Disrupted BMP-9 signaling impairs pulmonary vascular integrity in hepatopulmonary syndrome - 20/03/24

Hepatopulmonary syndrome (HPS) is a severe complication of liver diseases characterized by abnormal dilatation of pulmonary vessels, resulting in impaired oxygenation. Recent research highlights the pivotal role of liver-produced bone morphogenetic protein (BMP)-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 cirrhotic patients with and without HPS, and after liver transplantation. Two animal models were employed: the common bile duct ligation (CBDL) with cirrhosis and the long-term partial portal vein ligation (PPVL) without cirrhosis. Additionally, we investigated the therapeutic effect of low-dose BMP activator FK506 and analyzed the pulmonary vascular phenotype of BMP-9 knockout rats.

Patients with HPS exhibited lower levels of circulating BMP-9 compared to cirrhotic patients without HPS. However, BMP-9 levels normalized after liver transplantation. In the animal models, HPS characteristics, including intrapulmonary vascular dilations and alveolo-arterial gradient enlargement, were observed in CBDL and long-term PPVL rats at 4 and 10 weeks, respectively. HPS development in both models was associated with reduced intrahepatic BMP-9 expression, decreased circulating BRE activity, and impaired pulmonary BMP-9 endothelial pathway, marked by reduced phosphorylated Smad1/5/8 and Id1 levels. Daily treatment with FK506 for 2-weeks restored BMP pathway in the lungs, attenuated intrapulmonary vascular dilations, and improved 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.