interleukin-8 and Hypertension--Pulmonary

Chronic obstructive pulmonary disease (COPD) is currently one of the highest morbidity and mortality worldwide, a serious public health problem. Pulmonary hypertension is a common complication of COPD. At present, the pathogenesis of pulmonary hypertension is not clear. A concise overview of the known factors contributing to pulmonary hypertension in COPD includes hypoxia and inflammation. Hypoxia, resulting from lung damage and inadequate oxygen supply, can lead to pulmonary vasoconstriction and increased vascular resistance, thus contributing to the development of pulmonary hypertension in COPD patients. Inflammation also plays a significant role in the progression of pulmonary hypertension. COPD patients exhibit inflammatory responses in their lung tissues, with the release of various inflammatory mediators. These mediators can stimulate abnormal proliferation of endothelial cells and smooth muscle cells within the pulmonary arteries, leading to vascular wall thickening and restricted blood flow. This paper focuses on the pathogenesis of four inflammatory factors, namely interleukin (IL-1β), IL-6, IL-8, and tumor necrosis factor (TNF)-α, in pulmonary hypertension. IL-1β, IL-6, IL-8, and TNF-α are known as pro-inflammatory cytokines that play crucial roles in the inflammatory response. In the context of pulmonary hypertension, these inflammatory factors have been implicated in the remodeling of the pulmonary vasculature, leading to increased vascular resistance and impaired blood flow. The research presented in this paper will delve into the current scientific knowledge surrounding IL-1β, IL-6, IL-8, and TNF-α, and their roles in pulmonary vascular remodeling, endothelial dysfunction, smooth muscle cell proliferation, and inflammation. The goal is to provide a comprehensive overview of their involvement in pulmonary hypertension and how these factors may be influenced by the hypoxic environment prevalent in high-altitude regions. By focusing on the relevance of these inflammatory factors in high-altitude areas, we hope to contribute valuable insights that can inform clinical management strategies, prevention approaches, and potential therapeutic interventions for individuals residing in such regions who are at an increased risk of developing pulmonary hypertension.

Topics: Altitude; Endothelial Cells; Humans; Hypertension, Pulmonary; Hypoxia; Inflammation; Interleukin-6; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

Little is known about the effects of long-term nasal low-flow oxygen (NLFO) on mucus and symptoms and how this variable is affected by dry or cold humidified gas. The aim of this study was to investigate the effects of dry-NLFO and cold bubble humidified-NLFO on nasal mucociliary clearance (MCC), mucus properties, inflammation, and symptoms in subjects with chronic hypoxemia requiring long-term domiciliary oxygen therapy.. Eighteen subjects (mean age, 68 years; 7 male; 66% with COPD) initiating NLFO were randomized to receive dry-NLFO (n = 10) or humidified-NLFO (n = 8). Subjects were assessed at baseline, 12 h, 7 days, 30 days, 12 months, and 24 months by measuring nasal MCC using the saccharin transit test, mucus contact angle (surface tension), inflammation (cells and cytokine concentration in nasal lavage), and symptoms according to the Sino-Nasal Outcome Test-20.. Nasal MCC decreased significantly (40% longer saccharin transit times) and similarly in both groups over the study period. There was a significant association between impaired nasal MCC and decline in lung function. Nasal lavage revealed an increased proportion of macrophages, interleukin-8, and epidermal growth factor concentrations with decreased interleukin-10 during the study. No changes in the proportion of ciliated cells or contact angle were observed. Coughing and sleep symptoms decreased similarly in both groups. There were no outcome differences comparing dry vs cold bubble humidified NLFO.. In subjects receiving chronic NLFO, cold bubble humidification does not adequately humidify inspired oxygen to prevent deterioration of MCC, mucus hydration, and pulmonary function. The unheated bubble humidification performed no better than no humidification.. ClinicalTrials.gov; No.: NCT02515786; URL: www.clinicaltrials.gov.

Topics: Aged; Aged, 80 and over; Bronchiectasis; Cough; Cytokines; Disease Progression; Epidermal Growth Factor; Female; Humans; Humidifiers; Humidity; Hypertension, Pulmonary; Interleukin-10; Interleukin-8; Macrophages; Male; Middle Aged; Mucociliary Clearance; Mucus; Nasal Lavage Fluid; Oxygen Inhalation Therapy; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Respiratory Function Tests; Surface Tension

Pulmonary artery perfusion during cardiopulmonary bypass (CPB) is a novel adjunctive method, which can minimize the lung ischemic-reperfusion injury and inflammatory response. This study evaluated the protective effect of pulmonary perfusion with hypothermic HTK solution in corrections of congenital heart defects with pulmonary hypertension.. Between June 2009 and December 2009, 24 consecutive infants with congenital heart defects and pulmonary hypertension were randomly divided into perfused group (n = 12) and control group (n = 12). Oxygen index, alveolar-arterial O2 gradient, serum levels of malondialchehyche (MDA), interleukin (IL)-6, -8, -10, soluble intercellular adhesion molecule-1 (sICAM-1), and P-selectin were measured before commencement and serially for 48 hours after termination of bypass.. Oxygenation values were better preserved in the perfused group than in the control group. The serum levels of IL-6 increased immediately after CPB in both groups and returned to baseline at 48 hours after CPB,but it was restored faster and earlier in the perfused group. The serum levels of IL-8, sICAM-1, and MDA remained at baseline at each point after CPB in the perfused group and elevated significantly immediately after CPB in the control group, except for sICAM-1. The serum level of IL-10 increased immediately after CPB and decreased to baseline at 48 hours after CPB in both groups, but the IL-10 level in the perfused group was significantly higher than in the control group at 12 hours after CPB. The serum P-selectin levels in the control group immediately after CPB were significantly higher than prebypass levels. Moreover, there were no significant differences in postoperative clinical characters, except for the intubated time.. In infants with congenital heart defects, pulmonary perfusion with hypothermic HTK solution during cardiopulmonary bypass could ameliorate lung function and reduce the inflammatory response.

