Delayed treatment with sodium hydrosulfide improves regional blood flow and alleviates Cecal Ligation and Puncture (CLP)-induced septic shock

Cecal ligation and puncture (CLP)-induced sepsis is a serious medical condition, caused by a severe systemic infection resulting in a systemic inflammatory response. Recent studies have suggested the therapeutic potential of donors of hydrogen sulfide (H₂S), a novel endogenous gasotransmitter and biological mediator in various diseases. The aim of the present study was to assess the effect of H₂S supplementation in sepsis, with special reference to its effect on the modulation of regional blood flow. We infused sodium hydrosulfide (NaHS), a compound that produces H₂S in aqueous solution (1, 3, or 10mg/kg/h, for 1 h at each dose level) in control rats or rats 24h after CLP, and measured blood flow using fluorescent microspheres. In normal control animals, NaHS induced a characteristic redistribution of blood flow, and reduced cardiac, hepatic, and renal blood flow in a dose-dependent fashion. In contrast, in rats subjected to CLP, cardiac, hepatic, and renal blood flow was significantly reduced; infusion of NaHS (1mg/kg/h and 3mg/kg/h) significantly increased organ blood flow. In other words, the effect of H₂S on regional blood flow is dependent on the status of the animals (i.e., a decrease in blood flow in normal controls, but an increase in blood flow in CLP). We have also evaluated the effect of delayed treatment with NaHS on organ dysfunction and the inflammatory response by treating the animals with NaHS (3mg/kg) intraperitoneally (i.p.) at 24h after the start of the CLP procedure; plasma levels of various cytokines and tissue indicators of inflammatory cell infiltration and oxidative stress were measured 6h later. After 24h of CLP, glomerular function was significantly impaired, as evidenced by markedly increased (over 4-fold over baseline) blood urea nitrogen and creatinine levels; this increase was also significantly reduced by treatment with NaHS. NaHS also attenuated the CLP-induced increases in malondialdehyde levels (an index of oxidative stress) in heart as well as in liver and myeloperoxidase levels (an index of neutrophil infiltration) in heart and lung. Plasma levels of IL-1β, IL-5, IL-6, TNF-α, and HMGB1 were attenuated by NaHS. Treatment of NaHS at 3mg/kg i.p. (but not 1mg/kg or 6mg/kg), starting 24h post-CLP, with dosing repeated every 6h, improved the survival rate in CLP animals. In summary, treatment with 3mg/kg H₂S - when started in a delayed manner, when CLP-induced organ injury, inflammation and blood flow redistribution have already ensued - improves blood flow to several organs, protects against multiple organ failure, and reduces the plasma levels of multiple pro-inflammatory mediators. These findings support the view that H₂S donation may have therapeutic potential in sepsis.