A novel actor in mechanotransduction: transient receptor potential cation channel vanilloid (TRPV) 1 in ventilator‐induced lung injury (VILI)

Abstract

Study objectiveMechanical ventilation can damage the lung by causing endothelial barrier failure, edema formation and lung injury. Yet, the exact mechanisms underlying the mechanotransduction at the microvascular barrier are still unclear. In previous work, we had identified a critical role of the endothelial Ca2+ channel transient receptor potential vanilloid 4 (TRPV4) in endothelial barrier failure subsequent to mechanical overventilation. Here, we assessed the relevance of TRPV1 as novel regulator in VILI in vivo, and probed for its contribution to TRPV4‐induced Ca2+ signalling in vivo, ex vivo and in vitro.MethodsWild type, TRPV4‐ or TRPV1‐deficient mice were ventilated for 2 h with low (7 mL/kg) and high (20 mL/kg) tidal volumes (LVT/HVT) in vivo. Endothelial [Ca2+]i in isolated‐perfused lungs, inflated with 5 or 15 cmH2O, and in human pulmonary microvascular endothelial cells (HPMVECs) was quantified by real‐time imaging with or without pharmacological inhibition of TRPV1 and TRPV4, or after activation of TRPV1 and/or TRPV4 by capsaicin and/or GSK1016790A, respectively.ResultsTRPV1 or TRPV4 deficiency or inhibition by either SB366791 or HC‐067047, respectively, attenuated VILI, and reduced the endothelial [Ca2+]i response to high pressure inflation ex vivo, with exception of SB366791 treatment, which only diminished the sustained [Ca2+]i response, but not the initial Ca2+ influx. In vitro Ca2+ measurements from HPMVECs showed a characteristic increase in endothelial [Ca2+]i that in response to selective TRPV4, yet activation of TRPV1 alone had no effect. Dual activation of both TRPV channels, however, amplified and prolong the TRPV4‐mediated Ca2+ influx into HPMVECs.ConclusionsHere, we demonstrate a critical role of TRPV1 as amplifier of TRPV4‐mediated [Ca2+]i response and barrier failure for VILI in vivo, ex vivo and in vitro, and identify a novel signalling axis that may present putative pharmacological targets for the prevention or treatment of ventilator‐associated lung disease.