Topics: Cardiopulmonary Bypass; Child; Child, Preschool; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Intercellular Adhesion Molecule-1; Interleukin-10; Interleukin-6; Interleukin-8; Lung Injury; Male; Organ Preservation Solutions; P-Selectin; Perfusion; Pulmonary Artery

The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is considered to be associated with chronic inflammation; however, the underlying mechanism remains unclear. Recently, altered gut microbiota were found in patients with pulmonary arterial hypertension (PAH) and in experimental PAH models. The aim of this study was to characterize the gut microbiota in patients with CTEPH and assess the relationship between gut dysbiosis and inflammation in CTEPH.. In this observational study, fecal samples were collected from 11 patients with CTEPH and 22 healthy participants. The abundance of gut microbiota in these fecal samples was assessed using 16S ribosomal ribonucleic acid (rRNA) gene sequencing. Inflammatory cytokine and endotoxin levels were also assessed in patients with CTEPH and control participants.. The levels of serum tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-1α were elevated in patients with CTEPH. Plasma endotoxin levels were significantly increased in patients with CTEPH (P < 0.001), and were positively correlated with TNF-α, IL-6, IL-8, and MIP-1α levels. The 16S rRNA gene sequencing and the principal coordinate analysis revealed the distinction in the gut microbiota between patients with CTEPH (P < 0.01) and control participants as well as the decreased bacterial alpha-diversity in patients with CTEPH. A random forest analysis for predicting the distinction in gut microbiota revealed an accuracy of 80.3%.. The composition of the gut microbiota in patients with CTEPH was distinct from that of healthy participants, which may be associated with the elevated inflammatory cytokines and endotoxins in CTEPH.

Topics: Cytokines; Endotoxins; Gastrointestinal Microbiome; Humans; Hypertension, Pulmonary; Inflammation; Interleukin-8; Japan; Pulmonary Arterial Hypertension; RNA, Ribosomal, 16S; Tumor Necrosis Factor-alpha

Background: Inflammatory response and endothelial dysfunction contribute to the progression of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to assess changes in biomarkers involved in those processes in inoperable CTEPH patients treated with balloon pulmonary angioplasty (BPA). Methods: We enrolled 20 patients with inoperable CTEPH qualified for BPA and a control group. Interleukin 6, 8, 10 (IL-6, IL-8, IL-10), monocyte chemoattractant protein-1 (MCP-1), and C-reactive protein (hsCRP) constituted the markers of systemic inflammation. Endothelin 1 (ET-1) served as a marker of endothelial dysfunction. Selected markers were assessed before the BPA treatment, 24 h after the first BPA, and six months after completion of the BPA treatment. Results: At baseline, the CTEPH patients had increased serum concentrations of IL-6, IL-8 and ET-1. Twenty-four hours after a BPA session, we observed an increase in concentrations of IL-6 (∆ = 3.67 (1.41; 7.16); p < 0.001), of IL-10 (∆ = 0.25 (0; 0.47); p = 0.003), of MCP-1 (∆ = 111 (60.1; 202.8); p = 0.002), and of hsCRP (∆ = 4.81 (3.46; 8.47); p < 0.001). Six months after completion of the BPA treatment, there was a decrease in concentrations of IL-6 (∆ = −1.61 (−3.11; −0.20); p = 0.03), of IL8 (∆ = −3.24 (−7.72; 0.82); p = 0.01), and of ET-1 (∆ = −0.47 (−0.96; 0.05); p = 0.005). Conclusions: Patients with inoperable CTEPH exhibit increased systemic inflammation and endothelial dysfunction, which improves after completion of the BPA treatment. A single BPA session evokes an acute inflammatory response.

Topics: Angioplasty, Balloon; Biomarkers; C-Reactive Protein; Humans; Hypertension, Pulmonary; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Pulmonary Artery; Pulmonary Embolism

Pulmonary hypertension (PH) is defined by increased mean pulmonary artery pressure, and the clinical classification includes five etiologies, of which we investigated subgroup 1, pulmonary arterial hypertension (PAH) and subgroup 4, chronic thrombotic and/or embolic disease (CTEPH). Platelets participate in both innate and adaptive immune responses and could possibly contribute to the suggested systemic inflammation associated with PAH. In this study, we utilized flow cytometry to analyze platelet activation and platelet-monocyte (PMA) and granulocyte (PGA) aggregates in PAH and CTEPH patients and healthy control subjects. The plasma concentration of proinflammatory cytokines was measured by multiplex electrochemiluminescence. Our main finding is that circulating platelets are activated in the circulation and form aggregates with both monocytes and granulocytes in patients with idiopathic PAH (IPAH), associated PAH (APAH) and pulmonary hypertension due to CTEPH. There was a strong correlation between the platelet activation, assessed as P-selectin, and the number of aggregates formed. IL-6, IL-8, IL-10 and TNF-α were increased in all PH subgroups as compared to healthy controls, and PMAs were associated with circulating IL-6, IL-8 and IL-10, whereas PGAs were associated with IL-6. The increased concentrations of platelet-leukocyte aggregates found in PAH/CTEPH patients might thus contribute to the inflammatory state in PH.

