Blockade or deletion of transient receptor potential vanilloid 4 (TRPV4) is not protective in a murine model of sepsis

Abstract

Sepsis is a systemic inflammatory response triggered by microbial infection that can cause cardiovascular collapse, insufficient tissue perfusion and multi-organ failure. The cation channel transient receptor potential vanilloid 4 (TRPV4) is expressed in vascular endothelium and causes vasodilatation, but excessive TRPV4 activation leads to profound hypotension and circulatory collapse - key features of sepsis pathogenesis. We hypothesised that loss of TRPV4 signaling would protect against cardiovascular dysfunction in a mouse model of sepsis (endotoxaemia).Multi-parameter monitoring of conscious systemic haemodynamics (by radiotelemetry probe), mesenteric microvascular blood flow (laser speckle contrast imaging) and blood biochemistry (iSTAT blood gas analysis) was carried out in wild type (WT) and TRPV4 knockout (KO) mice. Endotoxaemia was induced by a single intravenous injection of lipopolysaccharide (LPS; 12.5 mg/kg) and systemic haemodynamics monitored for 24 h. Blood flow recording was then conducted under terminal anaesthesia after which blood was obtained for haematological/biochemical analysis. No significant differences were observed in baseline haemodynamics or mesenteric blood flow. Naïve TRPV4 KO mice were significantly acidotic relative to WT counterparts. Following induction of sepsis, all mice became significantly hypotensive, though there was no significant difference in the degree of hypotension between TRPV4 WT and KO mice. TRPV4 KO mice exhibited a higher sepsis severity score. While septic WT mice became significantly hypernatraemic relative to the naïve state, this was not observed in septic KO mice. Mesenteric blood flow was inhibited by topical application of the TRPV4 agonist GSK1016790A in naïve WT mice, but enhanced 24 h following LPS injection. Contrary to the initial hypothesis, loss of TRPV4 signaling (either through gene deletion or pharmacological antagonism) did not attenuate sepsis-induced cardiovascular dysfunction: in fact, pathology appeared to be modestly exaggerated in mice lacking TRPV4. Local targeting of TRPV4 signalling may be more beneficial than global inhibition in sepsis treatment.

Use of Biotelemetry to Define Physiology-Based Deterioration Thresholds in a Murine Cecal Ligation and Puncture Model of Sepsis

“…It has been used in multiple studies to describe physiologic changes in response to candidate sepsis therapies; however, this differs from utilizing the technology to define physiologic inclusion criteria to test a therapeutic, as performed here (14, 19, 21, 22, 24, 26, 29, 33–35, 38, 39). In our model, coupling of biotelemetry with a CLP model helped quantify physiologic differences in the murine response to sepsis that were indicative of significant biological differences, including inflammation and degree of shock and organ dysfunction.…”

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

“…In support of this, a recent study found no protective effect of TRPV4 channel antagonist HC067 on hemodynamic parameters over a 24-hour period in a mouse LPS (12.5 mg/kg, i.v.) endotoxemia model 56 . Furthermore, knockout of the TRPC6 channel was recently reported to protect against LPS-induced lung permeability, inflammation and injury, suggesting a more general role for members of the TRP family in inflammatory responses.…”

Involvement of Neural Transient Receptor Potential Channels in Peripheral Inflammation

“…In both LPS and CLP models of sepsis inhibition of TRPV4 significantly decreased systemic cytokines, maintained endothelial cell function, and reduced mortality in mice (9). However, there has been contrasting reports on the role of TRPV4 in sepsis, other studies have shown that inhibition has no significant effect on sepsis pathology (106). This inconsistency was found to be due to the antagonist dosage used.…”