endothelin-1 and Multiple-Organ-Failure

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

Sepsis causes significant alterations in the hepatic macro- and microcirculation. Diverging views exist on global hepatic blood flow during experimental sepsis because of the large variety in animal and sepsis models. Fluid-resuscitated clinical sepsis is characterized by ongoing liver ischemia due to a defective oxygen extraction despite enhanced perfusion. The effects of vasoactive agents on the hepatosplanchnic circulation are variable, mostly anecdotal, and depend on baseline perfusion, time of drug administration, and use of concomitant medication. Microvascular blood flow disturbances are thought to play a pivotal role in the development of sepsis-induced multiorgan failure. Redistribution of intrahepatic blood flow in concert with a complex interplay between sinusoidal endothelial cells, liver macrophages, and passing leukocytes lead to a decreased perfusion and blood flow velocity in the liver sinusoids. Activation and dysfunction of the endothelial cell barrier with subsequent invasion of neutrophils and formation of microthrombi further enhance liver tissue ischemia and damage. Substances that regulate (micro)vascular tone, such as nitric oxide, endothelin-1, and carbon monoxide, are highly active during sepsis. Possible interactions between these mediators are not well understood, and their therapeutic manipulation produces equivocal or disappointing results. Whether and how standard resuscitation therapy influences the hepatic microvascular response to sepsis is unknown. Indirect evidence supports the concept that improving the microcirculation may prevent or ameliorate sepsis-induced organ failure.

Topics: Animals; Carbon Monoxide; Endothelin-1; Humans; Liver; Liver Circulation; Microcirculation; Multiple Organ Failure; Nitric Oxide; Sepsis; Shock, Septic; Splanchnic Circulation

Topics: Animals; Bosentan; Bronchoconstriction; Capillary Permeability; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Humans; Multiple Organ Failure; Peptides, Cyclic; Receptor, Endothelin A; Receptor, Endothelin B; Shock, Septic; Sulfonamides; Vasoconstriction

Endothelin-1 (ET-1) is the most potent known vasoconstrictor. Elevated plasma levels have been demonstrated in patients with myocardial infarction, cardiogenic and septic shock, and respiratory, heart, and kidney failure, as well as in those undergoing elective abdominal aortic aneurysm (AAA) repair. However, endothelin levels have not previously been examined in patients undergoing repair of ruptured AAA. We hypothesized that hemorrhagic shock, lower torso ischemia, and reperfusion associated with ruptured AAA repair lead to increased synthesis and secretion of ET-1, which, in turn, predispose to organ failure, one of the principal causes of death in this condition.. Fourteen patients were studied. Plasma levels of big ET-1 and ET-1 were measured immediately before operation and immediately before, 5 minutes, and 6 hours after aortic clamp release.. All patients survived for at least 24 hours after operation. Big ET-1 levels were above the normal range at one or more sample points in all patients, and the ET-1 levels were above the normal range in all survivors and four of five nonsurvivors. Five patients who died of organ failure had significantly lower big ET-1 levels at all sample points and significantly lower ET-1 levels after 5 minutes of reperfusion when compared with survivors. Preoperative ET-1 levels were significantly lower in eight patients who subsequently developed kidney failure than in six patients who did not.. Contrary to our original hypothesis, these novel data demonstrate that patients with ruptured AAA in whom fatal postoperative organ failure develops have significantly lower perioperative endothelin levels than survivors.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Aneurysm, Ruptured; Aortic Aneurysm, Abdominal; Endothelin-1; Female; Follow-Up Studies; Humans; Male; Multiple Organ Failure; Postoperative Complications; Postoperative Period; Preoperative Care; Probability; Prospective Studies; Risk Assessment; Sensitivity and Specificity; Statistics, Nonparametric; Survival Rate; Treatment Outcome

