Targeting GPCR Signaling for Idiopathic Pulmonary Fibrosis Therapies

• Published in: Trends in pharmacological sciences (Regular ed.) Vol. 41; no. 3; pp. 172 - 182
• Main Authors: Haak, Andrew J., Ducharme, Merrick T., Diaz Espinosa, Ana M., Tschumperlin, Daniel J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2020
• Subjects: fibrosis; G protein-coupled receptor; MRTF; ROCK; TAZ; YAP; G protein-coupled receptor; YAP; fibrosis; ROCK; MRTF; TAZ
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2019.12.008

A variety of G protein-coupled receptors (GPCRs) have been implicated in the pathogenesis of pulmonary fibrosis, largely through their promotion of profibrotic fibroblast activation. By contrast, recent work has highlighted the beneficial effects of Gαs-coupled GPCRs on reducing fibroblast activation and fibrosis. This review highlights how fibrosis-promoting and -inhibiting GPCR signaling converges on downstream signaling and transcriptional effectors, and how the diversity and dynamics of GPCR expression challenge efforts to identify effective therapies for idiopathic pulmonary fibrosis (IPF). Next-generation strategies to overcome these challenges, focusing on target selection, polypharmacology, and personalized medicine approaches, are discussed as a path towards more effective GPCR-targeted therapies for pulmonary fibrosis. Multiple GPCR ligand/receptor pairs are implicated in IPF, and clinical trials are currently underway targeting GPCR pathways for the treatment of IPF.Individual GPCRs can promote profibrotic or antifibrotic phenotypes in lung fibroblasts, depending on the receptor class and downstream signaling pathways.The convergence of downstream pathways on common signaling and transcriptional mechanisms integrates diverse GPCR effects and may provide a path to overcome redundancy.Signaling programs downstream of GPCR signaling are also essential for alveolar epithelial regeneration and repair, highlighting the need to identify strategies that account for this complexity.