte chemoattractant chemokine-1 production, a key mediator of leukocyte transmigration (P<0.001). CRP caused a marked and sustained increase in native LDL uptake by macrophages (P<0.05). These proatherosclerotic effects of CRP were mediated, in part, via increased secretion of ET-1 and IL-6 (P<0.01) and were attenuated by both bosentan and IL-6 antagonism (P<0.01).. CRP actively promotes a proatherosclerotic and proinflammatory phenotype. These effects are mediated, in part, via the production of ET-1 and IL-6 and are attenuated by mixed ET(A/B) receptor antagonism and IL-6 inhibition. Bosentan may be useful in decreasing CRP-mediated vascular disease.

Topics: Antibodies; Arteriosclerosis; Biomarkers; Bosentan; C-Reactive Protein; Cell Adhesion Molecules; Cells, Cultured; Chemokine CCL2; Endothelin-1; Endothelium, Vascular; Humans; Inflammation; Interleukin-6; Lipoproteins, LDL; Macrophages; Models, Cardiovascular; Sulfonamides

Endothelin-converting enzyme (ECE)-1 activates endothelin-1 (ET-1) and may thus contribute to the regulation of vascular tone and cell growth during atherosclerosis.. To evaluate ECE-1 immunoreactivity concerning big ET-1/ET-1, we performed qualitative and quantitative immunohistochemistry in normal internal mammary arteries (n=10), in coronary arteries with adaptive intimal fibrosis (n=10), in aortic fatty streaks (n=10), and in distinct regions of advanced carotid plaques (n=15). Furthermore, we determined ECE-1 activity in the control specimens and in the inflammatory intimal regions of carotid plaques. Double immunolabeling showed that ECE-1 was present in endothelial cells, vascular smooth muscle cells, and macrophages. All ET-1(+) cells were simultaneously ECE-1(+). Most importantly, there were significantly more ET-1(+) cells in the intima and media when atherosclerosis was in an inflammatory stage than when it was in a noninflammatory stage. Moreover, ECE-1 activity was upregulated in the intima of carotid plaques, although immunohistochemically, there were no significant differences between the number of ECE(+) cells in the different compartments of the arterial wall.. Together with ET-1, ECE-1 is abundantly present in human arteries and at different stages of atherosclerotic plaque evolution. The upregulation of the ECE-1/ET-1 system is closely linked to the presence of chronic inflammation and is present in very early stages of plaque evolution. Therefore, enhanced production of active ET-1 may substantially contribute to cell growth and the regulation of vascular tone in advanced atherosclerotic lesions and in the very early stages of plaque evolution, when a plaque is still imperceptible clinically.

Topics: Aorta; Aortic Diseases; Arteriosclerosis; Aspartic Acid Endopeptidases; Carotid Arteries; Carotid Stenosis; Chronic Disease; Coronary Disease; Coronary Vessels; Disease Progression; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Activation; Humans; Immunohistochemistry; Inflammation; Mammary Arteries; Metalloendopeptidases; Tunica Intima; Tunica Media

Nuclear factor kappaB (NF-kappaB) is a transcriptional factor which may be pivotal in the pathogenesis of atherosclerosis. Endothelin-1 (ET-1) is a peptide with proatherogenic properties. We hypothesized that ET-1 may act through activation of NF-kappaB and degradation of IkappaB-alpha, the cytosolic inhibitor of NF-kappaB activation, to create an atherogenic environment. The human monocytic cell line THP-1 was stimulated with ET-1 +/- the ET antagonist, BQ788 and the proteosome inhibitor, PSI. LPS was used as a positive control. Gel shift assays for NF-kappaB activity and Western blot analysis for IkappaB-alpha were performed. Both LPS and ET-1 led to activation of NF-kappaB in nuclear extracts [3.4 +/- 0.45 (LPS) and 2.9 +/- 0.26 (ET-1) fold increase in Arbitrary Densitometric Units (ADU) compared with negative control (P < 0.005 in both cases)]. In the presence of the ETB antagonist, BQ788, NF-kappaB activation was attenuated and not different from control (1.7 +/- 0.24 fold DU compared with negative control; P = NS). In addition, both LPS and ET-1 mediated NF-kappaB activation were attenuated by preincubation with the proteosome inhibitor, PSI (1.3 +/- 0.58 and 1.1 +/- 0.3 fold increase in ADU compared with negative control respectively). Both LPS and ET-1 led to a decrease in the amount of IkappaB-alpha present in the THP-1 cytoplasmic extracts (2.1 +/- 1.5% and 54 +/- 15.7% of ADU vs negative control (P < 0.05). NF-kappaB is activated by ET-1 in human THP-1 monocytes. This data supports a role for the ETs in the development of inflammation in the vessel wall in atherosclerosis.