Topics: Humans; Hypertension, Pulmonary; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Leukocytes; P-Selectin; Pulmonary Arterial Hypertension; Tumor Necrosis Factor-alpha

Pulmonary hypertension (PH) complicates the care of patients with chronic lung disease, such as idiopathic pulmonary fibrosis (IPF), resulting in a significant increase in morbidity and mortality. Disease pathogenesis is orchestrated by unidentified myeloid-derived cells. We used murine models of PH and pulmonary fibrosis to study the role of circulating myeloid cells in disease pathogenesis and prevention. We administered clodronate liposomes to bleomycin-treated wild-type mice to induce pulmonary fibrosis and PH with a resulting increase in circulating bone marrow-derived cells. We discovered that a population of C-X-C motif chemokine receptor (CXCR) 2

Topics: Animals; Arginase; Bleomycin; Cell Movement; Clodronic Acid; Female; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Interleukin-8; Male; Mice; Mice, Inbred C57BL; Myeloid Cells; Myeloid-Derived Suppressor Cells; Nitric Oxide Synthase Type II; Phenylurea Compounds; Receptors, Interleukin-8B

To investigate the effect of high-mobility group box 1 (HMGB1) on the proliferation, migration and inflammatory response of human pulmonary artery smooth muscle cells (HPASMCs) and human pulmonary artery endothelial cells (HPAECs) through the receptor for advanced glycation end products (RAGE) and to investigate the mechanism of action underlying the effect of HMGB1 on pulmonary arterial hypertension.. The effect of HMGB1 on the proliferation of the two cell types was examined using the MTT assay under environmental hypoxia (incubation with 1.5% oxygen) to simulate the condition of pulmonary arterial hypertension in the body. The effect of HMGB1 on HPAEC migration was observed using the scratch assay. The effect of HMGB1 on the inflammatory mediators IL-6 and CXCL8 in the two cell types was assessed using qPCR (Real-time Quantitative PCR) and ELISA, and the RAGE mRNA and protein expression levels were also examined.. Hypoxia promoted the proliferation of both cell types but inhibited the migration of HPAECs. HMGB1 had no obvious effect on the proliferation and migration of the cells. Both hypoxia and HMGB1 promoted the expression of the pro-inflammatory factors IL-6 and CXCL8. HMGB1 significantly promoted RAGE expression compared to the normal control group.. HMGB1 affects the functions of HPASMCs and HPAECs through RAGE and may affect the course of pulmonary arterial hypertension.

Topics: Cell Hypoxia; Cell Line; Cell Movement; Cell Proliferation; Endothelial Cells; HMGB1 Protein; Humans; Hypertension, Pulmonary; Interleukin-6; Interleukin-8; Lung; Myocytes, Smooth Muscle; Receptor for Advanced Glycation End Products; Recombinant Proteins

Nuclear factor kappa B (NF-kB)-mediated inflammatory gene expression and vascular endothelial cell proliferation/remodelling are implicated in the pathophysiology of the fatal disease, pulmonary arterial hypertension (PAH). Bromodomain and extra-terminal (BET) proteins are essential for the expression of a subset of NF-kB-induced inflammatory genes. BET mimics including JQ1+ prevent binding of BETs to acetylated histones and down-regulate the expression of selected genes.. The effects of JQ1+ on the proliferation of primary human pulmonary microvascular endothelial cells (HPMECs) from healthy subjects were measured by bromodeoxyuridine (BrdU) incorporation. Cell cycle progression was assessed by flow cytometry; mRNA and protein levels of cyclin-dependent kinases (CDKs), inhibitors and cytokines were determined by reverse transcription-quantitative PCR (RT-qPCR), Western blotting or ELISA. Histone acetyltransferase (HAT) and deacetylase (HDAC) activities were determined in nuclear extracts from whole lung of PAH and control patients.. JQ1+ significantly inhibited IL6 and IL8 (IL6 and CXCL8) mRNA and protein in HPMECs compared with its inactive enantiomer JQ1-. JQ1+ decreased NF-kB p65 recruitment to native IL6 and IL8 promoters. JQ1+ showed a concentration-dependent decrease in HPMEC proliferation compared with JQ1--treated cells. JQ1+ induced G1 cell cycle arrest by increasing the expression of the CDK inhibitors (CDKN) 1A (p21. Inhibition of BETs in primary HPMECs decreases inflammation and remodelling. BET proteins could be a target for future therapies for PAH.

Topics: Azepines; Cell Culture Techniques; Cell Proliferation; Down-Regulation; Endothelial Cells; Humans; Hypertension, Pulmonary; Inflammation; Interleukin-8; Lung; Microvessels; NF-kappa B; Proteins; Pulmonary Circulation; Triazoles; Vascular Remodeling

IL-32 is a multifaceted cytokine with a role in infections, autoimmune diseases, and cancer, and it exerts diverse functions, including aggravation of inflammation and inhibition of virus propagation. We previously identified IL-32 as a critical regulator of endothelial cell (EC) functions, and we now reveal that IL-32 also possesses angiogenic properties. The hyperproliferative ECs of human pulmonary arterial hypertension and glioblastoma multiforme exhibited a markedly increased abundance of IL-32, and, significantly, the cytokine colocalized with integrin αVβ3. Vascular endothelial growth factor (VEGF) receptor blockade, which resulted in EC hyperproliferation, increased IL-32 three-fold. Small interfering RNA-mediated silencing of IL-32 negated the 58% proliferation of ECs that occurred within 24 h in scrambled-transfected controls. Reduction of IL-32 neither affected apoptosis (insignificant changes in Bak-1, Bcl-2, Bcl-xL, lactate dehydrogenase, annexin V, and propidium iodide) nor VEGF or TGF-β levels, but siIL-32-transfected adult and neonatal ECs produced up to 61% less NO, IL-8, and matrix metalloproteinase-9, and up to 3-fold more activin A and endostatin. In coculture-based angiogenesis assays, IL-32γ dose-dependently increased tube formation up to 3-fold; an αVβ3 inhibitor prevented this activity and reduced IL-32γ-induced IL-8 by 85%. In matrigel plugs loaded with IL-32γ, VEGF, or vehicle and injected into live mice, we observed the anticipated VEGF-induced increase in neocapillarization (8-fold versus vehicle), but unexpectedly, IL-32γ was equally angiogenic. A second signal such as IFN-γ was required to render cells responsive to exogenous IL-32γ; importantly, this was confirmed using a completely synthetic preparation of IL-32γ. In summary, we add angiogenic properties that are mediated by integrin αVβ3 but VEGF-independent to the portfolio of IL-32, implicating a role for this versatile cytokine in pulmonary arterial hypertension and neoplastic diseases.

