TRPV4 inhibition attenuates stretch-induced inflammatory cellular responses and lung barrier dysfunction during mechanical ventilation.

N Pairet,G Fois,S Mang,P Dietl,M Kühnbach,M Frick,D J Lamb,J Gindele,M Keck,Bernhard Ryffel

doi:10.1371/journal.pone.0196055

N Pairet, G Fois + Show 8 more

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https://doi.org/10.1371/journal.pone.0196055

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Abstract

Mechanical ventilation is an important tool for supporting critically ill patients but may also exert pathological forces on lung cells leading to Ventilator-Induced Lung Injury (VILI). We hypothesised that inhibition of the force-sensitive transient receptor potential vanilloid (TRPV4) ion channel may attenuate the negative effects of mechanical ventilation. Mechanical stretch increased intracellular Ca2+ influx and induced release of pro-inflammatory cytokines in lung epithelial cells that was partially blocked by about 30% with the selective TRPV4 inhibitor GSK2193874, but nearly completely blocked with the pan-calcium channel blocker ruthenium red, suggesting the involvement of more than one calcium channel in the response to mechanical stress. Mechanical stretch also induced the release of pro-inflammatory cytokines from M1 macrophages, but in contrast this was entirely dependent upon TRPV4. In a murine ventilation model, TRPV4 inhibition attenuated both pulmonary barrier permeability increase and pro-inflammatory cytokines release due to high tidal volume ventilation. Taken together, these data suggest TRPV4 inhibitors may have utility as a prophylactic pharmacological treatment to improve the negative pathological stretch-response of lung cells during ventilation and potentially support patients receiving mechanical ventilation.

Highlights

To investigate whether TRPV4 is involved in the mechanical strain induced stress response in NCI-H292, we studied the Ca2+ response after uni-axial cell-stretch with various combinations of stretch speeds and distances
After showing that TRPV4 plays a role in mediating the stretch induced stress on human lung epithelial cells and macrophages, we wanted to examine the effect of a TRPV4 antagonist in a murine mechanical ventilation in vivo model with high tidal volumes
In this study we investigated the potential of a TRPV4 inhibitor for the improvement of mechanical ventilation induced pathological response in lung cells, using the TRPV4 antagonist GSK2193874 in both in vitro and in vivo models of pathophysiological stretch

Summary

Introduction

A recent study in fetal mouse distal lung epithelial cells demonstrated that TRPV4 may play an important role in the transduction of mechanical signals in the lung epithelium during ventilation by modulating the stretch-induced release of pro-inflammatory cytokines [31].

Results

Conclusion