Topics: Antihypertensive Agents; Arteriosclerosis; Blotting, Western; Cell Line; Cell Nucleus; Cysteine Endopeptidases; Cytoplasm; Cytosol; DNA-Binding Proteins; Endothelin-1; Humans; I-kappa B Proteins; Inflammation; Macrophages; Monocytes; Multienzyme Complexes; NF-kappa B; NF-KappaB Inhibitor alpha; Oligopeptides; Peptides; Piperidines; Proteasome Endopeptidase Complex; Protein Binding

Mounting evidence from in vitro and in vivo studies in transgenic mice overproducing beta-amyloid peptides (A beta) suggests that A beta can induce vasoconstriction and decrease cerebral blood flow. In this report, we describe the vasoactive properties of A beta, in particular the enhancement of endothelin-1-induced vasoconstriction and A beta's induction of a long-lasting vasoconstrictive event. Furthermore, we show that low doses (as low as 50 nM) of freshly solubilized A beta similar to those observed in the plasma of patients suffering from Alzheimer's disease are vasoactive. By using various inhibitors and activators of the phospholipase A2 (PLA2)/arachidonic acid (AA) cascade, we demonstrate that A beta vasoactivity is dependent on activation of this intracellular signaling pathway, resulting in stimulation of downstream cyclooxygenase-2 and 5-lipoxygenase, which mediate production of proinflammatory eicosanoids. Taken together, our data show that A beta directly activates an intracellular proinflammatory pathway, which is responsible for its vasoactive properties.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Aorta; Cyclooxygenase Inhibitors; Endothelin-1; Humans; In Vitro Techniques; Inflammation; Lipoxygenase Inhibitors; Male; Mice; Mice, Transgenic; Muscle, Smooth, Vascular; Peptide Fragments; Rats; Rats, Sprague-Dawley; Signal Transduction; Vasoconstriction; Vasodilation

Topics: Amyloid beta-Peptides; Animals; Aorta; Cyclic GMP; Dipyridamole; Endothelin-1; In Vitro Techniques; Inflammation; Leukotriene B4; Microglia; Muscle, Smooth, Vascular; Nitroprusside; Peptide Fragments; Rats; Vasoconstriction

Topics: Arteriosclerosis; Biomarkers; Blood Coagulation; Cell Adhesion Molecules; Cytokines; E-Selectin; Endothelin-1; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukins; P-Selectin; Stress, Mechanical; Vascular Cell Adhesion Molecule-1

The pulmonary endothelin (ET) system has been implicated in the pathogenesis of chronic lung diseases such as pulmonary hypertension, asthma, chronic obstructive lung disease, idiopathic pulmonary fibrosis, and bronchiolitis obliterans. However, the etiologic role of ET-1 in these diseases has not yet been established. We recently demonstrated that ET-1 transgenic mice, generated using the human prepro-ET-1 expression cassette including the cis-acting transcriptional regulatory elements, had predominant transgene expression in lung, brain, and kidney. We used these mice in the present study to analyze the pathophysiologic consequences of long-term pulmonary overexpression of ET-1. We found that ET-1 overexpression in the lungs did not result in significant pulmonary hypertension, but did result in development of a progressive pulmonary fibrosis and recruitment of inflammatory cells (predominantly CD4-positive cells). Our study provides evidence that a long-term activated pulmonary ET system, without any other stimuli, produces chronic lymphocytic inflammation and lung fibrosis. This suggests that overexpression of ET-1 may be a central event in the pathogenesis of lung diseases associated with fibrosis and chronic inflammation, such as pulmonary fibrosis and bronchiolitis.

