Journal Article

Augmentation of Endothelial S1PR1 Attenuates Postviral Pulmonary Fibrosis

Hariri, Lida P., Knipe, Rachel S., Brazee, Patricia L., Cartier, Andreane, Griffith, Jason W., Nguyen, Trong, Medoff, Benjamin D., Kuo, Andrew, Hla, Timothy, Haring, Alexis M.

2024

Overview

Abstract Respiratory viral infections are frequent causes of acute respiratory distress syndrome (ARDS), a disabling condition with a mortality of up to 46%. The pulmonary endothelium plays an important role in the development of ARDS as well as the pathogenesis of pulmonary fibrosis; however, the therapeutic potential to modulate endothelium-dependent signaling to prevent deleterious consequences has not been well explored. Here, we used a clinically relevant influenza A virus infection model, endothelial cell–specific transgenic gain-of-function and loss-of-function mice as well as pharmacologic approaches and in vitro modeling, to define the mechanism by which S1PR1 expression is dampened during influenza virus infection and determine whether therapeutic augmentation of S1PR1 has the potential to reduce long-term postviral fibrotic complications. We found that the influenza virus–induced inflammatory milieu promoted internalization of S1PR1, which was pharmacologically inhibited with paroxetine, an inhibitor of GRK2. Moreover, genetic overexpression or administration of paroxetine days after influenza virus infection was sufficient to reduce postviral pulmonary fibrosis. Taken together, our data suggest that endothelial S1PR1 signaling provides critical protection against long-term fibrotic complications after pulmonary viral infection. These findings support the development of antifibrotic strategies that augment S1PR1 expression in virus-induced ARDS to improve long-term patient outcomes.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Animals / Cells / Endothelial cells / Endothelium - metabolism / Fibrosis / Gene expression / Humans / Inflammation / Influenza A / Internalization / Lung diseases / Mice / Original Research / Orthomyxoviridae Infections / Paroxetine / Pulmonary Fibrosis / Respiratory Distress Syndrome / Sphingosine-1-Phosphate Receptors - metabolism / Viral infections