Pharmacological inhibitors of TRPV4 channels reduce cytokine production, restore endothelial function and increase survival in septic mice

Thomas Dalsgaard; Swapnil K Sonkusare; Cory Teuscher; Matthew E Poynter; Mark T Nelson

doi:10.1038/srep33841

Pharmacological inhibitors of TRPV4 channels reduce cytokine production, restore endothelial function and increase survival in septic mice

Sci Rep. 2016 Sep 22:6:33841. doi: 10.1038/srep33841.

Authors

Thomas Dalsgaard¹, Swapnil K Sonkusare¹, Cory Teuscher², Matthew E Poynter³, Mark T Nelson^{1

4}

Affiliations

¹ Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405, USA.
² Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT 05405, USA.
³ Department of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont, Burlington, VT 05405, USA.
⁴ Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK.

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 Ca²⁺ signaling, integrity and endothelium-dependent vasodilation. These results suggest that TRPV4 antagonists may be of therapeutic utility in the management of sepsis.

Abstract

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