Topics: Animals; Apoptosis; Blood Gas Analysis; Bronchi; CD4-Positive T-Lymphocytes; Cell Division; Chronic Disease; Endothelin-1; Humans; Hypertension, Pulmonary; Immunohistochemistry; Inflammation; Lung; Male; Mice; Mice, Transgenic; Neovascularization, Physiologic; Organ Size; Organ Specificity; Pulmonary Artery; Pulmonary Fibrosis; Receptors, Endothelin; Transgenes; Ventricular Pressure

Hypercholesterolemia (HC) is associated with coronary endothelial dysfunction and increased circulating levels of endothelin-1. We show that pre-treatment of intact rat aortic rings with cholesterol synergistically enhances the vasoconstriction induced by endothelin-1 suggesting that elevated levels of cholesterol may predispose to hypertension by modulating the vascular reactivity to endogenous vasoconstrictors. Moreover, we report that SB202190, a selective inhibitor of p38 MAPK, and PD98059 an inhibitor of MEK1/2 are able to abolish the vasoactive properties of cholesterol. MK-886, an inhibitor of 5-lipoxygenase is inefficient at blocking the vasoactive properties of cholesterol whereas NS-398, a selective inhibitor of cyclooxygenase-2 (COX-2) completely abolishes cholesterol-induced vasoconstriction. In intact rat aortae, cholesterol stimulates prostaglandin E(2) and prostaglandin F(2 alpha) production, an effect that can be completely prevented by inhibiting p38 MAPK, or COX-2. In vitro, cholesterol appears to stimulate a similar pro-inflammatory pathway in human cerebrovascular smooth muscle cells. Disruption of the MAPK/COX-2 pathway may represent a valuable therapy to block the hypertension associated with HC, as well as the development of atherosclerosis.

Topics: Animals; Cells, Cultured; Cerebrovascular Circulation; Cholesterol; Cyclooxygenase 2; Dinoprost; Dinoprostone; Drug Synergism; Endothelin-1; Humans; Hypercholesterolemia; In Vitro Techniques; Inflammation; Isoenzymes; Lipoxygenase Inhibitors; Male; Membrane Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; p38 Mitogen-Activated Protein Kinases; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Signal Transduction; Vasoconstriction

Topics: Animals; Disease Models, Animal; Endothelin-1; Hemodynamics; Humans; Inflammation; Rats; Sepsis

The importance of early cardiac myocyte damage during postburn trauma has been emphasized in recent years. However, its pathogenesis, prevention, and treatment have not been fully clarified. The aim of this study is to define its pathogenesis.. Rats with 30% third-degree burns were used. Cardiac biochemical markers reflecting cardiac myocyte damage including troponin T, cardiac myosin light chain 1, creatinine kinase and its cardiac-specific isoenzyme compound, as well as inflammatory mediators such as tumor necrosis factor, endothelin/nitric oxide ratio, malondialdehyde, and superoxide dismutase, were determined.. Cardiac biochemical markers reflecting cardiac myocyte damage, including troponin T, cardiac myosin light chain 1, cardiac-specific isoenzyme compound, were all significantly elevated between 3 hours and 24 hours after burn. Changes in tumor necrosis factor, endothelin/nitric oxide ratio, and malondialdehyde were similar to those of cardiac biochemical markers. In contrast, levels of superoxide dismutase declined markedly after burn.. The findings of this study showed that considerable amounts of myocardial constructive protein degradation and release due to destruction of cardiac myocytes occurred early after severe burns. The inflammatory mediators released after burn injury may be involved in the pathogenesis of myocardial destruction.

