Delayed Treatment with Sodium Hydrosulfide Improves Regional Blood Flow and Alleviates Cecal Ligation and Puncture (CLP)-Induced Septic Shock

Abstract

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 10 mg/kg/h, for 1 hour at each dose level) in control rats or rats 24 hours 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 (1 mg/kg/h and 3 mg/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 (3 mg/kg) intraperitoneally (i.p) at 24 h after the start of the CLP procedure; plasma levels of various cytokines and tissue indicators of inflammatory cell infiltration and oxidative stress were measured 6 hours later. After 24 h 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 3 mg/kg i.p, (but not 1 mg/kg or 6 mg/kg), starting 24 hours post-CLP, with dosing repeated every 6 h, improved the survival rate in CLP animals. In summary, treatment with 3 mg/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.

Effect of endotoxemia in mice genetically deficient in cystathionine-γ-lyase, cystathionine-β-synthase or 3-mercaptopyruvate sulfurtransferase

“…As already mentioned in the 'Introduction', the current body of literature on endotoxemia, endotoxin shock, sepsis, as well as various other forms of critical illness (e.g., burn injury, ARDS and hemorrhagic shock) is fairly controversial with respect to the role of H 2 S in the pathogenesis of these diseases; some of the studies have demonstrated that pharmacological H 2 S donation is beneficial in some experimental models (11–16), while other studies have concluded that pharmacological inhibitors of H 2 S biosynthesis (17–21), or the genetic deletion of CSE (22,23) is beneficial. Moreover, there are also studies demonstrating that H 2 S donation can be detrimental (18–20), and there are even studies demonstrating that pharmacological inhibitors of H 2 S biosynthesis can be detrimental in certain models of critical illness (31,32).…”

“…Some studies have demonstrated the therapeutic effect of H 2 S donation in various models of circulatory shock (11–16), while others have reported that the pharmacological inhibition of H 2 S production (17–21) or the genetic deficiency of H 2 S-producing enzymes (22,23) results in beneficial effects.…”

S- Sulfhydration of ATP synthase by hydrogen sulfide stimulates mitochondrial bioenergetics

“…H 2 S exerts broad range of physiological effects as an antioxidant, cytoprotective agent [1,2], vasorelaxant [3–5], neurotransmitter [6,7], and endogenous promoter of angiogenesis [8,9]. H 2 S also plays important roles in the regulation of various inflammatory processes via a variety of mechanisms including the regulation of pro-inflammatory signaling [10–13]. Furthermore, H 2 S plays a role in the control of metabolism, via the regulation of glucose and lipid metabolism, insulin sensitivity and energy balance [14–16].…”

Endogenous Hydrogen Sulfide Ameliorates NOX4 Induced Oxidative Stress in LPS-Stimulated Macrophages and Mice

“…It has been reported that the increased H 2 S circulation detected in the burn injury [36] and its levels correlated with inflammatory and clinical indices in rheumatoid arthritis patients [37]. Moreover, multiple lines of studies, in multiple experimental models, showing that therapeutic elevation of H 2 S concentrations or H 2 S donors can exert anti-inflammation and decrease the mortality caused by endotoxemia [38][39][40]. We found that CSE expression was significantly increased in LPS-induced macrophage, which were accompanied by increased inflammatory mediators and inflammatory cytokines production.…”