Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension.

Humbert, Marc; Monti, Gianpaola; Brénot, F; Sitbon, Olivier; Portier, A; Grangeot-Keros, L.; Duroux, P; Galanaud, Pierre; Simonneau, Gérald; Émilie, Dominique

doi:10.1164/ajrccm.151.5.7735624

Cited by 696 publications

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“…IL-6 increases MAPKs (mitogen-activated protein kinases), c-myc, survivin, and bcl-2, with both proproliferative and antiapoptotic effects, and transgenic mice overexpressing IL-6 develop pulmonary hypertension. 15 These findings are consistent with studies showing increased circulating levels of IL-6 14,16 and increases in chemokine and chemokine receptor gene expression in PAH. 17 Matrix metalloproteinase (MMP)-2, MMP-9, and tenascin-C (TN-C) were elevated in NIPAH but not in IPAH patient plasma.…”

Section: Discussionsupporting

confidence: 87%

Erythropoietin Upregulation in Pulmonary Arterial Hypertension

et al. 2014

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The pathophysiologic alterations of patients with pulmonary arterial hypertension (PAH) are diverse. We aimed to determine novel pathogenic pathways from circulating proteins in patients with PAH. Multianalyte profiling (MAP) was used to measure 90 specifically selected antigens in the plasma of 113 PAH patients and 51 control patients. Erythropoietin (EPO) functional activity was assessed via in vitro pulmonary artery endothelial cell networking and smooth muscle cell proliferation assays. Fifty-eight patients had idiopathic PAH, whereas 55 had other forms of PAH; 5 had heritable PAH, 18 had connective tissue disease (15 with scleroderma and 3 with lupus erythematosis), 13 had portopulmonary hypertension, 6 had PAH associated with drugs or toxins, and 5 had congenital heart disease. The plasmaantigen profile of PAH revealed increased levels of several novel biomarkers, including EPO. Immune quantitative and histochemical studies revealed that EPO not only was significantly elevated in the plasma of PAH patients but also promoted pulmonary artery endothelial cell network formation and smooth muscle cell proliferation. MAP is a hypothesis-generating approach to identifying novel pathophysiologic pathways in PAH. EPO is upregulated in the circulation and lungs of patients with PAH and may affect endothelial and smooth muscle cell proliferation.

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Section: Discussionsupporting

confidence: 87%

Erythropoietin Upregulation in Pulmonary Arterial Hypertension

et al. 2014

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“…Loss of BMPRII in vivo and in vitro has been shown to increase the production of cytokines such as IL-6, monocyte chemoattractant protein-1, and TGF-␤ (42). It is worth noting here that the reduction in endothelial caveolin-1 associated with increased IL-6 expression and PY-STAT3 occurs in human and experimental forms of PH (11,49,51), which in turn can influence BMPRII expression and function. From these studies one could surmise that caveolin-1 and BMPRII cooperate to maintain vascular health.…”

Section: Caveolae and Caveolin-1mentioning

confidence: 86%

Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

Mathew

2014

American Journal of Physiology-Heart and Circulatory Physiology

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Mathew R. Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity. Am J Physiol Heart Circ Physiol 306: H15-H25, 2014. First published October 25, 2013 doi:10.1152/ajpheart.00266.2013.-Pulmonary hypertension (PH) is a progressive disease with a high morbidity and mortality rate. Despite important advances in the field, the precise mechanisms leading to PH are not yet understood. Main features of PH are loss of vasodilatory response, the activation of proliferative and antiapoptotic pathways leading to pulmonary vascular remodeling and obstruction, elevated pressure and right ventricular hypertrophy, resulting in right ventricular failure and death. Experimental studies suggest that endothelial dysfunction may be the key underlying feature in PH. Caveolin-1, a major protein constituent of caveolae, interacts with several signaling molecules including the ones implicated in PH and modulates them. Disruption and progressive loss of endothelial caveolin-1 with reciprocal activation of proliferative pathways occur before the onset of PH, and the rescue of caveolin-1 inhibits proliferative pathways and attenuates PH. Extensive endothelial damage/loss occurs during the progression of the disease with subsequent enhanced expression of caveolin-1 in smooth muscle cells. This caveolin-1 in smooth muscle cells switches from being an antiproliferative factor to a proproliferative one and participates in cell proliferation and cell migration, possibly leading to irreversible PH. In contrast, the disruption of endothelial caveolin-1 is not observed in the hypoxia-induced PH, a reversible form of PH. However, proliferative pathways are activated in this model, indicating caveolin-1 dysfunction. Thus disruption or dysfunction of endothelial caveolin-1 leads to PH, and the status of caveolin-1 may determine the reversibility versus irreversibility of PH. This article reviews the role of caveolin-1 and cell membrane integrity in the pathogenesis and progression of PH.caveolin-1; endothelial cells; pulmonary hypertension; smooth muscle cells THIS ARTICLE is part of a collection on Pathophysiology of Hypertension. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.In 1891, Ernst von Romberg, a German physician, described histological changes in pulmonary hypertension (PH) as pulmonary vascular sclerosis (30). Since then remarkable advances have been made in the understanding of PH, but the pathogenesis of PH still remains elusive, partly because a number of diseases can lead to PH and multiple signaling pathways are implicated in PH. Furthermore, not all signaling pathways are activated in a given patient, and their activation may depend on the stage of the disease. Experimental data suggest that the vascular changes occur before the onset of PH (47,48). Therefore, it is not surprising that by the time the diagnosis of PH is made, most patients have significant pathological changes in pulmonary vasculatu...

