Hydrogen sulfide is a novel mediator of lipopolysaccharide-induced inflammation in the mouse.
Hydrogen sulfide (H2S) is synthesized in the body from L-cysteine by several enzymes including cystathionine-gamma-lyase (CSE). To date, there is little information about the potential role of H2S in inflammation. We have now investigated the part played by H2S 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 H2S concentration. LPS (10 mg/kg ip, 6 h) increased plasma H2S concentration from 34.1 +/- 0.7 microM to 40.9 +/- 0.6 microM (n=6, P<0.05) while H2S 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 (NOx) concentration was additionally elevated in a time- and dose-dependent manner in LPS-injected animals. To examine directly the possible proinflammatory effect of H2S, mice were administered sodium hydrosulfide (H2S donor drug, 14 micromol/kg ip) that resulted in marked histological signs of lung inflammation, increased lung and liver MPO activity, and raised plasma TNF-alpha 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 microM c.f. 43.8+/-5.1 microM, n=5, P<0.05) plasma H2S levels in humans with septic shock. These findings suggest that H2S exhibits proinflammatory activity in endotoxic shock and suggest a new approach to the development of novel drugs for this condition.
Li
Ling
L
Department of Pharmacology, National University of Singapore, Singapore.
Bhatia
Madhav
M
Zhu
Yi Zhun
YZ
Zhu
Yi Chun
YC
Ramnath
Raina Devi
RD
Wang
Zhong Jing
ZJ
Anuar
Farhana Binte Mohammed
FB
Whiteman
Matthew
M
Salto-Tellez
Manuel
M
Moore
Philip K
PK
D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000097:blood / Q000633:toxicity*; D007249:Inflammation / Q000097:blood / Q000139:chemically induced*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008190:Lyases / Q000235:genetics; D008297:Male; D051379:Mice; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D012772:Shock, Septic / Q000097:blood; D013440:Sulfides / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000480:Alkynes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013440:Sulfides; C009055:propargylglycine; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D008190:Lyases; C019965:cystathionine beta-lyase; C025451:sodium bisulfide; D005998:Glycine; D006862:Hydrogen Sulfide