Topics: Activins; Animals; Apoptosis; Cells, Cultured; Endostatins; Familial Primary Pulmonary Hypertension; Glioblastoma; Human Umbilical Vein Endothelial Cells; Humans; Hypertension, Pulmonary; Integrin alphaVbeta3; Interferon-gamma; Interleukin-8; Interleukins; Matrix Metalloproteinase 9; Mice; Neovascularization, Pathologic; Nitrogen Oxides; Receptors, Vascular Endothelial Growth Factor; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

Airway inflammation and remodeling are major features of chronic obstructive pulmonary disease (COPD), whereas pulmonary hypertension is a common comorbidity associated with a poor disease prognosis. Recent studies in animal models have indicated that increased arginase activity contributes to features of asthma, including allergen-induced airway eosinophilia and mucus hypersecretion. Although cigarette smoke and lipopolysaccharide (LPS), major risk factors for COPD, may increase arginase expression, the role of arginase in COPD is unknown. This study aimed to investigate the role of arginase in pulmonary inflammation and remodeling using an animal model of COPD. Guinea pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pretreated by inhalation of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) or vehicle. Repeated LPS exposure increased lung arginase activity, resulting in increased l-ornithine/l-arginine and l-ornithine/l-citrulline ratios. Both ratios were reversed by ABH. ABH inhibited the LPS-induced increases in pulmonary IL-8, neutrophils, and goblet cells as well as airway fibrosis. Remarkably, LPS-induced right ventricular hypertrophy, indicative of pulmonary hypertension, was prevented by ABH. Strong correlations were found between arginase activity and inflammation, airway remodeling, and right ventricular hypertrophy. Increased arginase activity contributes to pulmonary inflammation, airway remodeling, and right ventricular hypertrophy in a guinea pig model of COPD, indicating therapeutic potential for arginase inhibitors in this disease.

Topics: Airway Remodeling; Animals; Arginase; Fibrosis; Guinea Pigs; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Interleukin-8; Lipopolysaccharides; Lung; Mucin 5AC; Neutrophils; Pneumonia; Pulmonary Disease, Chronic Obstructive

Aprotinin, a nonspecific serine protease inhibitor, has been primarily used as a haemostatic drug in cardiac surgery with cardio-pulmonary bypass (CPB). This study investigated the effect of aprotinin on the post-operative levels of procalcitonin (PCT) and a set of cytokines in patients undergoing pulmonary artery endarterectomy (PEA). We analyzed 60 patients with chronic thromboembolic pulmonary hypertension undergoing PEA. 30 patients (Group A) were treated with aprotinin (2,00,00 IU prior anesthesia, then 2,00,00 IU in CPB prime and 50,00 IU per hour continuously); a further 30 patients (Group B) received tranexamic Acid (1 g before anesthesia, 1 g after full heparin dose and 2 g in CPB prime). PCT, TNFalpha, IL-1beta, IL-6, and IL-8 arterial concentrations were measured from before until 72 hours after surgery. Aprotinin significantly affected early post-PEA plasma PCT. Patients treated with aprotinin (Group A) had lower peak PCT levels compared to patients in Group B (1.52 ng/ml versus 2.18, p=0.024). Postoperative peak values of PCT and IL-6 correlated closely in both groups (r=0.78, r=0.83 respectively). Aprotinin attenuates the post-PEA increase of PCT in the same manner as other pro-inflammatory cytokines. Significant correlation between PCT and IL-6 post-surgery may be indicative of an indirect IL-6-mediated pathway of PCT alteration.

Topics: Aged; Aprotinin; Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Endarterectomy; Female; Hemostatics; Humans; Hypertension, Pulmonary; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Middle Aged; Protein Precursors; Pulmonary Embolism; Time Factors; Tranexamic Acid; Treatment Outcome; Tumor Necrosis Factor-alpha; Up-Regulation

Mutations in the bone morphogenetic protein (BMP) type II receptor (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (HPAH) and a significant proportion of sporadic cases. Pulmonary artery smooth muscle cells (PASMCs) from patients with pulmonary arterial hypertension (PAH) not only exhibit attenuated growth suppression by BMPs, but an abnormal mitogenic response to transforming growth factor (TGF)-β1. We sought to define the mechanism underlying this loss of the antiproliferative effects of TGF-β1 in BMPR-II-deficient PASMCs. The effect of TGF-β1 on PASMC proliferation was characterized in three different models of BMPR-II dysfunction: 1) HPAH PASMCs, 2) Bmpr2(+/-) mouse PASMCs, and 3) control human PASMCs transfected with BMPR-II small interfering RNA. BMPR-II reduction consistently conferred insensitivity to growth inhibition by TGF-β1. This was not associated with altered canonical TGF-β1/Smad signaling but was associated with a secreted factor. Microarray analysis revealed that the transcriptional responses to TGF-β1 differed between control and HPAH PASMCs, particularly regarding genes associated with interleukins and inflammation. HPAH PASMCs exhibited enhanced IL-6 and IL-8 induction by TGF-β1, an effect reversed by NF-κB inhibition. Moreover, neutralizing antibodies to IL-6 or IL-8 restored the antiproliferative effect of TGF-β1 in HPAH PASMCs. This study establishes that BMPR-II deficiency leads to failed growth suppression by TGF-β1 in PASMCs. This effect is Smad-independent but is associated with inappropriately altered NF-κB signaling and enhanced induction of IL-6 and IL-8 expression. Our study provides a rationale to test anti-interleukin therapies as an intervention to neutralize this inappropriate response and restore the antiproliferative response to TGF-β1.