To investigate the expression levels of serum soluble Endoglin (sEng), plasma endothelin-1 (ET-1) and coagulation function in patients suffering from early onset severe preeclampsia with organ dysfunction, and to analyze the clinical significance.. Forty-nine early onset severe preeclampsia patients were enrolled in the study group, including 26 cases without organ dysfunction (study group I) and 23 cases with organ dysfunction (study group II). The control group included 30 cases of health pregnant women during the same period of gestation. The serum levels of sEng and plasma ET-1 were analyzed with enzyme-linked immunosorbent assay (ELISA), coagulation function was determined at the same time, and the relationship between the change in levels of sEng, ET-1, coagulation function and organ function, and also outcome of perinatal infants.. (1) The levels of sEng, ET-1, fibrinogen (Fib) and mean platelet volume (MPV) of the study group I and II were significantly higher compared with control group (sEng, microg/L: 10.96+/-3.21, 14.17+/-4.02 vs. 7.49+/-2.73; ET-1, microg/L: 41.54+/-10.37, 65.91+/-12.46 vs. 24.56+/-6.26; Fib, g/L: 4.41+/-1.02, 5.35+/-1.17 vs. 3.69+/-0.82; MPV, fl: 11.71+/-1.21, 13.89+/-1.76 vs. 11.03+/-0.82, all P<0.05), and prothrombin time (PT), activated partial thromboplastin time (APTT) and platelet (PLT) were significantly lower compared with control group (PT, s: 10.73+/-1.82, 8.37+/-1.51 vs. 12.95+/-1.91; APTT, s: 26.14+/-4.32, 22.69+/-3.77 vs. 30.25+/-4.71; PLT, x10(9)/L: 164.17+/-50.67, 136.43+/-51.21 vs. 201.63+/-59.83, all P<0.05). There were also statistical significances in all the values between study group I and II (all P<0.05). (2) There was positive correlation between the sEng level and systolic pressure, diastolic pressure, Fib, urine protein of 24 hours, serum creatinine (SCr); there was negative correlation between the sEng level and albumin (Alb) content, PT, estriol/creatinine (E/C) of 12-hour urine, fetal birth weight (all P<0.01). There was positive correlation between the level of ET-1 and the systolic pressure, diastolic pressure, Fib, urine protein of 24 hours, SCr, or alanine aminotransferase (ALT); there was negative correlation between the level of ET-1 and Alb, PT, E/C of 12-hour urine, or fetal birth weight (P<0.05 or P<0.01). (3)In the study group, the occurrence rate of the heart, kidney and lung dysfunction, placental abruption and perinatal death of infants increased (69.23% vs. 11.11%, 38.46% vs. 2.78%, 38.46% vs. 2.78%, 46.15% vs. 2.78%, 53.85% vs. 2.78%, all P<0.01) when the content of sEng>or=16 microg/L compared with sEng<16 microg/L; the occurrence rate of heart, kidney, liver and lung dysfunction, placental abruption and perinatal death of infants increased (64.28% vs. 11.43%, 35.71% vs. 2.86%, 28.57% vs. 5.71%, 28.57% vs. 5.71%, 35.71% vs. 5.71%, 42.86% vs. 5.71%, all P<0.01) when the level of ET-1>or=70 microg/L compared with ET-1<70 microg/L; the occurrence rate of multiple organ dysfunction syndrome was 90% (9/10) when PT<7 s, APTT<20 s and PLT<100x10(9)/L.. The elevation of levels of serum sEng, plasma ET-1 and coagulation abnormality may contribute to the pathogenesis of the organ dysfunction in early onset severe preeclampsia, and the detection of the above-mentioned indexes has important clinical value.

Topics: Antigens, CD; Blood Coagulation; Endoglin; Endothelin-1; Female; Humans; Multiple Organ Failure; Pre-Eclampsia; Pregnancy; Prospective Studies; Receptors, Cell Surface