Topics: Animals; Biomarkers; Burns; Creatine Kinase; Disease Models, Animal; Endothelin-1; Heart Diseases; Inflammation; Male; Malondialdehyde; Myocardium; Myosin-Light-Chain Kinase; Nitric Oxide; Rats; Rats, Wistar; Superoxide Dismutase; Time Factors; Troponin T; Tumor Necrosis Factor-alpha

Biosynthesis of endothelin-1 (ET-1), the most potent endogenous vasoconstrictor yet identified, is increased following myocardial infarction (MI) in man. Pathological events which occur in the connective tissues of the equine hoof during laminitis are similar in some respects, to changes occurring in the myocardial connective tissues following MI in man. The objective of this study was to determine whether ET-1 expression in connective tissues obtained from the hoof of laminitic horses is increased compared with tissues obtained from healthy horses. Expression of ET-1 in connective tissues of the equine hoof was measured following tissue extraction from 3 groups of horses: horses in which acute laminitis had been induced by the administration of starch; chronically foundered horses; nonlaminitic horses. The concentration of ET-1 in laminar connective tissues obtained from all laminitic horses (1573.0 +/- 392.8 pg/g of tissue; n = 10) was increased when compared with tissues obtained from nonlaminitic horses (392.5 +/- 117.4 pg/g of tissue; n = 5) (P<0.05). The concentration of ET-1 in laminar connective tissues obtained from the experimentally induced, acute laminitic horses (1043.6 +/- 254.4 pg/g of tissue; n = 7) and from the spontaneously affected, chronic laminitic horses (2808.3 +/- 878.6 pg/g of tissue; n = 3) was increased compared with the control group (P<0.05, P<0.01, respectively). The concentration of ET-1 in laminar connective tissues obtained from the chronic laminitic horses was greater than that of the experimentally induced, acute laminitic group (P<0.05). It is suggested that the data provide a strong argument that increased ET-1 expression in the connective tissues of the equine hoof represent a potentially important and hitherto unrecognised component of the pathophysiology of equine laminitis. Further studies are needed to determine whether inhibitors of ET-1 converting enzyme or antagonists of ET-1 receptors might be useful in the treatment and prevention of laminitis in horses.

Topics: Acute Disease; Animals; Chronic Disease; Connective Tissue; Endothelin-1; Female; Foot Diseases; Hoof and Claw; Horse Diseases; Horses; Inflammation; Male

Endothelins (ETs), in addition to their systematical activities, exert important functions at the skin level, such as increase of keratinocyte proliferation, neo-angiogenesis and leukocyte chemotaxis, which are among the main characteristics of psoriasis. To assess a possible ET-1 involvement in plaque-type psoriasis, ET-1 determinations were carried out in 15 sera and 8 lesional and non-lesional biopsy skin extracts from psoriatic patients and in 15 sera and 5 biopsy skin extracts from healthy volunteers, sex- and age-matched, using commercially available ELISA kits. A statistical analysis of the results showed that ET-1 levels were increased in sera of psoriatic patients, as compared to normal subjects (p = 0.04). In addition, there was a significant correlation between both serum (r = 0.60, p = 0.02) and lesional skin (r = 0.80, p = 0.03) ET-1 values versus the Psoriasis Area and Severity Index scores. Significant increases of the lesional versus the non-lesional (p = 0.01) and versus the normal (p = 0.04) ET-1 skin extract values were observed, together with a significant correlation between lesional and non-lesional ET-1 skin levels (r = 0.79, p = 0.03). These findings were also confirmed at the mRNA level, using RT-PCR analysis, where increased ET-1 mRNA levels, densitometrically measured, were found in the lesional samples versus non-lesional and normal skin. Since interleukin-8 is involved in psoriasis and shares some biological properties with ET-1, we further evaluated the levels of this cytokine in skin extracts. The behaviour of interleukin-8 paralleled that of ET-1, and a significant correlation between these two molecules was observed in the lesional skin (r = 0.76, p = 0.05). Taken together, these data stress that, as previously described for interleukin-8, ET-1 may be involved in inflammatory processes associated with psoriasis.

