Abstract
Hydrogen sulfide (H2S) 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 H2S-induced neurogenic inflammation in sepsis in a TRPV1-dependent manner, and if so, whether H2S 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 H2S formation, was administrated 1 hour before or 1 hour after sepsis, whereas sodium hydrosulfide (NaHS), an H2S donor, was given at the same time as CLP. Capsazepine significantly attenuated H2S-induced SP production, inflammatory cytokines, chemokines, and adhesion molecules levels, and protected against lung and liver dysfunction in sepsis. In the absence of H2S, 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 ERK1/2 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 H2S regulates TRPV1-mediated neurogenic inflammation in polymicrobial sepsis through enhancement of SP production and activation of the ERK-NF-κB pathway.
Highlights
The neuropeptide substance P (SP) is an 11 amino acid peptide encoded by the preprotachykinin-A (PPT-A) gene
Identifying endogenous neural elements that modulate H2S-induced neurogenic inflammation in sepsis and elucidating the underlying molecular mechanisms by which this occurs are of paramount importance
We showed that overproduction of SP significantly increases the severity of sepsis in a TRPV1dependent manner; and that this phenomenon occurred under the influences of the proinflammatory effects of H2S
Summary
The neuropeptide substance P (SP) is an 11 amino acid peptide encoded by the preprotachykinin-A (PPT-A) gene. It is distributed throughout the nervous system of human and animal species [1,2]. SP has been established to exert a vast range of proinflammatory effects in vitro and in vivo, influencing many immune and inflammatory disorders of the respiratory, gastrointestinal, and musculoskeletal systems [2]. SP provokes lymphocyte proliferation, immunoglobulin production, leukocyte chemotaxis, and activation of proinflammatory transcription factors; all of which exacerbate tissue injury and amplify the overall inflammatory response [2]. It is obvious that an extensive neuro-immune intersystem crosstalk exist between SP and the inflammatory response to injury
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
