Transient receptor potential cation channel vanilloid (TRPV) 4 in ventilator‐induced lung injury (VILI)

Abstract

Study objectiveCa2+ entry via TRPV4 has been implicated in stretch‐induced barrier failure in isolated lungs. Here, we assessed the relevance of TRPV4 in VILI in vivo, and probed for the contribution of serum/glucocorticoid‐regulated kinase (SGK) 1, which phosphorylates TRPV4, and of Ca2+‐activated K+ channels (SK, BK) as putative signalling mechanisms upstream and downstream of TRPV4, respectively.MethodsMale, anesthetized mice were mechanically ventilated for 2 h by low (7 ml/kg) and high (20 ml/kg) tidal volumes (LVT/HVT) in wild type and TRPV4‐deficient mice, and following pharmacological inhibition of SGK1, TRPV4, SK or BK channels.ResultsTRPV4 deficiency or inhibition by HC‐067047 attenuated VILI as demonstrated by reduced lung edema, protein leak, MPO activity, inflammatory cytokine levels, and histological features of lung injury. Inhibition of SK or BK channels by apamin or charybdotoxin attenuated lung edema in HVT mice, yet only charybdotoxin had concomitant anti‐inflammatory effects. Lung edema formation in HVT mice was also largely reduced by the SGK1 inhibitor GSK650394.ConclusionsHere, we demonstrate the critical role of TRPV4 for VILI in vivo, and identify potential upstream (SGK1) and downstream (SK, BK) signalling events that may present putative pharmacological targets for the prevention or treatment of ventilator‐associated lung disease.