Hydrogen sulfide is a novel mediator of lipopolysaccharide‐induced inflammation in the mouse

Abstract

Hydrogen sulfide (H 2 S) is synthesized in the body from l ‐cysteine by several enzymes including cystathionine‐γ‐lyase (CSE). To date, there is little information about the potential role of H 2 S in inflammation. We have now investigated the part played by H 2 S in endotoxin‐induced inflammation in the mouse. E. coli lipopolysaccharide (LPS) administration produced a dose (10 and 20 mg/kg ip)‐ and time (6 and 24 h)‐dependent increase in plasma H 2 S concentration. LPS (10 mg/kg ip, 6 h) increased plasma H 2 S concentration from 34.1 ± 0.7 µM to 40.9 ± 0.6 µM ( n =6, P <0.05) while H 2 S formation from added l ‐cysteine was increased in both liver and kidney. CSE gene expression was also increased in both liver (94.2±2.7%, n =6, P <0.05) and kidney (77.5±3.2%, n =6, P <0.05). LPS injection also elevated lung (148.2±2.6%, n =6, P <0.05) and kidney (78.8±8.2%, n =6, P <0.05) myeloperoxidase (MPO, a marker of tissue neutrophil infiltration) activity alongside histological evidence of lung, liver, and kidney tissue inflammatory damage. Plasma nitrate/nitrite (NO x ) concentration was additionally elevated in a time‐ and dose‐dependent manner in LPS‐injected animals. To examine directly the possible proinflammatory effect of H 2 S, mice were administered sodium hydrosulfide (H 2 S donor drug, 14 µmol/kg ip) that resulted in marked histological signs of lung inflammation, increased lung and liver MPO activity, and raised plasma TNF‐α concentration (4.6±1.4 ng/ml, n =6). In contrast, dl ‐propargylglycine (CSE inhibitor, 50 mg/kg ip), exhibited marked anti‐inflammatory activity as evidenced by reduced lung and liver MPO activity, and ameliorated lung and liver tissue damage. In separate experiments, we also detected significantly higher (150.5±43.7 µM c.f. 43.8±5.1 µM, n =5, P <0.05) plasma H 2 S levels in humans with septic shock. These findings suggest that H 2 S exhibits proinflammatory activity in endotoxic shock and suggest a new approach to the development of novel drugs for this condition.