硫化氢是小鼠体内脂多糖诱导炎症的一种新型介质。

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

作者信息

Li Ling, Bhatia Madhav, Zhu Yi Zhun, Zhu Yi Chun, Ramnath Raina Devi, Wang Zhong Jing, Anuar Farhana Binte Mohammed, Whiteman Matthew, Salto-Tellez Manuel, Moore Philip K

机构信息

Department of Pharmacology, National University of Singapore, Singapore.

出版信息

FASEB J. 2005 Jul;19(9):1196-8. doi: 10.1096/fj.04-3583fje. Epub 2005 Apr 29.

DOI:10.1096/fj.04-3583fje

PMID:15863703

Abstract

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.

摘要

硫化氢（H₂S）在体内由L-半胱氨酸通过包括胱硫醚-γ-裂解酶（CSE）在内的多种酶合成。迄今为止，关于H₂S在炎症中的潜在作用的信息很少。我们现在研究了H₂S在小鼠内毒素诱导的炎症中所起的作用。腹腔注射大肠杆菌脂多糖（LPS）可使血浆H₂S浓度呈剂量（10和20 mg/kg腹腔注射）和时间（6和24小时）依赖性增加。LPS（10 mg/kg腹腔注射，6小时）使血浆H₂S浓度从34.1±0.7 μM增加到40.9±0.6 μM（n = 6，P<0.05），同时肝脏和肾脏中添加L-半胱氨酸后的H₂S生成增加。肝脏（94.2±2.7%，n = 6，P<0.05）和肾脏（77.5±3.2%，n = 6，P<0.05）中的CSE基因表达也增加。LPS注射还使肺（148.2±2.6%，n = 6，P<0.05）和肾脏（78.8±8.2%，n = 6，P<0.05）中的髓过氧化物酶（MPO，组织中性粒细胞浸润的标志物）活性升高，同时伴有肺、肝和肾组织炎症损伤的组织学证据。在注射LPS的动物中，血浆硝酸盐/亚硝酸盐（NOx）浓度也以时间和剂量依赖性方式升高。为了直接研究H₂S可能的促炎作用，给小鼠注射氢硫化钠（H₂S供体药物，14 μmol/kg腹腔注射），导致出现明显的肺部炎症组织学迹象、肺和肝MPO活性增加以及血浆TNF-α浓度升高（4.6±1.4 ng/ml，n = 6）。相比之下，DL-炔丙基甘氨酸（CSE抑制剂，50 mg/kg腹腔注射）表现出明显的抗炎活性，表现为肺和肝MPO活性降低以及肺和肝组织损伤减轻。在单独的实验中，我们还检测到感染性休克患者的血浆H₂S水平显著更高（150.5±43.7 μM对比43.8±5.1 μM，n = 5，P<0.05）。这些发现表明H₂S在内毒素休克中表现出促炎活性，并为开发针对这种病症的新型药物提出了一种新方法。