Division of Pulmonary Inflammation, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Front Immunol. 2022 Jun 9;13:895501. doi: 10.3389/fimmu.2022.895501. eCollection 2022.
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) 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) remain obscure.
Serum levels of anti-ET 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 deficiency on pulmonary inflammation and the cardiovascular system were studied in mice. Rescued ET-deficient mice (ET) 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 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 lung microscopy and bronchoalveolar lavage fluid analyses.
Anti-ET autoantibody levels were elevated in patients with PAH secondary to SSc. Both overexpression of prepro-endothelin-1 and rescued ET 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 mice. Following induction of pulmonary Th2 inflammation, PAH-associated pathologies and perivascular collagen deposition were aggravated in ET mice.
This study provides evidence for an anti-inflammatory role of ET. ET seems to have protective effects on Th2-evoked pathologies of the cardiovascular system. Anti-ET autoantibodies may modulate ET-mediated immune homeostasis.
炎症是肺动脉高压（PAH）的主要病理特征，尤其是在系统性硬化症（SSc）等炎症情况下。内皮素系统和抗内皮素 A 受体（ET）自身抗体与 PAH 的发病机制有关，内皮素受体拮抗剂是 PAH 的常规治疗方法。然而，内皮素 B 受体（ET）的免疫功能仍不清楚。
在健康供体和有或没有 PAH 的 SSc 患者中定量检测抗 ET 受体自身抗体的血清水平。在小鼠中研究了前内皮素-1 过表达或 ET 缺乏对肺炎症和心血管系统的年龄依赖性影响。使用挽救性 ET 缺陷型（ET）小鼠预防先天性巨结肠。在 ET 小鼠中分析了肺辅助性 T 细胞 2（Th2）炎症对 PAH 相关病变的影响。在离体灌注的小鼠肺中研究了肺血管血液动力学。评估了心脏右心室肥厚。通过肺显微镜和支气管肺泡灌洗分析评估了肺炎症和胶原沉积。
继发于 SSc 的 PAH 患者的抗 ET 自身抗体水平升高。前内皮素-1 过表达和挽救性 ET 缺乏均导致肺动脉高压、肺血管高反应性和右心室肥厚，并伴有淋巴细胞性肺泡炎。在 ET 小鼠中仅发现明显的血管周围淋巴细胞浸润。在诱导肺 Th2 炎症后，ET 小鼠的 PAH 相关病变和血管周围胶原沉积加重。
本研究为 ET 的抗炎作用提供了证据。ET 似乎对 Th2 诱发的心血管系统病变具有保护作用。抗 ET 自身抗体可能调节 ET 介导的免疫稳态。
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