To investigate the effect of baicalin and octreotide on the expression levels of P-selectin protein in multiple organs of rats with severe acute pancreatitis and explore the underlying mechanism.. Rats were randomly divided into sham-operated, model control, baicalin-treated and octreotide-treated groups. At 3, 6 and 12 h after operation, the mortality rates of rats, the contents of plasma endotoxin as well as serum NO and ET-1, the pathological changes in multiple organs, and the expression levels of P-selectin protein in each group were observed.. At 12 h after operation, the mortality rates of rats in treated groups were significantly lower than that in the model control group (P < 0.05), and the pathological severity scores in multiple organs in treated groups were also significantly lower than those in the model control group (P < 0.05). The contents of plasma endotoxin, serum PLA(2) (at 6 and 12 h after operation), ET-1 and NO (at 3 and 12 h after operation) in treated groups were significantly lower than those in the model control group (P < 0.05, P < 0.01 or P < 0.001). In the baicalin-treated group, the expression levels of P-selectin protein in liver (at 3 h after operation), kidney (at 3 and 6 h after operation), pancreas, lung and spleen were significantly lower than those in the model control group (P < 0.01). In the octreotide-treated group, the expression levels of this protein in lung, intestinal mucosa (at 6 and 12 h after operation), lymph nodes (at 3 and 6 h after operation), spleen and thymus were significantly lower than those in the model control group (P < 0.05). Additionally, the products of the staining intensity and positive rate of P-selectin protein in pancreas, spleen (at 3 h after operation), intestinal mucosa (at 6 h after operation), thymus (at 6 h after operation) and lung (at 6 h after operation) in treated groups were significantly lower than those in the model control group (P < 0.05).. Both baicalin and octreotide can exert some protective effects on multiple organs and the former is superior to the latter in protecting pancreas. Furthermore, decreasing the expression levels of P-selectin protein in these organs is one of the possible mechanisms.

Topics: Acute Disease; Animals; Biomarkers; Disease Models, Animal; Endothelin-1; Endotoxins; Flavonoids; Immunohistochemistry; Male; Multiple Organ Failure; Nitric Oxide; Octreotide; P-Selectin; Pancreatitis; Phospholipases A2; Protective Agents; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Taurocholic Acid; Time Factors; Tissue Array Analysis

To establish an ideal model of multiple organ injury of rats with severe acute pancreatitis (SAP).. SAP models were induced by retrograde injection of 0.1 mL/100 g 3.5% sodium taurocholate into the biliopancreatic duct of Sprague-Dawley rats. The plasma and samples of multiple organ tissues of rats were collected at 3, 6 and 12 h after modeling. The ascites volume, ascites/body weight ratio, and contents of amylase, endotoxin, endothelin-1 (ET-1), nitrogen monoxidum (NO), phospholipase A(2) (PLA(2)), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) in plasma were determined. The histological changes of multiple organs were observed under light microscope.. The ascites volume, ascites/body weight ratio, and contents of various inflammatory mediators in blood were higher in the model group than in the sham operation group at all time points [2.38 (1.10), 2.58 (0.70), 2.54 (0.71) vs 0.20 (0.04), 0.30 (0.30), 0.22 (0.10) at 3, 6 and 12 h in ascites/body weight ratio; 1582 (284), 1769 (362), 1618 (302) (U/L) vs 5303 (1373), 6276 (1029), 7538 (2934) (U/L) at 3, 6 and 12 h in Amylase; 0.016 (0.005), 0.016 (0.010), 0.014 (0.015) (EU/mL) vs 0.053 (0.029), 0.059 (0.037), 0.060 (0.022) (EU/mL) at 3, 6 and 12 h in Endotoxin; 3.900 (3.200), 4.000 (1.700), 5.300 (3.000) (ng/L) vs 41.438 (37.721), 92.151 (23.119), 65.016 (26.806) (ng/L) at 3, 6 and 12 h in TNF-alpha, all P < 0.01]. Visible congestion, edema and lamellar necrosis and massive leukocytic infiltration were found in the pancreas of rats of model group. There were also pathological changes of lung, liver, kidney, spleen, ileum, lymphonode, thymus, myocardium and brain.. This rat model features reliability, convenience and a high achievement ratio. Complicated with multiple organ injury, it is an ideal animal model of SAP.

