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

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.

Transient receptor potential vanilloid 4 channel regulates vascular endothelial permeability during colonic inflammation in dextran sulphate sodium‐induced murine colitis

“…Dalsgaard et al . () reported that pharmacological inhibition of TRPV4 prevents LPS‐induced endothelial dysfunction and increase in mesenteric artery permeability in mouse mesenteric arteries. Endothelial damage increases colonic vascular permeability, contributing to the pathogenesis of experimental colitis in rats and mice (Tolstanova et al, ).…”

“…Additionally, endothelial TRPV4 regulates vascular permeability and/or relaxation in the lung (Sukumaran et al, ). Pharmacological blockade of TRPV4 was shown to result in a reduction in pro‐inflammatory cytokines and preserve the functions of the endothelium in a LPS‐induced murine model of sepsis (Dalsgaard et al, ). However, the localization and role of the TRPV4 channel in vascular endothelial (VE) cells in the gastrointestinal tract have not been elucidated.…”

Transient receptor potential vanilloid 4 (TRPV4) activation by arachidonic acid requires protein kinase A–mediated phosphorylation

“…As discussed above, a gain-of-function of TRPV4 contributes to several pathological processes such as neurogenic inflammation and hyperalgesia (5, 16 -18), adipose cell inflammation (19), and pulmonary and cardiac tissue fibrosis (20,21). In the vascular system, prolonged or excessive activation of endothelial TRPV4 causes disruption of endothelial barrier, tissue edema, and endothelial dysfunction in inflammation and other pathological conditions (57,58). It remains of interest to determine whether H 2 O 2induced enhancement of TRPV4 activation by AA contributes to excessive TRPV4 activity under the above pathophysiological conditions.…”

TRPV4 Channel-Regulated ATP Release Contributes to γ-Irradiation-Induced Production of IL-6 and IL-8 in Epidermal Keratinocytes

“…21) TRPV4 is also activated by thermal stimulation 22,23) (27-35°C). It is expressed in various locations, including the nervous system, kidneys, skin, blood vessels, lungs and bladder, 24,25) and was recently shown to be involved in production of inflammatory mediators, 26) including IL-6 [27][28][29] and IL-8. 30) It has also been reported to be involved in ATP release.…”