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“…Lung tissue biopsy samples of patients with idiopathic pulmonary arterial hypertension (IPAH) demonstrate perivascular inflammatory cell infiltrates of T cells, B cells, and macrophages 20, 21. Circulating levels of serum cytokines including interleukin (IL)‐1β, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, and tumor necrosis factor α are significantly elevated when compared with controls 22, 23. IPAH shares a number of features with CHD‐APAH,24 and inflammation could develop in CHD‐APAH because of the high stresses associated with increased pulmonary blood flow and hypoxemia 25.…”

Section: Introductionmentioning

confidence: 99%

Lung Function, Inflammation, and Endothelin‐1 in Congenital Heart Disease–Associated Pulmonary Arterial Hypertension

Low

George

Howard

et al. 2018

JAHA

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BackgroundBreathlessness is the most common symptom in people with pulmonary arterial hypertension and congenital heart disease (CHD‐APAH), previously thought to be caused by worsening PAH, but perhaps also by inflammation and abnormalities of lung function. We studied lung function and airway inflammation in patients with CHD‐APAH and compared the results with controls.Methods and ResultsSixty people were recruited into the study: 20 CHD‐APAH, 20 CHD controls, and 20 healthy controls. Spirometry, gas transfer, whole body plethysmography and lung clearance index, 6‐minute walk distance, and medical research council dyspnea scoring were performed. Inflammatory markers and endothelin‐1 levels were determined in blood and induced sputum. The CHD‐APAH group had abnormal lung function with lung restriction, airway obstruction, and ventilation heterogeneity. Inverse correlations were shown for CHD‐APAH between medical research council dyspnea score and percent predicted peak expiratory flow (r=−0.5383, P=0.0174), percent predicted forced expiratory flow rate at 50% of forced vital capacity (r=−0.5316, P=0.0192), as well as for percent predicted forced expiratory volume in 1 s (r=−0.6662, P=0.0018) and percent predicted forced vital capacity (r=−0.5536, P=0.0186). The CHD‐APAH patients were more breathless with lower 6‐minute walk distance (360 m versus 558 m versus 622 m, P=0.00001). Endothelin‐1, interleukin (IL)‐β, IL‐6, IL‐8, tumor necrosis factor α, and vascular endothelial growth factor were significantly higher in CHD‐APAH than controls. Serum endothelin‐1 for CHD‐APAH correlated with airflow obstruction with significant negative correlations with percent predicted forced expiratory flow rate at 75% of forced vital capacity (r=−0.5858, P=0.0135).ConclusionsRaised biomarkers for inflammation were found in CHD‐APAH. Significant abnormalities in airway physiology may contribute to the dyspnea but are not driven by inflammation as assessed by circulating and sputum cytokines. A relationship between increased serum endothelin‐1 and airway dysfunction may relate to its bronchoconstrictive properties.

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Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension.

Cited by 696 publications

References 0 publications

Erythropoietin Upregulation in Pulmonary Arterial Hypertension

Erythropoietin Upregulation in Pulmonary Arterial Hypertension

Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

Lung Function, Inflammation, and Endothelin‐1 in Congenital Heart Disease–Associated Pulmonary Arterial Hypertension

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