Topics: Acute Disease; Amylases; Animals; Ascitic Fluid; Body Weight; Brain; Disease Models, Animal; Endothelin-1; Endotoxins; Feasibility Studies; Ileum; Interleukin-6; Kidney; Liver; Lymph Nodes; Male; Multiple Organ Failure; Myocardium; Nitric Oxide; Pancreas; Pancreatitis; Phospholipases A; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Severity of Illness Index; Taurocholic Acid; Thymus Gland; Time Factors; Tumor Necrosis Factor-alpha

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

Heme oxygenase (HO)-1 is an enzyme that degrades heme to generate CO (a vasodilatory gas), iron, and the potent antioxidant bilirubin. A disease process characterized by decreases in vascular tone and increases in oxidative stress is endotoxic shock. Moreover, HO-1 is markedly induced in multiple organs after the administration of endotoxin (lipopolysaccharide [LPS]) to mice.. To determine the role of HO-1 in endotoxemia, we administered LPS to mice that were wild-type (+/+), heterozygous (+/-), or homozygous null (-/-) for targeted disruption of HO-1. LPS produced a similar induction of HO-1 mRNA and protein in HO-1(+/+) and HO-1(+/-) mice, whereas HO-1(-/-) mice showed no HO-1 expression. Four hours after LPS, systolic blood pressure (SBP) decreased in all the groups. However, SBP was significantly higher in HO-1(-/-) mice (121+/-5 mm Hg) after 24 hours, compared with HO-1(+/+) (96+/-7 mm Hg) and HO-1(+/-) (89+/-13 mm Hg) mice. A sustained increase in endothelin-1 contributed to this SBP response. Even though SBP was higher, mortality was increased in HO-1(-/-) mice, and they exhibited hepatic and renal dysfunction that was not present in HO-1(+/+) and HO-1(+/-) mice. The end-organ damage and death in HO-1(-/-) mice was related to increased oxidative stress.. These data suggest that the increased mortality during endotoxemia in HO-1(-/-) mice is related to increased oxidative stress and end-organ (renal and hepatic) damage, not to refractory hypotension.

Topics: Animals; Endothelin-1; Endotoxemia; Female; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hypotension; Lipopolysaccharides; Lung; Membrane Proteins; Mice; Mice, Inbred BALB C; Mortality; Multiple Organ Failure; Oxidative Stress; RNA, Messenger

Recently much attention has been paid to the circulatory disturbance and peripheral vascular damage in patients with sepsis and septic shock. We intended to elucidate the interaction between nitric oxide (NO) and endothelin (ET)-1 under various pathological conditions by measuring the concentrations of NO3-, the principal metabolite of NO and immunoreactive ET-1. In cases with good prognosis after the septic shock, ET-1 was significantly higher as compared with these in sepsis without shock. In lethal cases with septic shock, these parameters were abnormally high as compared with the survived case. These levels elevated as the degree of severity progressed. When patients recovered from the septic shock, plasma ET-1 levels rapidly decreased. These results may mean that the level of the concentration of ET-1 plays a key role for prevention of the multiple organ failure even after the recovery from septic shock. The elevated level of NO3- during the initial several days in septic shock will mean that NO is acting to prevent platelet aggregation and to keep blood flow by dilating the arteries during septic shock. On the contrary, it may also be suggested that the elevated level of NO3- and ET-1 leads to the dysfunction of vascular endothelial cells and the apoptosis.

Topics: Adult; Biomarkers; Endothelin-1; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Nitric Oxide; Prognosis; Sepsis; Severity of Illness Index; Shock, Septic

The vasodilator nitric oxide (NO) is involved in the regulation of systemic blood pressure and local organ blood flow. Inhibitors of the constitutively expressed nitric oxide synthase in endothelial cells (eNOS), e.g., Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME), aggravated liver injury in a variety of models. On the other hand, inhibitors of the inducible NOS (iNOS), e.g., 2-aminoethyl-isothiourea (AET), were found to be beneficial during endotoxemia. The aim of this investigation was to study the effect of AET compared with L-NAME on liver microvascular blood flow and injury in more complex models with multiple insults, i.e., ischemia (20 min)-reperfusion (8 h) in combination with .5 mg/kg endotoxin (IRE). Male Fisher rats were treated with 10 mg/kg AET or L-NAME and subjected to IRE. At 8 h, liver injury (plasma ALT: 1320+/-164 U/L) was significantly increased in AET-treated (5,018+/-1,379 U/L) and L-NAME-treated groups (2,429+/-228 U/L). Each inhibitor attenuated microvascular blood flow (assessed by laser Doppler flowmetry) to a similar degree. In striking contrast, AET completely reversed the endotoxin-induced impairment of the microvascular blood flow and significantly protected against an endotoxin-induced liver injury (plasma ALT: 3,007+/-268 U/L (ET); 460+/-39 U/L (ET+AET)). Infusion of endothelin-1 reduced microvascular blood flow by 50-60% and caused liver injury. Our data demonstrated that an inhibitor of eNOS (L-NAME) has a consistent detrimental effect on liver injury during ischemia-reperfusion and endotoxemia mainly because it can cause additional ischemia by reducing the microvascular blood flow. However, selective inhibitors of iNOS (AET) can impair hepatic blood flow and aggravate the injury or improve blood flow and attenuate organ injury depending on the experimental model. These results suggest that iNOS inhibitors may not be universally beneficial and should be tested in a variety of experimental models of sepsis/endotoxemia before used in clinical settings.

