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. 2024 Sep 1;210(5):648-661.
doi: 10.1164/rccm.202307-1289OC.

Disrupted BMP-9 Signaling Impairs Pulmonary Vascular Integrity in Hepatopulmonary Syndrome

Fabien Robert  1   2 , Marie-Caroline Certain  1   2   3 , Audrey Baron  1   2   3 , Raphaël Thuillet  1   2 , Léa Duhaut  4   5 , Mina Ottaviani  1   2 , Mustapha Kamel Chelgham  1   2 , Corinne Normand  1   2 , Nihel Berrebeh  1   2 , Nicolas Ricard  6 , Valerie Furlan  7 , Agnès Desroches-Castan  6 , Emmanuel Gonzales  5   8 , Emmanuel Jacquemin  5   8 , Olivier Sitbon  1   2   3 , Marc Humbert  1   2   3 , Sabine Bailly  6 , Audrey Coilly  4   5 , Christophe Guignabert  1   2 , Ly Tu  1   2 , Laurent Savale  1   2   3
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Free article

Disrupted BMP-9 Signaling Impairs Pulmonary Vascular Integrity in Hepatopulmonary Syndrome

Fabien Robert et al. Am J Respir Crit Care Med. .
Free article

Abstract

Rationale: Hepatopulmonary syndrome (HPS) is a severe complication of liver diseases characterized by abnormal dilation of pulmonary vessels, resulting in impaired oxygenation. Recent research highlights the pivotal role of liver-produced BMP-9 (bone morphogenetic protein-9) in maintaining pulmonary vascular integrity. Objectives: This study aimed to investigate the involvement of BMP-9 in human and experimental HPS. Methods: Circulating BMP-9 levels were measured in 63 healthy control subjects and 203 patients with cirrhosis with or without HPS. Two animal models of portal hypertension were employed: common bile duct ligation with cirrhosis and long-term partial portal vein ligation without cirrhosis. Additionally, the therapeutic effect of low-dose BMP activator FK506 was investigated, and the pulmonary vascular phenotype of BMP-9-knockout rats was analyzed. Measurements and Main Results: Patients with HPS related to compensated cirrhosis exhibited lower levels of circulating BMP-9 compared with patients without HPS. Patients with severe cirrhosis exhibited consistently low levels of BMP-9. HPS characteristics were observed in animal models, including intrapulmonary vascular dilations and an increase in the alveolar-arterial gradient. HPS development in both rat models correlated with reduced intrahepatic BMP-9 expression, decreased circulating BMP-9 level and activity, and impaired pulmonary BMP-9 endothelial pathway. Daily treatment with FK506 for 2 weeks restored the BMP pathway in the lungs, alleviating intrapulmonary vascular dilations and improving gas exchange impairment. Furthermore, BMP-9-knockout rats displayed a pulmonary HPS phenotype, supporting its role in disease progression. Conclusions: The study findings suggest that portal hypertension-induced loss of BMP-9 signaling contributes to HPS development.

Keywords: BMP-9; cirrhosis; hepatopulmonary syndrome; intrapulmonary vascular dilatations; portal hypertension.

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