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

作者：F. Robert, Marie-Caroline Certain, Audrey Baron, Raphaël Thuillet, Léa Duhaut, Mina Ottaviani, Mustapha Kamel Chelgham, Corinne Normand, Nihel Berrebeh, Nicolas Ricard, Valérie Furlan, Agnès Desroches‐Castan, Emmanuel Gonzalès, Emmanuel Jacquemin, Olivier Sitbon, Marc Humbert, Sabine Bailly, Audrey Coilly, Christophe Guignabert, Ly Tu, Laurent Savale · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2024 · DOI：10.1164/rccm.202307-1289oc · 被引用次数：27 · 研究领域：Liver Disease and Transplantation、Organ Transplantation Techniques and Outcomes、Pulmonary Hypertension Research and Treatments

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 th...