Topics: Animals; Bone Morphogenetic Protein Receptors, Type II; Cell Growth Processes; Cells, Cultured; Familial Primary Pulmonary Hypertension; Gene Expression; Humans; Hypertension, Pulmonary; Interleukin-6; Interleukin-8; Mice; Myocytes, Smooth Muscle; NF-kappa B; Pulmonary Artery; RNA, Small Interfering; Smad Proteins; Transfection; Transforming Growth Factor beta1

Pulmonary arterial hypertension (PAH) is a rare but fatal condition in which raised pulmonary vascular resistance leads to right heart failure and death. Endothelin-1 is a potent endogenous vasoconstrictor, which is considered to be central to many of the events that lead to PAH, and is an important therapeutic target in the treatment of the condition. In many cases of PAH, the aetiology is unknown but inflammation is increasingly thought to play an important role and viruses have been implicated in the development of disease. The Toll Like Receptors (TLRs) play a key role in innate immune responses by initiating specific anti-bacterial and anti-viral defences in recognition of signature molecular motifs on the surface of invading pathogens. In this study, we set out to examine the expression of bacterial and viral TLRs in human pulmonary artery smooth muscle cells and to establish whether their activation could be relevant to PAH. We found that the viral TLR3 and bacterial TLRs 4 and 6 were most abundantly expressed in human pulmonary artery smooth muscle cells. Using specific TLR ligands, we found that activation of TLRs 3 and 4 resulted in IL-8 release by human pulmonary artery smooth muscle cells but that only TLR3 stimulation resulted in IP10 and endothelin-1 release. These data suggest that human pulmonary artery smooth muscle cells express significant levels of viral TLR3 and respond to its activation by releasing endothelin-1. This may have importance in understanding the association between viruses and the development of PAH.

Topics: Cells, Cultured; Chemokines; Cytokines; Endothelin-1; Familial Primary Pulmonary Hypertension; Gene Expression; Humans; Hypertension, Pulmonary; Interleukin-8; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Poly I-C; Receptors, Cytokine; Toll-Like Receptor 3; Tumor Necrosis Factor-alpha

The chemokine receptor CCR7 regulates lymphocyte trafficking, and CCR7 deficiency induces infiltration of T and B cells adjacent to vessels in mouse lungs. Perivascular infiltration of T and B cells has also been found in human pulmonary arterial hypertension, and downregulation of the CCR7 receptor in circulating leukocytes of such patients has been observed. To investigate whether changes in the CCR7 system contribute to the pathogenesis of pulmonary hypertension, we utilized mice deficient of the CCR7 receptor. The cardiopulmonary and inflammatory responses of CCR7 depletion were evaluated in CCR7-deficient and wild-type mice. Measurements of cytokines upregulated in the animal model were also performed in patients with pulmonary hypertension and controls and in vascular smooth muscle cells. We found that mice lacking CCR7 had increased right ventricular systolic pressure, reduced pulmonary artery acceleration time, increased right ventricular/tibial length ratio, Rho kinase-mediated pulmonary vasoconstriction, and increased muscularization of distal arteries, indicating pulmonary hypertension. These mice also showed increased perivascular infiltration of leukocytes, consisting mainly of T and B cells, and increased mRNA levels of the inflammatory cytokines interleukin-12 and CX3CL1 within pulmonary tissue. Increased serum levels of interleukin-12 and CX3CL1 were also observed in patients with pulmonary hypertension, particularly in those with pulmonary hypertension associated with connective tissue disorder. In smooth muscle cells, interleukin-12 induced secretion of the angiogenic cytokine interleukin-8. We conclude that these results suggest a role for CCR7 in the development of pulmonary arterial hypertension, at least in some subgroups, possibly via pulmonary infiltration of lymphocytes and secretion of interleukin-12 and CX3CL1.

Topics: Adult; Animals; Cell Movement; Chemokine CX3CL1; Familial Primary Pulmonary Hypertension; Female; Gene Expression Regulation; Hemodynamics; Humans; Hypertension, Pulmonary; Interleukin-12; Interleukin-8; Leukocytes; Lung; Male; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle; Organ Size; Pneumonia; Pulmonary Artery; Receptors, CCR7; RNA, Messenger

Schistosomiasis is the most common worldwide cause of pulmonary arterial hypertension. The anti-schistosome drug praziquantel has been shown to reverse the liver fibrosis associated with Schistosoma mansoni in mice.. We sought to determine whether praziquantel reverses established pulmonary vascular remodeling and pulmonary hypertension in a mouse model of S. mansoni.. Mice were infected percutaneously with S. mansoni. At 17 weeks after infection mice were either killed or received two doses of praziquantel or vehicle by oral gavage. Treated mice were studied at 25 weeks after infection.. Vehicle-treated mice demonstrated significant increases in right ventricular systolic pressures (RVSP) and right ventricular hypertrophy (RVH) at 25 weeks, accompanied by pulmonary vascular remodeling. The degree of vascular remodeling correlated with proximity to granulomas. The elevation of RVSP and RVH at 25 weeks was dependent on the presence of eggs in the lung. Praziquantel eliminated the production of eggs in feces and led to clearance of eggs from the lung and to a lesser extent from liver. Praziquantel prevented the rise in RVSP and RVH seen in vehicle-treated mice and reversed established pulmonary vascular remodeling. Praziquantel significantly reduced lung mRNA expression of IL-13, IL-8, and IL-4, but did not reduce serum cytokine levels.. The development of pulmonary hypertension associated with S. mansoni infection can be prevented by praziquantel, and established vascular remodeling can be reversed. The mechanism involves clearance of lung eggs and reduced local expression of lung cytokines.

Topics: Animals; Anthelmintics; Blood Pressure; Blood Vessels; Cytokines; Down-Regulation; Female; Granuloma; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Inflammation Mediators; Interleukin-13; Interleukin-4; Interleukin-8; Liver; Lung; Mice; Mice, Inbred C57BL; Ovum; Praziquantel; RNA, Messenger; Schistosoma mansoni; Schistosomiasis mansoni