Topics: Adult; Aged; DNA Primers; Endothelin-1; Female; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Polymerase Chain Reaction; Psoriasis; Severity of Illness Index; Skin; Transcription, Genetic; Up-Regulation

To investigate the characteristics of anterior chamber inflammatory reaction induced by intravitreal injection of endothelin-1 (ET-1).. The time course of changes in aqueous protein concentration (APC) after intravitreal injection of 10(-4), 10(-5), 10(-6) and 10(-7) M ET-1 into rabbit eyes was measured with a laser flare-cell meter. The influence of a topical diclofenac sodium (DFNa) pre- and post-treatment was assessed. Aqueous prostaglandin E2 and leukotriene B4 concentration was quantified using a radioimmunoassay technique.. Intravitreal injection of 10(-4) and 10(-5) M ET-1 significantly increased APC, while 10(-6) and 10(-7) M ET-1 did not induce anterior chamber inflammation. After 10(-5) M ET-1 injection, APC reached a maximum at 4 h post-treatment and returned to a normal level 48 h after injection. Eyes treated with 10(-4) M ET-1 displayed a bi-phasic time course, with peak values observed 4 to 8 h as well as 48 h after administration. Pre- and post-treatment with topical DFNa completely suppressed the APC increase in the 10(-5) M ET-1 preparation, and considerably inhibited it in the 10(-4) M ET-1 preparation. After ET-1 injection, aqueous prostaglandin E2 concentration increased significantly, followed by an increase in APC. There were no changes in leukotriene B4 concentration.. ET-1 induces anterior chamber inflammation via the cyclooxygenase pathway of the arachidonic acid cascade. The lipoxygenase pathway is not involved in this reaction.

Topics: Administration, Topical; Animals; Anterior Chamber; Aqueous Humor; Cyclooxygenase Inhibitors; Diclofenac; Dinoprostone; Endothelin-1; Eye Proteins; Female; Inflammation; Injections; Leukotriene B4; Male; Rabbits; Radioimmunoassay; Uveitis, Anterior; Vitreous Body

The "American Heart Association Committee on Vascular Lesions" suggests the following morphologic classification of atherosclerotic plaques: the classification is based on large autopsy studies facilitating the assessment of the natural course of atherosclerotic lesions at precisely defined progression prone areas of the coronary tree from their clinically silent beginning to the stage where they produce symptoms. Lesion evolution is divided in 5 phases reflecting the possible time course of plaque development. Each phase is characterized by plaques with a distinctive morphology. The classification offers a framework of typical morphologies which the results of clinical investigations may be related to. Looking at the plaque composition, it is readily conceivable that atherosclerosis shares many characteristics with the general pathology of chronic inflammation and wound healing. Clinical symptoms e.g. acute coronary syndromes, arise from inflammation-mediated endothelial erosion and/or plaque rupture with ensuring coronary thrombosis. Advanced or complicated plaques are composed of different kinds of constituents in varying proportions. However, plaques at risk display a large lipid core occupying more than 40% of the plaque's volume, increased numbers of macrophages, reduced numbers of smooth muscle cells, an increased expression of tissue factor, and a thin plaque cap. Functionally, active plaques are characterized by a locally enhanced vasoreactivity with evidence coming from our own recent investigations that localised chronic inflammatory processes within the atherosclerotic plaque are responsible not only for the plaque rupture itself, but also for the hyperreactivity of these vessels to vasoconstrictor stimuli. In this context endothelin 1 (ET-1), a very potent vasoconstrictor peptide, may play an important role. ET-1 was originally reported to be produced by endothelial cells and to act locally in a paracrine fashion to regulate vascular tone. However, further studies have clarified that ET-1 is not only produced by endothelial cells but also by human inflammatory cells suggesting a role for ET-1 in inflammatory processes. Additionally, ET-1 displays a potent mitogenic activity. We examined immunohistochemically the presence of ET-1 in coronary plaque tissue obtained by directional coronary atherectomy. ET-1 immunoreactivity preferentially localized in plaque components indicative of a chronic inflammatory process. In addition, semiquantitative a

