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Title: Hydrogen Sulfide and Neurogenic Inflammation in a Murine Model of Polymicrobial Sepsis
Keywords: hydrogen sulfide, neurogenic, inflammation, sepsis, substance P, transient receptor potential vanilloid type 1
Issue Date: 17-Aug-2011
Citation: ANG SEAH FANG (2011-08-17). Hydrogen Sulfide and Neurogenic Inflammation in a Murine Model of Polymicrobial Sepsis. ScholarBank@NUS Repository.
Abstract: Hydrogen sulfide (H2S), a malodorous gas with the characteristic odor of rotten eggs, has been recognized as an important endogenous gaseous signaling molecule of the cardiovascular, gastrointestinal, genitourinary, and nervous systems. Besides acting as a potent vasodilator and an atypical neuromodulator, H2S is increasingly being established as a novel mediator of inflammation. However, the part played by H2S in modulating neurogenic inflammatory response in sepsis is not known. Therefore, this study aimed to investigate the role of H2S in mediating neurogenic inflammation in a mouse model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Of major significance in the development of neurogenic inflammation is the transient receptor potential vanilloid type 1 (TRPV1) receptor, a non-selective cation channel found predominantly in primary sensory neurons. In particular, the results of the present study indicate that H2S promotes TRPV1-mediated neurogenic inflammation in sepsis. It was found that capsazepine, a selective receptor antagonist of TRPV1, significantly attenuated systemic inflammation and multiple organ damage caused by CLP-induced sepsis under the pro-inflammatory impact of H2S. Capsazepine also delayed the onset of lethality and protected against sepsis-associated mortality. Administration of sodium hydrosulfide, an H2S donor, exacerbated but capsazepine reversed deleterious effects of sepsis. In the presence of DL-propargylglycine, an inhibitor of endogenous H2S synthesis, capsazepine caused no further changes to the DL-propargylglycine-mediated attenuation of systemic inflammation, multiple organ damage, and mortality in sepsis. Moreover, capsazepine had no effect on endogenous generation of H2S, suggesting that H2S is located upstream of TRPV1 activation, and may play a critical role in regulating the release of sensory neuropeptides in sepsis. Importantly, the neuropeptide substance P has been identified as an important endogenous neural mediator that is implicated in H2S-driven neurogenic inflammation in sepsis in a TRPV1 channel-dependent manner. Furthermore, the H2S-induced neurogenic inflammatory response following septic insults was found to be regulated by the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) pathways. In addition, our results indicate that H2S augmented cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) metabolite production in septic lungs by a TRPV1 channel-dependent mechanism. Notably, COX-2 inhibition with parecoxib attenuated H2S-augmented lung PGE2 metabolite production, neutrophil infiltration, edema, pro-inflammatory cytokines, chemokines, and adhesion molecules levels, restored lung histoarchitecture, and protected against CLP-induced lethality. In summary, the present study suggests that endogenous H2S induces TRPV1-mediated neurogenic inflammation in polymicrobial sepsis through the enhancement of substance P production and activation of the ERK-NF-κB signal transduction pathways. In addition, H2S works in conjunction with other prominent mediators of inflammation such as COX-2 and PGE2 in a TRPV1-dependent manner, thereby contributes to sepsis-evoked acute lung injury. Finally, our data also indicate that blockade of TRPV1 channels provides potent anti-inflammatory effects and protection against multi-organ injury and mortality in sepsis, thus highlighting the potential utility of TRPV1 antagonist as a promising therapeutic target for the management of sepsis and its associated complications in critically ill patients.
Appears in Collections:Ph.D Theses (Open)

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