Dexamethasone inhibits lipopolysaccharide-induced hydrogen sulphide biosynthesis in intact cells and in an animal model of endotoxic shock

被引:50
|
作者
Li, Ling [1 ]
Whiteman, Matthew [2 ,3 ]
Moore, Philip K. [1 ]
机构
[1] Kings Coll London, Pharmaceut Sci Res Div, London SE1 9NH, England
[2] Univ Exeter, Inst Biomed & Clin Sci, Peninsula Med Sch, Exeter, Devon, England
[3] Univ Plymouth, Inst Biomed & Clin Sci, Peninsula Med Sch, Exeter, Devon, England
关键词
hydrogen sulphide; steroids; inflammation; NF-KAPPA-B; NITRIC-OXIDE; MESSENGER-RNA; RAT; MECHANISMS; INFLAMMATION; NEUTROPHILS; DICLOFENAC; EXPRESSION; KINASE;
D O I
10.1111/j.1582-4934.2008.00610.x
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Dexamethasone (1 mg/kg, i.p.) administered either 1 hr before or 1 hr after E. coli lipopolysaccharide (LPS, 4 mg/kg, i.p.) in conscious rats inhibited the subsequent (4 hrs) rise in plasma cytokine (interleukin [IL]-1 beta, tumour necrosis factor [TNF]-alpha), nitrate/nitrite (NOx), soluble intercellular adhesion molecule-1 (sICAM-1) concentration and lung/liver myeloperoxidase activity indicative of an anti-inflammatory effect. Dexamethasone also reduced the LPS-evoked rise in plasma hydrogen sulphide (H2S) concentration, liver H2S synthesizing activity and expression of cystathionine gamma lyase (CSE) and inducible nitric oxide synthase (iNOS). Mifepristone (RU-486) inhibited these effects. Dexamethasone (1-10 mu M) reduced the LPS-evoked release of IL-1 beta, TNF-alpha and L-selectin, decreased expression of CSE and iNOS and diminished nuclear factor kappa B (NF-kappa B)-DNA binding in isolated rat neutrophils. In contrast, NaHS (100 mu M) increased L-selectin release from rat neutrophils. Dexamethasone also reduced LPS-induced up-regulation of CSE in foetal liver cells. 6-amino-4-(4-phenoxyphenylethylamino) quinazoline (QNZ, 10 nM), a selective inhibitor of transcription via the NF-kappa B pathway, abolished LPS-induced up-regulation of CSE expression. We propose that inhibition of CSE expression and reduction in formation of the pro-inflammatory component of H2S activity contributes to the anti-inflammatory effect of dexamethasone in endotoxic shock. Whether H2S plays a part in the anti-inflammatory effect of this steroid in other forms of inflammation such as arthritis or asthma warrants further study.
引用
收藏
页码:2684 / 2692
页数:9
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