Effects of a TRPV4 antagonist and pirfenidone on idiopathic pulmonary fibrosis
2020
Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by extracellular matrix deposition in the lung interstitium. Pirfenidone is an anti-fibrotic drug to treat patients with IPF, but its precise anti-fibrotic mechanisms are still being investigated. TRPV4 (transient receptor potential vanilloid 4) is a cation channel that is responsive to a variety of biochemical and biomechanical stimuli. The involvement of TRPV4 and its interaction with pirfenidone in lung fibrosis are poorly understood. Aims and Objectives: Using a new TRPV4 antagonist and pirfenidone, we investigated the role of TRPV4 in wound healing and its anti-fibrotic activities. Methods: The anti-fibrotic and wound-healing response to the TRPV4 antagonist (Compound 26i; Shionogi Co, Ltd: Bioorg Med Chem. 2017;25:2177-2190) and pirfenidone were investigated. Furthermore, immunohistochemistry was carried out to evaluate localization of TRPV4 in lungs of IPF patients. Results: TRPV4 was expressed in the epithelium and myofibroblasts of fibrotic foci in IPF patients. The TRPV4 antagonist 26i suppressed BLM-induced lung fibrosis in mice. Pirfenidone also inhibited Ca2+ influx mediated by TRPV4 and its endogenous ligand production in both a microsome assay and mice. Furthermore, 26i suppressed TGF-β-induced fibroblast-to-myofibroblast transition of WI-38 cells and promoted wound healing of A549 cells. Conclusions: The TRPV4 channel is involved in lung fibrosis and an antagonistic compound is a potential candidate for IPF treatment. Furthermore, the anti-fibrotic action of pirfenidone appears to be partly mediated through modulation of TRPV4 signaling.
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