Evaluation of GSK2789917-induced TRPV4 inhibition in animal models of fluid induced lung injury.

Administration of bolus intravenous fluids, common in pre-hospital and hospitalised patients, is associated with increased lung vascular permeability and mortality outside underlying disease states. In our laboratory, the induction of lung injury and oedema through rapid administration of intravenous fluid in rats was reduced by a non-specific antagonist of transient receptor potential vanilloid 4 (TRPV4) channels. The aims of this study were to determine the effect of selective TRPV4 inhibition on fluid-induced lung injury (FILI) and compare the potency of FILI inhibition to that of an established model of TRPV4 agonist-induced lung oedema. In a series of experiments, rats received specific TRPV4 inhibitor (GSK2789917) at high (15 μg/kg), medium (5 μg/kg) or low (2 μg/kg) dose or vehicle prior to induction of lung injury by intravenous infusion of TRPV4 agonist (GSK1016790) or saline. GSK1016790 significantly increased lung wet weight/body weight ratio by 96% and lung wet-to-dry weight ratio by 43% in vehicle pre-treated rats, which was inhibited by GSK2789917 in a dose-dependent manner (IC50 = 3 ng/mL). Similarly, in a single-dose study, bolus saline infusion significantly increased lung wet weight/body weight by 17% and lung wet-to-dry weight ratio by 15%, which was attenuated by high dose GSK2789917. However, in a final GSK2789917 dose-response study, inhibition did not reach significance and an inhibitory potency was not determined due to the lack of a clear dose-response. In the FILI model, TRPV4 may have a role in lung injury induced by rapid-fluid infusion, indicated by inconsistent amelioration with high dose TRPV4 antagonist.