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Hydrogen sulfide acts as an inflammatory mediator in cecal ligation and puncture-induced sepsis in mice by upregulating the production of cytokines and chemokines via NF-B

¹Department of Pharmacology, National University of Singapore; and ²Center for Biomedical Science, Defence Medical and Environmental Research Institute, Defence Science Organization, Singapore

Submitted 3 October 2006 ; accepted in final form 11 December 2006

Recent studies have implied that hydrogen sulfide (H₂S) plays a crucial role in several inflammatory conditions. However, so far little is known about the mechanism by which H₂S provokes the inflammatory response in sepsis. Thus the aim of this study was to investigate if H₂S regulates sepsis-associated systemic inflammation and production of proinflammatory mediators via the activation of NF-B. Male Swiss mice were subjected to cecal ligation and puncture (CLP)-induced sepsis and treated with DL-propargylglycine (PAG; 50 mg/kg ip), NaHS (10 mg/kg ip), or saline. PAG, an inhibitor of H₂S formation, was administered either 1 h before or 1 h after CLP, whereas NaHS, an H₂S donor, was given at the time of CLP. Some normal mice were given NaHS (10 mg/kg ip) to induce lung inflammation with or without pretreatment with the NF-B inhibitor BAY 11-7082. Eight hours after CLP, both prophylactic and therapeutic administration of PAG significantly reduced the mRNA and protein levels of IL-1, IL-6, TNF-, monocyte chemotactic protein-1, and macrophage inflammatory protein-2 in lung and liver coupled with decreased activation and translocation of NF-B in lung and liver. Inhibition of H₂S formation also significantly reduced lung permeability and plasma alanine aminotransferase activity. In contrast, injection of NaHS significantly aggravated sepsis-associated systemic inflammation and increased NF-B activation. In addition, H₂S-induced lung inflammation was blocked by BAY 11-7082. Therefore, H₂S upregulates the production of proinflammatory mediators and exacerbates the systemic inflammation in sepsis through a mechanism involving NF-B activation.

DL-propargylglycine; nuclear factor-B

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