Chemokine RANTES in Severe Pulmonary Arterial Hypertension

Dorfmüller, Peter; Zarka, Véronique; Durand-Gasselin, Ingrid; Monti, Gianpaola; Balabanian, Karl; Garcia, Gilles; Capron, Frédérique; Coulomb-L’Herminé, Aurore; Marfaing-Koka, Anne; Simonneau, Gérald; Émilie, Dominique; Humbert, Marc

doi:10.1164/ajrccm.165.4.2012112

Cited by 243 publications

(172 citation statements)

References 44 publications

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“…The recognition of an inflammatory component in PH [16;74] supports the investigation of expression of cytokines that might potentially drive perivascular inflammation and thus contribute to the disease. Remodeled pulmonary arteries express IL-1, IL-6, and PDGF in infiltrating inflammatory cells [78;79], the chemokine RANTES (acronym for regulated upon activation, normal T-cell expressed and secreted), an important chemoattractant for monocytes and T cells [80], and the macrophage inflammatory protein-1α (MIP-1 α) [76]. Lungs of IPAH patients have increased expression of fractalkine, a chemokine involved in T cell trafficking and monocyte recruitment, and their circulating CD4 and CD8 T-cells have higher levels of the fractalkine receptor CX3CR1 when compared with controls or samples of patients with thromboembolic PH [81].…”

Section: Pathobiologymentioning

confidence: 99%

Pathology of Pulmonary Hypertension

Tuder

Marecki

Richter

et al. 2013

Clinics in Chest Medicine

220

107

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Section: Pathobiologymentioning

confidence: 99%

Pathology of Pulmonary Hypertension

Tuder

Marecki

Richter

et al. 2013

Clinics in Chest Medicine

220

107

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“…Patients with underlying inflammatory and autoimmune diseases such as scleroderma (75), polyneuropathy, organomegaly, endocrinopathym M-protein, skin abnormalities (POEMS) syndrome (71), acquired immunodeficiency syndrome (21), sarcoidosis (94), and schistosomiasis (66) have a propensity to develop PH. Furthermore, patients with PH exhibit perivascular infiltrates of inflammatory cells (126), regulated on activation, normal T cell expressed and secreted (RANTES) associated with CD45 ϩ inflammatory cells (26), and increased circulating levels of proinflammatory cytokines such as IL-1, IL-6 (51), fractalkine (7), and monocyte chemoattractant protein-1, currently known as chemokine (C-C motif) ligand 2 (57).…”

Section: Endothelial Cell Functionmentioning

confidence: 99%

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.…”

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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Chemokine RANTES in Severe Pulmonary Arterial Hypertension

Cited by 243 publications

References 44 publications

Pathology of Pulmonary Hypertension

Pathology of Pulmonary 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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