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

• Published in: American journal of respiratory and critical care medicine Vol. 210; no. 5; pp. 648 - 661
• Main Authors: Robert, Fabien, Certain, Marie-Caroline, Baron, Audrey, Thuillet, Raphaël, Duhaut, Léa, Ottaviani, Mina, Chelgham, Mustapha Kamel, Normand, Corinne, Berrebeh, Nihel, Ricard, Nicolas, Furlan, Valerie, Desroches-Castan, Agnès, Gonzales, Emmanuel, Jacquemin, Emmanuel, Sitbon, Olivier, Humbert, Marc, Bailly, Sabine, Coilly, Audrey, Guignabert, Christophe, Tu, Ly, Savale, Laurent
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.09.2024
• Subjects: Adult; Aged; Animals; Case-Control Studies; Disease Models, Animal; Female; Growth Differentiation Factor 2; Hepatopulmonary Syndrome - metabolism; Hepatopulmonary Syndrome - physiopathology; Humans; Hypertension, Portal - physiopathology; Life Sciences; Liver cirrhosis; Liver Cirrhosis - complications; Liver Cirrhosis - physiopathology; Lung - metabolism; Lung diseases; Male; Medical research; Middle Aged; Proteins; Pulmonary arteries; Rats; Signal Transduction; Tacrolimus - pharmacology; Tacrolimus - therapeutic use; Vein & artery diseases; intrapulmonary vascular dilatations; portal hypertension; hepatopulmonary syndrome; cirrhosis; BMP-9
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.202307-1289OC

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. This study aimed to investigate the involvement of BMP-9 in human and experimental HPS. 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. 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. The study findings suggest that portal hypertension-induced loss of BMP-9 signaling contributes to HPS development.