Targeting GPCR Signaling for Idiopathic Pulmonary Fibrosis Therapies

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. 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. 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. molecules that affect protein activity by binding to a secondary, allosteric, site rather than to a primary, orthosteric, site. refer to an alveolus (plural, alveoli), a small, balloon-shaped air cavity arranged in clusters at the end of the respiratory tree in the lung parenchyma. fluid collected following the insertion of a device that can infuse solutions into specific parts of the lung. second messenger molecule which is elevated following Gαs activation. a subtype of a condition defined by a distinct pathophysiological mechanism. breath is condensed following exhalation and allows the determination of biomolecules present in respiratory compartments. non-cellular component that provides structural support to cells and organs. spindle-shaped cells in connective tissue that are responsible for the synthesis and degradation of the ECM. the largest family of cell-membrane receptors that mediate physiological responses through the transduction of extracellular stimuli. a class of enzymes that remove acetyl groups from histones. This removal causes histones to bind more tightly to DNA, leading to an overall decrease in gene expression. a progressive lung disease characterized by uncontrolled scarring of the lung connective tissue by activated fibroblasts. transcriptional coactivators which are regulated by cytoskeletal dynamics and regulate the expression of profibrotic genes. an approved small-molecule therapeutic for the treatment of IPF. It has been shown to elicit antifibrotic activity by inhibiting a wide range of tyrosine kinase receptors. an approved small-molecule therapeutic for the treatment of IPF. It has proven antifibrotic activity but an unknown mechanism of action. the design and development of pharmaceutical agents that simultaneously interact with multiple targets. respectively promote or reduce fibrosis – the pathological accumulation of fibrous proteins in an organ. a pair of serine/threonine kinases that are important for a wide range of processes in IPF. a profibrotic cytokine involved in fibroblast proliferation and recruitment, cell differentiation, and matrix regulation transcriptional coactivators that are regulated by G proteins and mechanosignaling, and that regulate the expression of profibrotic genes.