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. 2011 May;114(5):1190-9.
doi: 10.1097/ALN.0b013e318212515b.

Disruption of the transient receptor potential vanilloid 1 can affect survival, bacterial clearance, and cytokine gene expression during murine sepsis

Virginia Guptill  1 , Xizhong Cui, Alfia Khaibullina, Jason M Keller, Nicholas Spornick, Andrew Mannes, Michael Iadarola, Zenaide M N Quezado
Affiliations

Disruption of the transient receptor potential vanilloid 1 can affect survival, bacterial clearance, and cytokine gene expression during murine sepsis

Virginia Guptill et al. Anesthesiology. 2011 May.

Abstract

Background: Previous studies suggest that the transient receptor potential vanilloid 1 (TRPV1) channel 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-knockout vs. wild-type [WT] 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-induced sepsis.

Results: After cecal ligation and puncture, genetic disruption of TRPV1 in Trpv1-knockout versus WT mice was associated with increased mortality risk (hazard ratio, 2.17; 95% CI, 1.23-3.81; P = 0.01). Furthermore, pharmacologic disruption of TRPV1 with intrathecal resiniferatoxin, compared with vehicle, increased mortality risk (hazard ratio, 1.80; 95% CI, 1.05-3.2; P = 0.03) in WT, but not in Trpv1-knockout, mice. After lipopolysaccharide, neither genetic (Trpv1 knockout) 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 (hazard ratio, 1.92; 95% CI, 1.02-3.61; P = 0.04) in WT animals. Furthermore, after cecal ligation and puncture, increased mortality in resiniferatoxin-treated WT animals was associated with higher blood bacterial count (P = 0.0004) and higher nitrate/nitrite concentrations and down-regulation 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.

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Figures

Figure 1
Figure 1
Effect of disruption of transient receptor potential vanilloid 1 (TRPV1) on survival after polymicrobial sepsis (cecal ligation and puncture) or lipopolysaccharide challenge. Panel A shows effects of TRPV1 disruption by genetic deletion (Trpv1-knock out, KO) or pharmacologic ablation with intrathecal resiniferatoxin (RTX) [WT (wild-type) control group includes 55 WT animals (20 receiving no treatment and 35 vehicle-treated WT combined); Trpv1-KO group includes 50 animals (20 Trpv1-KO mice receiving no treatment and 30 receiving vehicle)]. Panel B shows the effect of intrathecal resiniferatoxin in animals lacking the TRPV1 gene (Trpv1-KO) after cecal ligation and puncture. Panel C shows the effects of TRPV1 disruption by genetic deletion or pharmacologic ablation with intrathecal resiniferatoxin after lipopolysaccharide-induced toxicity [WT control group includes 48 WT animals (21 receiving no treatment and 27 vehicle-treated WT combined)]. Panel D shows effects of TRPV1 disruption with capsazepine (CPZ) after lipopolysaccharide challenge.
Figure 2
Figure 2
Effects of disruption of the transient receptor potential vanilloid 1 (TRPV1) by pharmacologic disruption [with resiniferatoxin (RTX) or capsazepine (CPZ)] or genetic deletion (Trpv1-KO) on hazard ratio of death (95% confidential interval) based on the respective controls as indicated in Figure 1. The triangle, circle, and square represent the hazard ratio and the horizontal brackets, the 95% confidence interval. P values indicate the significance level of hazard ratio of death of each treatment in either cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) compared to their respective controls.
Figure 3
Figure 3
Effect of disruption of the transient receptor potential vanilloid-1 (TRPV1) gene by pharmacologic ablation with intrathecal resiniferatoxin, in wild-type (WT) animals (panels A and C) or genetic deletion (Trpv1-Knock Out, KO, panels B and D) on bacterial clearance from the blood (panels A and B) and nitrate/nitrite (NOx) serum levels at 6 and 24 h (panels C and D). Results are shown as means±SEM, number of animals sacrificed at respective time points are shown in parenthesis inside each bar, and * indicates P<0.05 comparing groups with respective controls.
Figure 4
Figure 4
Serial mean±SEM body temperature measurements in Trpv1-knock out (Trpv1-KO) and wild-type (WT, N=4 per group) mice before and after lipopolysaccharide challenge.
Figure 5
Figure 5
In vitro effects of pharmacologic disruption with capsazepine (CPZ), an agonist of the transient receptor potential vanilloid-1 on wild-type splenocytes challenged with lipopolysaccharide for 16 h on tumor necrosis factor alpha (panel A), macrophage inflammatory protein (panel B), and interleukin-10 (panel C) gene expression. Relative expressions (y-axis) for each gene were normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and are relative to the gene expression in vehicle-treated WT splenocytes challenged with phosphate buffered saline (PBS). Results are shown as means±SEM of three separate experiments and each of these three experiments was performed by pooling the spleens of 2 animals in each of the groups studied. Log relative expressions and p values indicate comparison between groups indicated by brackets.
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