Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/30699
Title: Hydrogen Sulfide and Neurogenic Inflammation in a Murine Model of Polymicrobial Sepsis
Authors: ANG SEAH FANG
Keywords: hydrogen sulfide, neurogenic, inflammation, sepsis, substance P, transient receptor potential vanilloid type 1
Issue Date: 17-Aug-2011
Source: ANG SEAH FANG (2011-08-17). Hydrogen Sulfide and Neurogenic Inflammation in a Murine Model of Polymicrobial Sepsis. ScholarBank@NUS Repository.
Abstract: Hydrogen sulfide (H<sub>2</sub>S), 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, H<sub>2</sub>S is increasingly being established as a novel mediator of inflammation. However, the part played by H<sub>2</sub>S in modulating neurogenic inflammatory response in sepsis is not known. Therefore, this study aimed to investigate the role of H<sub>2</sub>S 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 H<sub>2</sub>S 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 H<sub>2</sub>S. Capsazepine also delayed the onset of lethality and protected against sepsis-associated mortality. Administration of sodium hydrosulfide, an H<sub>2</sub>S donor, exacerbated but capsazepine reversed deleterious effects of sepsis. In the presence of DL-propargylglycine, an inhibitor of endogenous H<sub>2</sub>S 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 H<sub>2</sub>S, suggesting that H<sub>2</sub>S 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 H<sub>2</sub>S-driven neurogenic inflammation in sepsis in a TRPV1 channel-dependent manner. Furthermore, the H<sub>2</sub>S-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-&kappa;B (NF-&kappa;B) pathways. In addition, our results indicate that H<sub>2</sub>S augmented cyclooxygenase-2 (COX-2) and prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) metabolite production in septic lungs by a TRPV1 channel-dependent mechanism. Notably, COX-2 inhibition with parecoxib attenuated H<sub>2</sub>S-augmented lung PGE<sub>2</sub> 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 H<sub>2</sub>S induces TRPV1-mediated neurogenic inflammation in polymicrobial sepsis through the enhancement of substance P production and activation of the ERK-NF-&kappa;B signal transduction pathways. In addition, H<sub>2</sub>S works in conjunction with other prominent mediators of inflammation such as COX-2 and PGE<sub>2</sub> 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.
URI: http://scholarbank.nus.edu.sg/handle/10635/30699
Appears in Collections:Ph.D Theses (Open)

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