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

Doi : 10.1016/j.rmr.2024.01.034

F. Robert ^1,^⁎,² , M.C. Certain ^1,^2,³, A. Baron ^1,^2,³, R. Thuillet ^1,², L. Duhaut ^4,⁵, M. Ottaviani ^1,², M.K. Chelgham ^1,², C. Normand ^1,², N. Berrebeh ^1,², N. Ricard ⁶, V. Furlan ⁷, A. Desroches-Castan ⁶, E. Gonzales ^5,⁸, E. Jacquemin ^5,⁸, O. Sitbon ^1,^2,³, M. Humbert ^1,^2,³, S. Bailly ⁶, A. Coilly ^4,⁵, C. Guignabert ^1,², L. Tu ^1,², L. Savale ^1,^2,³
¹ Inserm UMR_S 999 “pulmonary hypertension: pathophysiology and novel therapies”, hôpital Marie-Lannelongue, Le Plessis-Robinson, France
² Université Paris-Saclay, faculté de médecine, Le Kremlin-Bicêtre, France
³ Assistance publique–Hôpitaux de Paris (AP–HP), service de pneumologie et soins intensifs respiratoires, hôpital Bicêtre, Le Kremlin-Bicêtre, France
⁴ AP–HP, hôpital Paul-Brousse, centre hépato-biliaire, université Paris-Saclay, France
⁵ Inserm UMR_S 1193, Hepatinov, university Paris-Saclay, Orsay, France
⁶ Biosanté unit U1292, Grenoble Alpes university, Inserm, CEA, Grenoble, France
⁷ Service de pharmacologie-toxicologie, hôpital Bicêtre, AP–HP, université Paris-Saclay, Le Kremlin-Bicêtre, France
⁸ Pediatric hepatology and liver transplantation, National reference centre for biliary atresia and genetic cholestasis, FILFOIE, ERN RARE LIVER

^⁎Corresponding author.

Résumé

Introduction

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.

Methods

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.

Results

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.

Conclusion

The study findings suggest that portal hypertension-induced loss of BMP-9 signaling contributes to HPS development.

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Vol 41 - N° 3

P. 198 - mars 2024 Retour au numéro

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