Role of Transient receptor potential vanilloid 4 in neutrophil activation and acute lung injury

Abstract

IntroductionTransient receptor potential vanilloid 4 (TRPV4) is a cation channel expressed in lung parenchyma and inflammatory cells. TRP channels have been implicated in the activation of inflammatory cells and the pathogenesis of acute lung injury (ALI), thus we hypothesized that TRPV4 deficiency or inhibition may attenuate inflammatory responses and ALI.MethodTo test this, in vivo and ex vivo studies were performed using TRPV4−/− mice.ResultsGenetic deficiency or pharmacologic inhibition of TRPV4 attenuated the functional, histological and inflammatory hallmarks of ALI following intratracheal instillation of hydrochloric acid or lipopolysaccharide (LPS). TRPV4−/− compared to TRPV4+/+mice had an increased survival rate following i.p. LPS. Perfused lung studies showed decreased lung weight increase in TRPV4−/− mice in response to platelet activating factor (PAF). Transfusion of TRPV4+/+ vs. TRPV4−/− blood into perfused lungs led to greater Evans blue extravasation following PAF administration. Neutrophils from TRPV4−/− mice had attenuated increases in intracellular calcium and reactive oxygen species and showed reduced endothelial transmigration in response to PAF.ConclusionOur findings identify a role for TRPV4 in neutrophil activation, and suggest TRPV4 as a promising pharmacological target for the prevention and potentially treatment of ALI.Supported by CREMS, University of Toronto and NSFC # 81000028