Topics: Alanine Transaminase; Animals; beta-Aminoethyl Isothiourea; Blood Circulation; Blood Pressure; Endothelin-1; Endotoxemia; Glutathione; Ischemia; Liver; Liver Circulation; Male; Multiple Organ Failure; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; Rats; Rats, Inbred Strains; Reperfusion

This experiment was designed to help understand the cascade of events that end in renal impairment in septic animals.. Twenty 3- to 8-day-old piglets were anesthetized and the femoral artery, jugular and femoral veins, and bladder were catheterized. After stabilization under anesthesia with ventilatory support, they were divided into a control group and three groups that received endotoxin (ETX) in doses of 0.01 mg/kg, 0.025 mg/kg, and 0.05 mg/kg. Blood pressure and blood gases were monitored continuously. Blood and urine samples were obtained before (B), 1 hour (E1), and 3 hours (E3) after the bolus of ETX to determine glomerular filtration rate (GFR), fractional excretion of sodium (FENa), tumor necrosis factor (TNF), and endothelin-1 (ET-1) levels.. Incremental doses of ETX induce greater release of ET-1 with an early proportionate increase in FENa (P< .05) and late decrease in GFR (P< .05). TNF release is dose and time dependent after ETX injection (P < .05).. ET-1 and FENa are the best tests to evaluate renal failure during early sepsis in neonatal piglets.

Topics: Acute Kidney Injury; Animals; Animals, Newborn; Endothelin-1; Multiple Organ Failure; Sepsis; Sodium; Swine; Tumor Necrosis Factor-alpha

Septic shock is characterised by a decrease in systemic vascular resistance. Nevertheless, regional increases in vascular resistance can occur which may predispose to organ dysfunction, including the adult respiratory distress syndrome (ARDS). Because endothelial damage is a major feature of acute lung injury, we examined whether the potent endothelial vasoconstrictor peptide endothelin-1 plays a pathophysiological role in sepsis or ARDS.. Plasma endothelin was measured in mixed venous, pulmonary capillary and arterial blood, and the relationship with outcome measures was determined.. The intensive care unit of a university teaching hospital.. A consecutive series of well-characterised patients with sepsis syndrome, both with (n = 11) and without (n = 15) ARDS, and ventilated controls without sepsis or ARDS (n = 7).. Plasma endothelin was significantly elevated in patients with sepsis alone and in patients with sepsis and ARDS. Plasma endothelin did not differ among mixed venous, pulmonary capillary and systemic arterial blood. On multiple regression analysis, plasma endothelin correlated positively with organ failure score and with oxygen consumption, and negatively with the PaO2 : FiO2 ratio. There was no correlation with plasma creatinine, suggesting that decreased renal clearance did not account for the high plasma endothelin concentrations.. Although the lung does not appear to be the major site of endothelin production in critically ill patients with sepsis, increased endothelin production may contribute to regional increases in vascular [correction of vacular] resistance, hyperfusion, and the development of organ failure, including ARDS, in patients with sepsis.

Topics: Case-Control Studies; Endothelin-1; Endothelium, Vascular; Humans; Lung; Multiple Organ Failure; Oxygen Consumption; Pulmonary Circulation; Pulmonary Gas Exchange; Regression Analysis; Respiratory Distress Syndrome; Severity of Illness Index; Systemic Inflammatory Response Syndrome; Vascular Resistance