Decoding the Link Between Inflammation and Pulmonary Arterial Hypertension.
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ABSTRACT:
SUBMITTER: Zhong Y
PROVIDER: S-EPMC9669927 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
Publications
Decoding the Link Between Inflammation and Pulmonary Arterial Hypertension.
Circulation 20220926 13
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Project description:Perivascular inflammation is a prominent pathologic feature in most animal models of pulmonary hypertension (PH) as well as in pulmonary arterial hypertension (PAH) patients. Accumulating evidence suggests a functional role of perivascular inflammation in the initiation and/or progression of PAH and pulmonary vascular remodeling. High levels of cytokines, chemokines, and inflammatory mediators can be detected in PAH patients and correlate with clinical outcome. Similarly, multiple immune cells, including neutrophils, macrophages, dendritic cells, mast cells, T lymphocytes, and B lymphocytes characteristically accumulate around pulmonary vessels in PAH. Concomitantly, vascular and parenchymal cells including endothelial cells, smooth muscle cells, and fibroblasts change their phenotype, resulting in altered sensitivity to inflammatory triggers and their enhanced capacity to stage inflammatory responses themselves, as well as the active secretion of cytokines and chemokines. The growing recognition of the interaction between inflammatory cells, vascular cells, and inflammatory mediators may provide important clues for the development of novel, safe, and effective immunotargeted therapies in PAH.
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Project description:Microarray analysis of peripheral blood mononuclear (PBMC) cells in pulmonary arterial hypertension. Keywords = mononuclear cells Keywords = gene microarray Keywords = pulmonary arterial hypertension Keywords = Herpesvirus Keywords = biomarker Keywords: other
2003-11-15 | GSE703 | GEO
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Project description:Sotatercept is an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that improves cardiopulmonary function in patients with pulmonary arterial hypertension (PAH) by selectively trapping activins and growth differentiation factors. However, the cellular and molecular mechanisms of ActRIIA-Fc action are incompletely understood. Here, we determined through genome-wide expression profiling that inflammatory and immune responses are prominently upregulated in the lungs of a Sugen-hypoxia rat model of severe angio-obliterative PAH, concordant with profiles observed in PAH patients. Therapeutic treatment with ActRIIA-Fc-but not with a vasodilator-strikingly reversed proinflammatory and proliferative gene expression profiles and normalized macrophage infiltration in diseased rodent lungs. Furthermore, ActRIIA-Fc normalized pulmonary macrophage infiltration and corrected cardiopulmonary structure and function in Bmpr2 haploinsufficient mice subjected to hypoxia, a model of heritable PAH. Three high-affinity ligands of ActRIIA-Fc each induced macrophage activation in vitro, and their combined immunoneutralization in PAH rats produced cardiopulmonary benefits comparable to those elicited by ActRIIA-Fc. Our results in complementary experimental and genetic models of PAH reveal therapeutic anti-inflammatory activities of ActRIIA-Fc that, together with its known anti-proliferative effects on vascular cell types, could underlie clinical activity of sotatercept as either monotherapy or add-on to current PAH therapies.
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Project description:This review summarizes an expanding body of knowledge indicating that failure to resolve inflammation and altered immune processes underlie the development of pulmonary arterial hypertension. The chemokines and cytokines implicated in pulmonary arterial hypertension that could form a biomarker platform are discussed. Pre-clinical studies that provide the basis for dysregulated immunity in animal models of the disease are reviewed. In addition, we present therapies that target inflammatory/immune mechanisms that are currently enrolling patients, and discuss others in development. We show how genetic and metabolic abnormalities are inextricably linked to dysregulated immunity and adverse remodeling in the pulmonary arteries.
| S-EPMC4097142 | biostudies-literature
Project description:Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of severe PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH in its later stage, which may differ from the earlier stage of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH. Global profiles were determined in human lung tissue and compared across 11 normal and 12 severe pulmonary arterial hypertension patients. Using a combination of microarray and high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung.
