Inflammation and Immunity in the Pathogenesis of Pulmonary Arterial Hypertension

Rabinovitch, Marlene; Guignabert, Christophe; Humbert, Marc; Nicolls, Mark R.

doi:10.1161/circresaha.113.301141

Cited by 800 publications

(832 citation statements)

References 140 publications

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“…Herein, we are showing that dysfunctional P-ECs represent an abnormal local source of Ob, which, in turn, acts on different cell types via autocrine and paracrine effects: P-ECs, PA-SMCs and monocyte/macrophage lineage cells, respectively. Indeed, with human data obtained in situ and in vitro, as well as with in vivo experiments, we are demonstrating here that Ob/ObR-b axis is able to induce PA-SMC proliferation, perivascular monocyte/macrophage lineage cell accumulation and contribute to the P-EC pro-inflammatory phenotype, which represent major contributors of pulmonary vascular remodelling in PAH [36,37]. Consistent with these findings, we show that chronic Ob injections worsen PH severity in mice.…”

Section: Discussionsupporting

confidence: 90%

Leptin signalling system as a target for pulmonary arterial hypertension therapy

Huertas

Thuillet

et al. 2015

Eur Respir J

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Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH.In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ⩽5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH ( pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-induced PH.We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH. @ERSpublications Targeting Ob/ObR-b axis represents an important tool for anti-proliferative and antiinflammatory strategies in PH http://ow.ly/I00jh

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Section: Discussionsupporting

confidence: 90%

Leptin signalling system as a target for pulmonary arterial hypertension therapy

Huertas

Thuillet

et al. 2015

Eur Respir J

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“…In the lung, CD74 has been demonstrated in type II cells, macrophages, and lymphocyte populations (2,3,42). Most recently, CD74 has been demonstrated in endothelial cells of patients with pulmonary HTN (43,44). Although the protective effect of MIF in endothelial cells has been described previously, the involvement of CD74 and its inducible expression as a consequence of hyperoxia are novel observations (6,22).…”

Section: Discussionmentioning

confidence: 95%

Endothelial CD74 mediates macrophage migration inhibitory factor protection in hyperoxic lung injury

et al. 2015

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Exposure to hyperoxia results in acute lung injury. A pathogenic consequence of hyperoxia is endothelial injury. Macrophage migration inhibitory factor (MIF) has a cytoprotective effect on lung endothelial cells; however, the mechanism is uncertain. We postulate that the MIF receptor CD74 mediates this protective effect. Using adult wild-type (WT), MIF-deficient (Mif 2/2 ), CD74-deficient (Cd74 2/2 ) mice and MIF receptor inhibitor treated mice, we report that MIF deficiency or inhibition of MIF receptor binding results in increased sensitivity to hyperoxia. Mif 2/2 and Cd74 2/2 mice demonstrated decreased median survival following hyperoxia compared to WT mice. Mif 2/2 mice demonstrated an increase in bronchoalveolar protein (48%) and lactate dehydrogenase (LDH) (68%) following 72 hours of hyperoxia. Similarly, treatment with MIF receptor antagonist resulted in a 59% and 91% increase in bronchoalveolar lavage protein and LDH, respectively. Inhibition of CD74 in primary murine lung endothelial cells (MLECs) abrogated the protective effect of MIF, including decreased hyperoxia-mediated AKT phosphorylation and a 20% reduction in the antiapoptotic effect of exogenous MIF. Treatment with MIF decreased hyperoxia-mediated H2AX phosphorylation in a CD74-dependent manner. These data suggest that therapeutic manipulation of the MIF-CD74 axis in lung endothelial cells may be a novel approach to protect against acute oxidative stress.-Sauler,

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“…22 The plexiform lesion, which is characterized by tumorous proliferation of endothelial and smooth muscle cells, is a typical histologic feature in patients with PAH associated with SLE or MCTD. 23, 24 The infiltration of inflammatory cells composed of macrophages and lymphocytes and the deposition of IgG and complements are detected in the pulmonary vessel walls from those patients.…”

Section: Discussionmentioning

confidence: 99%

Predictors of Favorable Responses to Immunosuppressive Treatment in Pulmonary Arterial Hypertension Associated With Connective Tissue Disease

Yasuoka

Shirai

Tamura

et al. 2018

Circ J

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Background:The potential efficacy of immunosuppressive (IS) treatment has been reported in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD), but its positioning in the treatment algorithm remains uncertain. The aim of this study was to identify predictors of favorable responses to first-line IS treatment. Methods and Results:This single-center retrospective study included 30 patients with PAH accompanied by systemic lupus erythematosus (SLE), mixed CTD (MCTD), or primary Sjögren's syndrome (SS) who received first-line IS treatment alone or in combination with pulmonary vasodilators. When short-term treatment response was defined as an improvement in World Health Organization functional class at 3 months, 16 patients (53%) were short-term responders. Simultaneous diagnosis of PAH and CTD, and the use of immunosuppressants, especially intravenous cyclophosphamide, in addition to glucocorticoids were identified as independent predictors of a short-term response (P=0.004 and 0.0002, respectively). Cumulative rates free of PAH-related death were better in short-term responders than non-responders (P=0.04), and were best in patients with a simultaneous diagnosis of PAH and CTD who were treated initially with a combination of glucocorticoids and immunosuppressants. Conclusions:Patients with a simultaneous diagnosis of PAH and CTD, including SLE, MCTD, and primary SS, should receive intensive IS treatment regimens to achieve better short-and long-term outcomes.

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Inflammation and Immunity in the Pathogenesis of Pulmonary Arterial Hypertension

Cited by 800 publications

References 140 publications

Leptin signalling system as a target for pulmonary arterial hypertension therapy

Leptin signalling system as a target for pulmonary arterial hypertension therapy

Endothelial CD74 mediates macrophage migration inhibitory factor protection in hyperoxic lung injury

Predictors of Favorable Responses to Immunosuppressive Treatment in Pulmonary Arterial Hypertension Associated With Connective Tissue Disease

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