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

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

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


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.

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