To investigate the effects of hydrogen sulfide (H2S) on vascular inflammation in pulmonary hypertension induced by high pulmonary blood flow.. Forty-four male SD rats were randomly divided into 8 groups: 4-week control group (n = 7), 4-week shunt group (n = 7), 4-week shunt + propargylglycine (PPG, an endogenous H2S release inhibitor) intraperitoneal injection group (n = 8), 11-week control group (n = 7), 11-week shunt group (n = 7), and 11-week shunt + sodium hydrosulfide (NaHS, a H2S donor) intraperitoneal injection group (n = 8). Right ventricular catheterization was used to measure the mean pulmonary arterial pressure (mPAP). Immunohistochemistry was used to detect the expression of inflammatory related factor intercellular adhesion molecule-1 (ICAM-1), and the key molecules of nuclear factor-kappaB (NF-kappaB) signal transduction pathway, including NF-kappaB p65 and inhibitor of NF-kappaB (IkappaBalpha), in the pulmonary artery, and ELISA was used to detect the concentrations of the inflammatory related factors, including ICAM-1, interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1) in blood plasma and lung tissues so as to reflect the corresponding inflammatory responsiveness.. The plasma and lung tissue ICAM-1, IL-8 and MCP-1 contents of the 4-week shunt group were all significantly higher than those of the 4-week control group (P < 0.05 or P < 0.01). The mPAP of the 4 week shunt + PPG group was (20.3 +/- 1.7) mm Hg, significantly higher than that of the 4-week shunt group [(16.2 +/- 1.5) mm Hg, P < 0.01]. The expression levels of ICAM-1 and NF-kappaB p65 in the small and median pulmonary artery endothelin cells of the 4-week shunt + PPG group were both significantly stronger than those of the 4-week shunt group (P < 0.05 or P < 0.01), whereas the expression of IkappaBalpha was weaker than that of the 4-week shunt group (P < 0.05). The plasma IL-8 content of the 4-week shunt + PPG group was (148 +/- 29) micromol/L, significantly higher than that of the 4 week-shunt group [(118 +/- 23) micromol/L, P < 0.05], and the lung tissue ICAM-1 and MCP-1 levels of the 4-week shunt + PPG group were (27.3 +/- 5.0) micromol/g and (12.9 +/- 1.1) micromol/g respectively, both significantly higher than those of the 4-week shunt group [(21.9 +/- 2.1) and (10.2 +/- 1.4) micromol/g respectively, both P < 0.05]. The mPAP and expression levels of ICAM-1 and NF-kappaB p65 of the large, median, and small pulmonary artery endothelia cells of the 11-week shunt group were all higher than those of the 11-week control group (P < 0.05 or P < 0.01), whereas the expression levels of IkappaBalpha were all less obvious (P < 0.05 or P < 0.01). The plasma and lung tissue ICAM-1, IL-8, and MCP-1 levels of the 11-week shunt group were all significantly higher than those of the 11-week control group (all P < 0.01). The mPAP of the 11 week shunt + NaHS group was (23.2 +/- 3.0) mm Hg, significantly lower than that of the 11-week shunt group [(27.5 +/- 1.9) mm Hg, P < 0.05]. The ICAM-1 and NF-kappaB p65 expression levels of large, median, and small pulmonary artery endothelia cells of the 11-week shunt + NaHS group were all significantly weaker than those of the 11-week shunt group (P < 0.05 or P < 0.01), whereas the protein expression levels of IkappaBalpha in small and median pulmonary artery endothelia cells of the 11-week shunt + NaHS group were significantly higher than those of the 11-week shunt group (both P < 0.05). The plasma and lung tissue ICAM-1 contents of the 11-week shunt + NaHS group were (124 +/- 11) micromol/L and (19.9 +/- 2.5) micromol/g, both significantly lower than those of the 11-week shunt group [(154 +/- 20) micromol/L and (23.9 +/- 3.6) micro. H2S attenuates the development of pulmonary hypertension induced by high pulmonary blood flow through ameliorating pulmonary vascular inflammation. The inhibitory effect of H2S on the pulmonary vascular inflammation involves elevating IkappaBalpha expression, down-regulating NF-kappaB p65 expression and then inhibiting the expression of inflammatory related factors.

Topics: Animals; Chemokine CCL2; Hydrogen Sulfide; Hypertension, Pulmonary; Immunohistochemistry; Injections, Intraperitoneal; Intercellular Adhesion Molecule-1; Interleukin-8; Lung; Male; Pulmonary Artery; Pulmonary Circulation; Random Allocation; Rats; Rats, Sprague-Dawley; Sulfides; Transcription Factor RelA; Vasculitis

Inflammatory processes seem to be involved in pulmonary arterial hypertension (PAH). CD40 ligand (L) may promote inflammation and thrombus formation, and we hypothesized that CD40L could be involved in the pathogenesis of PAH.. Several significant findings were revealed when examining the possible role of CD40L in PAH. (1) Patients with primary (n=13) and secondary (n=11) PAH but not those with chronic thromboembolic pulmonary hypertension (n=8) had increased plasma levels of soluble (s) CD40L compared with control subjects (n=8). (2) PAH patients using warfarin had markedly lower sCD40L levels than those without such therapy. (3) sCD40L levels were higher in arterial (femoral artery) compared with mixed venous blood (pulmonary artery), suggesting enhanced release or reduced clearance in the pulmonary vasculature. (4) Platelets from PAH patients showed enhanced spontaneous and SFLLRN-stimulated release of sCD40L compared with control subjects. (5) In vitro, recombinant sCD40L induced monocyte chemoattractant protein (MCP)-1 and interleukin-8 gene expression in endothelial cells, and plasma levels of these chemokines were raised in all PAH groups, significantly correlated to sCD40L and hemodynamic parameters. (6) Although prostacyclin therapy (3 months) showed clinical benefit, this therapy had no effect on sCD40L and increased MCP-1 levels in PAH patients, and prostacyclin enhanced MCP-1 in CD40L-stimulated endothelial cells.. Our findings suggest a role for CD40L in the pathogenesis of PAH, possibly operating through an interaction between platelets and endothelial cells involving chemokine-related mechanisms.

