• Fabien Robert, Marie-Caroline Certain, Audrey Baron, Raphaël Thuillet, Léa Duhaut, Mina Ottaviani, ChelghamMustapha KamelMKUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 "Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT)", Le Kremlin-Bicêtre, France.Institut National de la Santé et de la Recherche Méd, Corinne Normand, Nihel Berrebeh, Nicolas Ricard, Valerie Furlan, Agnès Desroches-Castan, Emmanuel Gonzales, Emmanuel Jacquemin, Olivier Sitbon, Marc Humbert, Sabine Bailly, Audrey Coilly, Christophe Guignabert, Ly Tu, and Laurent Savale.
• Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 "Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT)", Le Kremlin-Bicêtre, France.
• Am. J. Respir. Crit. Care Med. 2024 Sep 1; 210 (5): 648661648-661.

AbstractRationale: 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.

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