Dataset Information

Endothelin B Receptor Immunodynamics in Pulmonary Arterial Hypertension.

ABSTRACT:

Introduction

Inflammation is a major pathological feature of pulmonary arterial hypertension (PAH), particularly in the context of inflammatory conditions such as systemic sclerosis (SSc). The endothelin system and anti-endothelin A receptor (ET_A) autoantibodies have been implicated in the pathogenesis of PAH, and endothelin receptor antagonists are routinely used treatments for PAH. However, immunological functions of the endothelin B receptor (ET_B) remain obscure.

Methods

Serum levels of anti-ET_B receptor autoantibodies were quantified in healthy donors and SSc patients with or without PAH. Age-dependent effects of overexpression of prepro-endothelin-1 or ET_B deficiency on pulmonary inflammation and the cardiovascular system were studied in mice. Rescued ET_B-deficient mice (ET_B ^-/-) were used to prevent congenital Hirschsprung disease. The effects of pulmonary T-helper type 2 (Th2) inflammation on PAH-associated pathologies were analyzed in ET_B ^-/- mice. Pulmonary vascular hemodynamics were investigated in isolated perfused mouse lungs. Hearts were assessed for right ventricular hypertrophy. Pulmonary inflammation and collagen deposition were assessed via lung microscopy and bronchoalveolar lavage fluid analyses.

Results

Anti-ET_B autoantibody levels were elevated in patients with PAH secondary to SSc. Both overexpression of prepro-endothelin-1 and rescued ET_B deficiency led to pulmonary hypertension, pulmonary vascular hyperresponsiveness, and right ventricular hypertrophy with accompanying lymphocytic alveolitis. Marked perivascular lymphocytic infiltrates were exclusively found in ET_B ^-/- mice. Following induction of pulmonary Th2 inflammation, PAH-associated pathologies and perivascular collagen deposition were aggravated in ET_B ^-/- mice.

Conclusion

This study provides evidence for an anti-inflammatory role of ET_B. ET_B seems to have protective effects on Th2-evoked pathologies of the cardiovascular system. Anti-ET_B autoantibodies may modulate ET_B-mediated immune homeostasis.

SUBMITTER: Tabeling C

PROVIDER: S-EPMC9221837 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPulmonary arterial hypertension is a devastating disease, which leads to right heart failure and premature death. Recent evidence suggests that endothelin receptor antagonists may be promising drugs in the treatment of pulmonary arterial hypertension.ObjectivesTo evaluate the efficacy of endothelin receptor antagonists in pulmonary arterial hypertension.Search methodsWe searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE, and the reference section of retrieved articles. Searches are current as of January 2012.Selection criteriaWe included randomised trials (RCTs) and quasi-randomised trials involving patients with pulmonary arterial hypertension.Data collection and analysisFive review authors independently selected studies, assessed study quality and extracted data.Main resultsWe included 12 randomised controlled trials involving 1471 patients. All the trials were of relatively short duration (12 weeks to six months). After treatment, patients treated with endothelin receptor antagonists could walk on average 33.71 metres (95% confidence interval (CI) 24.90 to 42.52 metres) further than those treated with placebo in a six-minute walk test. Endothelin receptor antagonists improved more patients' World Health Organization/New York Heart Association (WHO/NYHA) functional class status than placebo (odds ratio (OR) 1.60; 95% CI 1.20 to 2.14), and reduced the odds of functional class deterioration compared with placebo (OR 0.26; 95% CI 0.16 to 0.42). There was a reduction in mortality that did not reach statistical significance on endothelin receptor antagonists (OR 0.57; 95% CI 0.26 to 1.24), and limited data suggest that endothelin receptor antagonists improve the Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients. Hepatic toxicity was not common, and endothelin receptor antagonists were well tolerated in this population. However, several cases of irreversible liver failure caused by sitaxsentan have been reported that led to license holder for sitaxsentan to withdraw the product from all markets worldwide.Authors' conclusionsEndothelin receptor antagonists can increase exercise capacity, improve WHO/NYHA functional class, prevent WHO/NYHA functional class deterioration, reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III. However, there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension. Efficacy data are strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in patients treated with endothelin receptor antagonists.