Hydrogen sulfide (H(2)S) has been shown to induce transient receptor potential vanilloid 1 (TRPV1)-mediated
neurogenic inflammation in polymicrobial
sepsis. However, endogenous neural factors that modulate this event and the molecular mechanism by which this occurs remain unclear. Therefore, this study tested the hypothesis that whether
substance P (SP) is one important neural
element that implicates in H(2)S-induced
neurogenic inflammation in
sepsis in a TRPV1-dependent manner, and if so, whether H(2)S regulates this response through activation of the
extracellular signal-regulated kinase-nuclear factor-κB (ERK-NF-κB) pathway. Male Swiss mice were subjected to cecal
ligation and
puncture (CLP)-induced
sepsis and treated with TRPV1 antagonist
capsazepine 30 minutes before CLP. DL-
propargylglycine (PAG), an inhibitor of H(2)S formation, was administrated 1 hour before or 1 hour after
sepsis, whereas
sodium hydrosulfide (
NaHS), an H(2)S donor, was given at the same time as CLP.
Capsazepine significantly attenuated H(2)S-induced SP production, inflammatory
cytokines,
chemokines, and adhesion molecules levels, and protected against lung and
liver dysfunction in
sepsis. In the absence of H(2)S,
capsazepine caused no significant changes to the PAG-mediated attenuation of lung and plasma SP levels,
sepsis-associated systemic inflammatory response and multiple organ dysfunction. In addition,
capsazepine greatly inhibited phosphorylation of ERK(1/2) and inhibitory κBα, concurrent with suppression of NF-κB activation even in the presence of
NaHS. Furthermore,
capsazepine had no effect on PAG-mediated abrogation of these levels in
sepsis. Taken together, the present findings show that H(2)S regulates TRPV1-mediated
neurogenic inflammation in polymicrobial
sepsis through enhancement of SP production and activation of the ERK-NF-κB pathway.