Pharmacological Inhibitors of TRPV4 Channels Reduce Cytokine Production, Restore Endothelial Function and Increase Survival in Septic Mice

Overview

Journal Sci Rep

Specialty Science

Date 2016 Sep 23

PMID 27653046

Citations 38

Authors

Thomas Dalsgaard

Swapnil K Sonkusare

Cory Teuscher

Matthew E Poynter

Mark T Nelson

Affiliations

Soon will be listed here.

Abstract

Sepsis is characterized by systemic inflammation, edema formation and hypo-perfusion leading to organ dysfunction and ultimately death. Activation of the transient receptor potential vanilloid type 4 (TRPV4) channel is associated with edema formation and circulatory collapse. Here, we show that TRPV4 channels are involved in the hyper-inflammatory response and mortality associated with sepsis. Pharmacological inhibition of TRPV4 channels in mice reduced mortality in lipopolysaccharide and cecal-ligation-and-puncture models of sepsis, but not in a tumor necrosis factor-α (TNFα)-induced sepsis model. These protective effects of TRPV4 channel inhibition were attributable to prevention of the sepsis-induced surge of a broad spectrum of pro-inflammatory cytokines, including TNFα, interleukin (IL)-1 and IL-6, and subsequent preservation of endothelial cell function, including Ca signaling, integrity and endothelium-dependent vasodilation. These results suggest that TRPV4 antagonists may be of therapeutic utility in the management of sepsis.

Citing Articles

Synergetic role of TRPV4 inhibitor and mechanical loading on reducing inflammation.

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The Role of the TRPV4 Channel in Intestinal Physiology and Pathology.

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TRPV4 Channel in Neurological Disease: from Molecular Mechanisms to Therapeutic Potential.

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