The transient receptor potential vanilloid 1 (TRPV1) receptor protects against the onset of sepsis after endotoxin

Abstract

Transient potential vanilloid 1 (TRPV1) receptor is an ion channel receptor primarily localized on sensory nerves and activated by specific stimuli to initiate and amplify pain and inflammation, as typified by murine models of scald and arthritis. Little is known of the role of TRPV1 in sepsis, an infective disease associated with inflammation. Through use of a sublethal murine model of lipopolysaccharide-induced peritoneal sepsis, we provide novel evidence that genetic deletion of TRPV1 leads to an enhanced onset of various pathological components of systemic endotoxemia. Paired studies of TRPV1 knockout (KO) and wild-type mice demonstrate significantly enhanced hypotension (56+/-2% vs. 38+/-6% decrease in blood pressure, n=12), hypothermia (13+/-3% vs. 7+/-1% decrease in core temperature, n=6), and peritoneal exudate mediator levels (TNF-alpha, 0.78+/-0.2 vs. 0.38+/-0.1 ng/ml; nitrite, for NO, 35+/-10 vs. 15+/-3 microM; n=8) in TRPV1 KO mice, indicating loss of protective effect. Findings correlated with liver edema and raised plasma levels of aspartate aminotransferase in TRPV1 KO mice. These data suggest that TRPV1 may play an important regulatory role in sepsis independent of the major sensory neuropeptide substance P. The findings are relevant to developing strategies that increase the beneficial, and reduce the harmful, components of sepsis to prevent and treat this often fatal condition.

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.…”

Is TRPV1 a useful target in respiratory diseases?

“…Other studies have also demonstrated that particulate matter increases intracellular Ca 2+ and induces apoptosis of cultured lung epithelial cells via activation of TRPV1 [38,99]. These results indicate that TRPV1 is a mediator of lung injury and inflammation.…”

“…However, more recently, counter-regulatory functions of TRPV1 have been described in an endotoxin-induced sepsis model in the TRPV1 knock-out mouse. In TRPV1 knock- demonstrated enhanced hypotension, hypothermia and mediator levels in peritoneal exudates, which indicated a loss of protective effects [99]. Helyes et al also investigated the role of TRPV1 in endotoxin-induced airway inflammation and subsequent bronchial hyperreactivity in TRPV1 knock-out mice using intranasal LPS administration.…”

Transient Receptor Potential Vanilloid 1 Agonists as Candidates for Anti-inflammatory Agents

“…At the same time, however, it has emerged that TRPV1 has important functions in homeostasis, for example, in thermoregulation. The role of TRPV1 in inflammation is under debate; several studies have demonstrated a proinflammatory effect 3,4) , while other studies have identified a protective role for TRPV1 in systemic inflammation and sepsis [5][6][7] .…”