2014-11-14 | E-GEOD-53408 | biostudies-arrayexpress
Project description:BackgroundPulmonary arterial compliance (PAC) was previously shown to be an important prognostic factor in pulmonary arterial hypertension (PAH), in addition to the conventional pulmonary vascular resistance (PVR). The product of PAC and PVR, the arterial time (RC) constant, expresses the logarithmic relationship between the hemodynamic parameters. The objective of the study was to test RC constant stability in PAH patients followed beyond 12 months after diagnosis, and to report possible RC variations in different etiologies.MethodsFourteen PAH patients followed between 2008 and 2019 were included. Type 1 PAH was defined as a mean pulmonary artery pressure (PAP) ≥25 mmHg at rest and PVR ≥3 Wood units (WU). All patients who fulfilled WHO group I PAH criteria and had undergone two right heart catheterizations at least 1 year apart were included. The recorded hemodynamic data for each patient were used to compute PVR and PAC.ResultsPAH etiologies included scleroderma (n=2), liver cirrhosis (n=1), hereditary hemorrhagic telangiectasia (HHT) (n=1), mixed connective tissue disease (MCTD) (n=3), and idiopathic (n=7). The RC constant remained stable for all 14 patients over a follow-up period of 3.9±2 years. Patients with MCTD displayed more favorable hemodynamics, evidenced by higher RC (12.54 vs. 10.01, P<0.01) and PAC values (2.59 vs. 1.62, P=0.02), when compared with non-MCTD PAH patients. For the entire cohort the mean PAP measured 51±14 mmHg at baseline, and 46±13 mmHg at follow-up, respectively.ConclusionsThe relationship between PAC and PVR remains stable in follow-up periods averaging 4 years, making compliance an important disease marker past the early stages. Patients with MCTD displayed more advantageous hemodynamic profiles when compared with patients with other PAH etiologies.
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Project description:Arterial pulmonary hypertension is a rare disease, with little knowledge regarding its etiology, and high mortality. Development of right and later on also left ventricular heart insufficiency, secondary to pulmonary hypertension, is a negative predictive factor. Genetic and molecular processes underlying left heart ventricle remodeling over the course of pulmonary hypertension remain unknown. In particular, there is no knowledge regarding the mechanisms of left heart ventricle atrophy which was completely avoided by researchers until recently.The aim of this study was to assess changes in protein abundance in left and right heart ventricle free wall of rats in monocrotaline model of PAH.
2020-09-07 | PXD015896 | Pride
Project description:Mechanisms underlying pulmonary arterial hypertension (PAH) remain elusive. Pulmonary arterial hypertension and exercise PH share similar physiologic consequences; it is debated whether they share biologic mechanisms and if exercise PH represents an early phase of pulmonary arterial hypertension. We conducted an observational study to test if there is a graded metabolic disturbance along the severity of PH, which may indicate shared or disparate pathophysiology. Individuals referred to an academic medical dyspnea center with unexplained exertional intolerance underwent invasive cardiopulmonary exercise testing. We identified controls with no hemodynamic exercise limitation, individuals with exercise PH (mean pulmonary arterial pressure (mPAP) < 25 mmHg at rest but ≥ 30 mmHg during exercise without pulmonary venous hypertension) and pulmonary arterial hypertension (mPAP > 25 mmHg at rest without pulmonary venous hypertension) (n = 26 in each group). Unbiased metabolomics with chromatography mass spectrometry was performed on pulmonary arterial blood at rest and peak exercise. Random forest analysis and hierarchical clustering were used to quantify metabolite prediction of group membership and rank metabolites which were significantly different between groups. Compared to controls, pulmonary arterial hypertension subjects exhibited perturbations in pathways involving glycolysis, TCA cycle, fatty acid and complex lipid oxidation, collagen deposition and fibrosis, nucleotide metabolism, and others. The metabolic signature of exercise PH was uniquely between that of control and pulmonary arterial hypertension subjects. Accuracy predicting control, exercise PH, and pulmonary arterial hypertension group was 96%, 90%, and 88%, respectively, using paired rest-exercise metabolic changes. Our data suggest the metabolic profile of exercise PH is between that of controls and patients with pulmonary arterial hypertension.
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