Topics: Aged; Anticoagulants; Blood Platelets; CD40 Ligand; Cells, Cultured; Chemokine CCL2; Collagen Diseases; Endothelial Cells; Endothelium, Vascular; Epoprostenol; Female; Femoral Artery; Gene Expression Regulation; Heart Defects, Congenital; HIV Infections; Humans; Hypertension, Pulmonary; Interleukin-8; Liver Cirrhosis; Male; Middle Aged; Peptide Fragments; Pulmonary Artery; Recombinant Proteins; Solubility; Thromboembolism; Umbilical Veins; Warfarin

The peptide endothelin-1 (ET-1) plays an unknown role in the pathogenesis and progression of two important neonatal pulmonary disorders, chronic lung disease (CLD) of prematurity and persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (INO) is a proven vasodilator therapy in PPHN and is an experimental therapy in CLD. We sought to determine the effects, if any, of the interaction of inhaled INO with ET-1 in these two separate disorders. Infants (n=21) with PPHN (mean gestation age, 39.4 weeks; mean birth weight, 3470 g) were treated with INO. All infants were <72 h of age at baseline. Plasma obtained at baseline and after 24 h of INO therapy was assessed for ET-1. The change in ET-1 levels with INO was inversely correlated with change in arterial partial pressure of O(2) (r=-0.71, P=0.0003). A separate group of 33 patients with CLD (mean gestational age, 27 weeks; mean birth weight, 740 g; mean age, 19 days) had tracheal aspirate levels of ET-1 obtained before, during, and after 7 days' administration of INO. Values were normalized by soluble secretory component of IgA. Tracheal aspirate ET-1 levels were detectable before INO therapy. There was no significant change during or after treatment with INO. There was not a significant correlation between baseline fractional inspired O(2) and ET-1 levels. There was a non-significant trend in the correlation between the change in ET-1 and the change in interleukin-8 levels in tracheal aspirate. This report confirms the presence of ET-1 in tracheal aspirate of premature infants who are developing CLD and reaffirms the presence of ET-1 in plasma of infants with PPHN. Short-term INO therapy was associated with a decrease in plasma ET-1 levels in PPHN, but did not affect tracheal aspirate ET-1 in CLD. Given the vasconstrictive, profibrotic, and proinflammatory properties of ET-1, specific ET-1 receptor antagonists could be considered as candidates for trials as adjunct therapy in either or both of these disorders.

Topics: Administration, Inhalation; Biomarkers; Endothelin-1; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Interleukin-8; Nitric Oxide; Persistent Fetal Circulation Syndrome; Pulmonary Disease, Chronic Obstructive

To investigate the mechanism of perioperative lung injury in patients of ventricular septal defect (VSD) with severe pulmonary hypertension.. The thromboxane B(2) (TXB(2)), 6-keto-prostagladin F(1 alpha) (6-keto-PGF(1 alpha)), malonyldiadehyde (MDA), interleukin-6 (IL-6), and IL-8, and blood pressure, pulmonary arterial pressure (PAP) and total pulmonary pressure (TPR) in thirty-one patients of VSD, 16 cases without pulmonary hypertension and 15 cases with severe pulmonary hypertension, were examined after anesthesia (AA), over extracorporeal circulation (OEC), and 1 hour (PEC1), 6 hours (PEC6), 24 hours (PEC24), 48 hours (PEC48), and 72 hours (PEC72) post extracorporeal circulation. The respiratory index (RI) and ratio of 6-keto-PGF(1alpha) and TXB(2) (P/T) were calculated. Before and after extracorporeal circulation, pulmonary tissues were taken to be examined by light microscopy and electron microscopy.. In the cases with severe pulmonary hypertension the P/T was 0.81 +/- 0.26 after anesthesia, then decreased 0.65 +/- 0.28 over extracorporeal circulation, and reached its lowest value (0.51 +/- 0.32) 1 hour post extracorporeal circulation. MDA was 2.4 micromol/L +/- 0.6 micromol/L after anesthesia, then increased, was 7.0 micromol/L +/- 1.7 micromol/L OEC, and reached its peak value (7.3 micromol/L +/- 0.9 micromol/L) PEC1. IL-6 was 0.27 ng/L +/- 0.12 ng/L after anesthesia, then increased, and reached its peak value (0.50 ng/L +/- 0.19 ng/L) PEC1. IL-8 was 7.5 ng/L +/- 1.5 ng/L after anesthesia, then increased, was 152 ng/L +/- 50 ng/L PEC1, and reached its peak (183 ng/L +/- 63 ng/L) PEC6. TXB(2) was 251 ng/L +/- 44 ng/L after anesthesia, then increased, and reached its peak (967 ng/L +/- 145 ng/L) at PEC1. The PAP was 72.1 +/- 18.8 mm Hg after anesthesia, 55 mm Hg +/- 15.3 mm Hg OPC, and 7.4 +/- 2.1 at PEC1, then decreased, and was 53 mm Hg +/- 15 mm Hg at PEC72. The total pulmonary resistance (TPR) was 10.6 +/- 2.9 mm Hg x min(-1) x L(-1) after anesthesia, then increased, and reached its peak (15.0 +/- 3.9 mm Hg x min(-1) x L(-1) at PEC6. Respiratory index (RI) was 0.88 +/- 0.23, then increased, and reached its peak (2.35 +/- 0.72) at PEC6. TXB(2) and RI were positively correlated with pulmonary vascular resistance (gamma = 0.283, P < 0.05; gamma = 0.403, P < 0.05). RI was positively correlated with MDA (gamma = 0.403, P < 0.05). Morphologic studies revealed discontinuities in the endothelial cell lining of pulmonary capillaries, infiltration of inflammatory cells, plugging of pulmonary capillaries with neutrophils, and intraalveolar hemorrhage.. During the perioperative period, the pulmonary damage, which leads to pulmonary hypertensive crisis, is more severe among the cases of VSD with severe pulmonary hypertension than among the case without pulmonary hypertension.