Topics: Adult; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Femoral Artery; Humans; Immunohistochemistry; Inflammation

To clarify relationships between the (endothelial vasodilatory and vasoconstrictive function) and leukocyte inflammatory mediators in subjects with asymptomatic atherosclerosis, we measured (intraplatelet cyclic 3',5'-guanosine monophosphate [cGMP] and cyclic 3',5'-adenosine monophosphate [cAMP]), plasma endothelin (ET-1), and plasma neopterin in 197 subjects with asymptomatic atherosclerosis (median age 63 years, range 49-69 years). We measured neutrophil protease 4 (NP4), tumor necrosis factor (TNFmu), soluble tumor necrosis factor receptor-1 (sTNFR-1), and neutrophil gelatinase associated lipocalin (NGAL) in 152 of the 197 subjects. Intraplatelet cGMP correlated inversely with plasma ET-1 (r=-0.22; p=0.01), which confirms earlier in vitro data of the inhibitory effect of ET-1 on NO production and/or the cGMP mediated inhibitory effect of NO on ET-1 production. Plasma neopterin as well as NP4 correlated directly with intraplatelet cGMP (r=0.24; p<0.01 and r=0.33; p<0.001, respectively). Intraplatelet cAMP correlated directly with plasma TNFmu (r=0.17; p<0.05) and sTNFR-1 (r=0.20; p<0.05). The relationship between leukocyte derived inflammatory mediators and intraplatelet cyclic nucleotides suggest an antiaggregating effect of leukocytes upon platelets, which may constitute a negative feedback mechanism that inhibits platelet activation during the atherosclerotic inflammatory process.

Topics: Aged; Arteriosclerosis; Blood Platelets; Carotid Artery, Common; Carotid Stenosis; Cyclic AMP; Cyclic GMP; Cytokines; Endothelin-1; Female; Humans; Inflammation; Leukocytes; Male; Middle Aged; Myeloblastin; Neopterin; Platelet Aggregation; Prospective Studies; Risk Factors; Serine Endopeptidases; Ultrasonography

We measured the time course of aqueous protein concentration (APC) with a laser flare-cell meter after the injection of endothelin-1 (ET-1) into the vitreous cavity of pigmented rabbits and investigated the influence of pre- or post-treatment with an anti-prostaglandin agent on these effects of ET-1. Injection of ET-1 significantly increased APC in a dose-dependent fashion. After 10(-5)M ET-1 injection, APC reached maximum at 4 hours after treatment and returned to the normal level 24 hours after the injection. On the other hand, the 10(-4)M ET-1 model displayed a bi-phase time course, with a peak value observed at 4 approximately 8 hours and 48 hours post-treatment, and APC did not return to normal even 7 days after treatment. Treatment with anti-prostaglandin agents before and after the injection blocked APC increase completely in the 10(-5)M ET-1 model, and partially in the 10(-4)M ET-1 model. These results indicate that ET-1 effects on APC are at least partially mediated by the cyclooxygenase pathway of the arachidonic acid cascade.

