Alveolar Type 2 Cell Dysfunction Is Associated with Bile Acid Alterations in Experimental Hepatopulmonary Syndrome

Area of Science:

• Pulmonary Medicine
• Gastroenterology
• Cell Biology

Background:

• Hepatopulmonary syndrome (HPS) is a severe cirrhosis complication with hypoxemia and pulmonary vascular changes.
• Restrictive ventilatory defects in HPS correlate with bile acids, suggesting alveolar dysfunction.

Purpose of the Study:

• Investigate alveolar function, cell types, and the role of bile acids in experimental HPS.
• Determine the impact of altered bile acids on alveolar type 2 (AT2) cells.

Main Methods:

• Common bile duct ligation (CBDL) mouse model for HPS.
• AT2 cell-specific RNA sequencing, single-cell RNA sequencing (sc-RNA-seq), and bile acid profiling.
• In vitro and in vivo experiments with bile acids and FXR agonist on AT2 cells.

Main Results:

• CBDL mice showed HPS with restrictive defects, reduced surfactant protein C (SP-C) from AT2 cells, and elevated bile acids.
• sc-RNA-seq revealed decreased AT2 cells and increased AT2-to-AT1 transitional cells.
• Bile acids impaired SP-C production in vitro; FXR agonist restored AT2 cells and SP-C in vivo.

Conclusions:

• Cirrhosis-associated HPS involves AT2 cell dysfunction and reduced surfactant due to elevated bile acids.
• Altered bile acid signaling impacts AT2 cell integrity and surfactant production.
• Targeting bile acid signaling presents a potential therapeutic avenue for HPS.