Topics: Adolescent; Blood Pressure; Child; Extracorporeal Circulation; Female; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Interleukin-6; Interleukin-8; Lung Diseases; Lung Injury; Male; Malondialdehyde; Postoperative Complications; Pulmonary Artery; Thromboxane B2; Time Factors

The effects of a second generation p38 mitogen-activated protein kinase (MAPK) inhibitor, SB 239063 [trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyridim idi n-4-yl)imidazole; IC(50) = 44 nM vs. p38 alpha], were assessed in models that represent different pathological aspects of chronic obstructive pulmonary disease (COPD) [airway neutrophilia, enhanced cytokine formation and increased matrix metalloproteinase (MMP)-9 activity] and in a model of lung fibrosis. Airway neutrophil infiltration and interleukin (IL)-6 levels, assessed by bronchoalveolar lavage 48 h after lipopolysaccharide (LPS) inhalation, were inhibited dose dependently by 3-30 mg/kg of SB 239063 given orally twice a day. In addition, SB 239063 (30 mg/kg orally) attenuated IL-6 bronchoalveolar lavage fluid concentrations (>90% inhibition) and MMP-9 activity (64% inhibition) assessed 6 h after LPS exposure. In guinea pig cultured alveolar macrophages, SB 239063 inhibited LPS-induced IL-6 production (IC(50) of 362 nM). In a bleomycin-induced pulmonary fibrosis model in rats, treatment with SB 239063 (2.4 or 4.8 mg/day via osmotic pump) significantly inhibited bleomycin-induced right ventricular hypertrophy (indicative of secondary pulmonary hypertension) and increases in lung hydroxyproline synthesis (indicative of collagen synthesis and fibrosis). Therefore, SB 239063 demonstrates activity against a range of sequelae commonly associated with COPD and fibrosis, supporting the therapeutic potential of p38 MAPK inhibitors such as SB 239063 in chronic airway disease.

Topics: Animals; Bleomycin; Cells, Cultured; Cytokines; Disease Models, Animal; Enzyme Inhibitors; Guinea Pigs; Humans; Hypertension, Pulmonary; Imidazoles; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Lung Diseases, Obstructive; Male; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinases; Neutrophils; p38 Mitogen-Activated Protein Kinases; Pulmonary Alveoli; Pulmonary Fibrosis; Pyrimidines; Rats; Rats, Inbred Lew; Sialoglycoproteins; Tumor Necrosis Factor-alpha

The effect of ultrafiltration during cardiopulmonary bypass (CPB) was evaluated for correcting ventricular septal defects with associated pulmonary hypertension in patients less than 18 months old. Interleukin (IL)-6 and IL-8 concentrations in the blood, ultrafiltrate, and urine were measured. The blood IL-6 concentration increased to 128.4+/-20.2 pg/ml by the end of surgery, which is lower than the concentration seen in adult patients (273.1+/-48.2 pg/ml, p < 0.02). The blood IL-8 concentration was not significantly different than that of adults. The total amounts of excreted IL-6 in the ultrafiltrate and urine during CPB were 11.5+/-0.32 pg/kg and 0.32+/-0.07 pg/kg, respectively (p < 0.05). The total amounts of excreted IL-8 in the ultrafiltrate and urine were 4.64+/-0.69 pg/kg and 1.92+/-0.56 pg/kg, respectively (p < 0.05). No differences were seen in these values for excretion between children and adults. We conclude that ultrafiltration during CPB in pediatric patients is more effective in removing proinflammatory cytokines than in adults and more effective than renal filtration alone.

Topics: Cardiopulmonary Bypass; Cell Adhesion Molecules; Heart Septal Defects, Ventricular; Hemofiltration; Humans; Hypertension, Pulmonary; Infant; Interleukin-6; Interleukin-8; Water-Electrolyte Balance

We present a case of high altitude pulmonary oedema (HAPE) with pulmonary hypertension and polymorphonuclear leucocyte (PMN) accumulation in bronchoalveolar lavage fluid (BALF), which occurred in a 21 year old man. Plasma endothelin-1 (ET-1) and interleukin-8 (IL-8) concentration in BALF were elevated on admission, and returned to normal level at recovery, when the pulmonary artery pressure and the PMN counts in BALF were normal. In addition, E-selectin and intercellular adhesion molecule-1 (ICAM-1) in BALF were also slightly increased on admission. These findings suggest that endothelin-1 is a vasoconstrictor which contributes to the pulmonary hypertension in high altitude pulmonary oedema, and that some of the inflammatory mediators play an important role in chemotaxis and accumulation of polymorphonuclear leucocytes in the development of high altitude pulmonary oedema.

Topics: Adult; Altitude Sickness; Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; E-Selectin; Endothelin-1; Humans; Hypertension, Pulmonary; Intercellular Adhesion Molecule-1; Interleukin-8; Leukocyte Count; Male; Mountaineering; Neutrophils; Pulmonary Edema; Pulmonary Wedge Pressure; Vasoconstrictor Agents

The combined effects of hypoxia and interleukin 1, lipopolysaccharide, or tumor necrosis factor alpha on the expression of genes encoding endothelial constitutive and inducible nitric oxide synthases, endothelin 1, interleukin 6, and interleukin 8 were investigated in human primary pulmonary endothelial cells and whole pulmonary artery organoid cultures. Hypoxia decreased the expression of constitutive endothelial nitric oxide synthase (NOS-3) mRNA and NOS-3 protein as compared with normoxic conditions. The inhibition of expression of NOS-3 corresponded with a reduced production of NO. A combination of hypoxia with bacterial lipopolysaccharide, interleukin 1 beta, or tumor necrosis factor alpha augmented both effects. In contrast, the combination of hypoxia and the inflammatory mediators superinduced the expression of endothelin 1, interleukin 6, and interleukin 8. Here, we have shown that inflammatory mediators aggravate the effect of hypoxia on the down-regulation of NOS-3 and increase the expression of proinflammatory cytokines in human pulmonary endothelial cells and whole pulmonary artery organoid cultures.

Topics: Blotting, Northern; Blotting, Western; Cell Hypoxia; Endothelin-1; Endothelium, Vascular; Enzyme Induction; Gene Expression Regulation, Enzymologic; Humans; Hypertension, Pulmonary; Interleukin-1; Interleukin-6; Interleukin-8; Isoenzymes; Lipopolysaccharides; Nitric Oxide; Nitric Oxide Synthase; Pulmonary Artery; RNA, Messenger; Vasculitis