Topics: Animals; Anterior Chamber; Cyclooxygenase Inhibitors; Diclofenac; Endothelin-1; Female; Inflammation; Male; Prostaglandin Antagonists; Proteins; Rabbits; Vitreous Body

To assess the receptors which mediate the inflammatory reaction induced by endothelin-1 (ET-1), we investigated the influence of pre-treatment with an ETA receptor antagonist (97-139) on the increase of aqueous protein concentration (APC) after the injection of ET-1 (10(-4), 10(-5)M) into the vitreous cavity of pigmented rabbits. The concentration of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the aqueous humor after the injection of 10(-4)M ET-1 with or without pre-treatment with 97-139 (10(-1), 10(-2), 10(-3)M) was also studied. Pre-treatment with 10(-2)M and 10(-1)M 97-139 completely prevented the APC increase induced by 10(-5)M and 10(-4)M ET-1, respectively. Increases in aqueous PGE2 concentration were observed after the injection of ET-1, which was inhibited by pre-treatment with 97-139. Aqueous LTB4 concentration was not changed significantly by ET-1. These results indicate that the effects of ET-1 on APC are at least partially mediated by the cyclooxygenase pathway of arachidonic acid cascade, and that ETA receptors play an important role in these reactions.

Topics: Animals; Anterior Chamber; Aqueous Humor; Caffeic Acids; Dinoprostone; Endothelin Receptor Antagonists; Endothelin-1; Female; Inflammation; Leukotriene B4; Male; Oleanolic Acid; Rabbits; Receptor, Endothelin A; Receptors, Endothelin; Vitreous Body

There is evidence that tumour necrosis factor alpha (TNF alpha) may be an important mediator in initiating asthmatic airway inflammation. It has been proposed that endothelin-1 (ET-1) is involved in bronchoconstriction and airway remodelling in asthma. It is not known, however, if there is any interaction between TNF alpha and ET in perpetuating airway inflammation in asthma.. The present study aimed to determine the activities of ET-1 and TNF alpha in ovalbumin-sensitized guinea pigs and their roles in the development of airway inflammation.. Twelve guinea pigs were sensitized by ovalbumin injection and aerosol inhalation. ET-1 levels were measured in both bronchoalveolar lavage fluid (BALF) and plasma by 125-labelled endothelin-1 (ET-1) radioimmunoassay. The TNF alpha activity released from alveolar macrophage (AM) in BALF was estimated by ELISA. Cultured bovine airway smooth muscle cells (BASMCs) were treated with TNF alpha (1000 units/5 x 10(4) cells) for different times. ET-1 levels in harvested medium from these cells were measured by radioimmunoassay. Cultured human fetal lung fibroblasts (HFLFs) were incubated with ET-1 (10(-8) approximately 10(-6)M), then 3HTdR incorporation to these cells and cell counting were performed. The effects of ET-1 stimulation on the granulocyte macrophage colony stimulating factor (GM-CSF) gene expression in HFLFs were estimated by using RT-PCR method.. ET-1 levels in both plasma and BALF were significantly higher in ovalbumin-sensitized guinea-pigs compared with those in controls (422.27 +/- 175.0 pg/mL vs 277.311 +/- 88.0 pg/mL, P < 0.05, 81.22 +/- 16.15 vs 49.81 +/- 12.64 pg/mL, P < 0.05) while TNF alpha activity was also significantly increased in the OVA-sensitized group compared with that in the control group (6010 +/- 1900 pg/mL vs 2810 +/- 450 pg/mL, P < 0.05). The ET-1 level in harvested medium of BASMCs rose significantly in 12 h in the TNF-alpha treated group (from < 5 pg/mL to 53.72 +/- 14.3 pg/mL, P < 0.001), and remained at a similar level for 24 h in the TNF alpha treated group. It was shown that ET-1 not only stimulated cell proliferation but also induced GM-CSF mRNA expression in HFLFs.. ET-1 levels in both plasma and BALF and TNF alpha release from macrophage are increased significantly in ovalbumin-sensitized guinea-pigs. TNF alpha stimulates ET-1 secretion from cultured BASMCsw; ET-1 accelerates cell proliferation and induces GM-CSF mRNA expression in the human fetal lung fibroblast.

