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-kappaB.
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-kappaB. 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-kappaB inhibitor BAY 11-7082. Eight hours after CLP, both prophylactic and therapeutic administration of PAG significantly reduced the mRNA and protein levels of IL-1beta, IL-6, TNF-alpha, monocyte chemotactic protein-1, and macrophage inflammatory protein-2 in lung and liver coupled with decreased activation and translocation of NF-kappaB 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-kappaB 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-kappaB activation.