Disruption of the Transient Receptor Potential Vanilloid 1 Can Affect Survival, Bacterial Clearance, and Cytokine Gene Expression during Murine Sepsis

Abstract

Background Previous studies suggest that the transient receptor potential vanilloid-1 (TRPV1) has a role in sepsis but it is unclear whether its effect on survival and immune response is beneficial or harmful. Methods We studied the effects of genetic (Trpv1-knock out vs. wild-type mice) and pharmacologic disruption of TRPV1 with resiniferatoxin (an agonist) or capsazepine (an antagonist) on mortality, bacterial clearance, and cytokine expression during lipopolysaccharide or cecal ligation and puncture (CLP)-induced sepsis. Results After CLP, genetic disruption of TRPV1 in Trpv1-knock out mice was associated with increased mortality risk [2.17 (1.23 to 3.81) hazard ratio (95% confidence interval), p=0.01] compared with wild-type. Further, pharmacologic disruption of TRPV1 with intrathecal resiniferatoxin, compared with vehicle, increased mortality risk [1.80 (1.05 to 3.2) hazard-ratio (95% confidence interval), p=0.03] in wild-type animals, but not in Trpv1-knock out mice. After lipopolysaccharide, neither genetic (Trpv1-knock out) nor pharmacologic disruption of TRPV1 with resiniferatoxin had significant effect on survival compared with respective controls. In contrast, after lipopolysaccharide, pharmacologic disruption of TRPV1 with capsazepine, compared with vehicle, increased mortality risk [1.92 (1.02 to 3.61) hazard-ratio (95% confidence interval), p=0.04] in wild-type animals. Further, after CLP, increased mortality in resiniferatoxin-treated-wild-type animals was associated with higher blood bacterial count (p=0.0004) and nitrate/nitrite levels and downregulation of tumor necrosis factor α expression (p=0.004) compared with controls. Conclusions Genetic or pharmacologic disruption of TRPV1 can affect mortality, blood bacteria clearance, and cytokine response in sepsis in patterns that may vary according to the sepsis-inducing event and the method of TRPV1 disruption.

TRPV1 Deletion Enhances Local Inflammation and Accelerates the Onset of Systemic Inflammatory Response Syndrome

“…However, we cannot overrule a role for TRPV1 in changes in the presence of bacteria in the lung at later time points. Indeed, in support of our findings, it was recently demonstrated that blood samples obtained from CLP TRPV1KO exhibited a higher bacterial load 24 h after sepsis induction that was associated with higher mortality when compared with WT mice (51).…”

N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1

“…Consistent with the cumulative evidence that points to a protective role for TRPV1 in murine sepsis models, we observe that TRPV1 activation displays a protective phenotype of reduced proinflammation, increased anti-inflammation, and downregulation of PAI-1 in toxicity and infection models of sepsis (17,27,39,40). However, in contrast to other reports on TRPV1 in sepsis, we did not detect differences in the cytokine responses of Trpv1 2/2 and WT mice treated with LPS or Pam3Cys in the absence of NADA.…”

“…The majority of the in vivo work on NADA has focused on its neurologic and behavioral effects, and NADA's effects on inflammation have not been characterized (2,(35)(36)(37)(38). Although there are mixed studies suggesting that TRPV1 activation affects inflammation in models of sepsis, to our knowledge, no prior study has investigated in vivo the role of NADA or the NADA-TRPV1 axis in sepsis (17,27,39,40). Therefore, we tested the hypothesis that the administration of NADA would reduce acute systemic inflammation in sepsis via activation of TRPV1.…”

Up‐regulation of transient receptor potential vanilloid (TRPV) and down‐regulation of brain‐derived neurotrophic factor (BDNF) expression in patients with functional dyspepsia (FD)

“…Interestingly, inflammatory bowel disease is associated with up‐regulation of TRPV1 in nerve fibers of the colon . Previous animal study showed that TRPV1 is involved in bacterial clearance and cytokine secretion …”