Topics: Administration, Inhalation; Animals; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Cells, Cultured; Endothelin-1; Fibroblasts; Gene Expression; Granulocyte-Macrophage Colony-Stimulating Factor; Guinea Pigs; Inflammation; Macrophages, Alveolar; Male; Ovalbumin; Plasma; Tumor Necrosis Factor-alpha

To investigate the mechanism of endothelin (ET) inflammatory effects on human mesangial cells (HMC).. The following experiments were performed on cultured HMC after ET-1 stimulation: (1) the expression of tumor necrosis factor-alpha (TNF alpha), interleukin-1 beta (IL-1 beta), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelin-1 (ET-1) itself messenger ribonucleic acid (mRNA) was determined by Northern Blot analysis; (2) the TNF alpha concentration was tested with radioimmunoassay; the IL-1 activity was assayed by the enhancement of thymocyte proliferation in response to mitogen; the surface expression of ICAM-1 and VCAM-1 was measured with cell enzyme linked immunoadsorbent assay (ELISA) analysis.. ET-1 (10(-7) mol/L) induced the following changes on HMC: (1) up-regulation of the expression of TNF alpha mRNA and protein; (2) up-regulation of the expression of ICAM-1 and VCAM-1 mRNA and protein; (3) up-regulation of the expression of ET-1 itself mRNA. However, the expression of IL-1 mRNA and protein was not changed.. ET-1 can stimulate HMC to produce TNF alpha, ICAM-1 and VCAM-1, and thereby induce inflammatory effects. ET-1 can also stimulate HMC to up-regulate the expression of ET-1 itself, so as to amplify inflammatory effects. So, ET-1 is actually an inflammatory mediator and may play an important role in the pathogenesis of glomerulonephritis.

Topics: Cells, Cultured; Endothelin-1; Glomerular Mesangium; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-1beta; Interleukin-6; Peptide Fragments; Tumor Necrosis Factor-alpha; Up-Regulation; Vascular Cell Adhesion Molecule-1

Interferon-inducible protein-10 (IP-10) is a member of the C-X-C chemokine family. Using mRNA differential display, we isolated a rat homologue to murine and human IP-10 from lipopolysaccharide-stimulated carotid arteries. Our studies demonstrated that IP-10 is a potent mitogenic and chemotactic factor for vascular smooth muscle cells, the critical features of smooth muscle cells for their contribution to the pathogenesis of atherosclerosis and restenosis. IP-10 induced a concentration-dependent stimulation of DNA synthesis, cell proliferation, and cell migration of rat aortic smooth muscle cells. A concentration- and time-dependent IP-10 mRNA induction was observed in lipopolysaccharide- or interferon-gamma-stimulated, but not interleukin-1beta- or tumor necrosis factor-alpha-stimulated smooth muscle cells. A marked synergistic effect on IP-10 mRNA expression was observed when smooth muscle cells were challenged with interferon-gamma together with interleukin-1beta or tumor necrosis factor-alpha. Furthermore, IP-10 mRNA expression was induced in the rat carotid artery after balloon angioplasty. The mitogenic and chemotactic features of IP-10 for smooth muscle cells, along with its discrete induction in cultured vascular smooth muscle cells and in carotid arteries after balloon angioplasty (neointima formation) suggest that IP-10 may play an active and distinct role in vascular remodeling processes.

Topics: Angioplasty, Balloon; Animals; Base Sequence; Carotid Arteries; Cell Division; Cell Movement; Chemokine CXCL10; Chemokines, CXC; Cytokines; DNA; Endothelin-1; Gene Expression; Inflammation; Interferon-gamma; Interleukin-1; Lipopolysaccharides; Molecular Sequence Data; Muscle, Smooth, Vascular; Platelet-Derived Growth Factor; Rats; RNA, Messenger; Tumor Necrosis Factor-alpha