PROTECTION BY PHOSPHODIESTERASE INHIBITORS AGAINST ENDOTOXIN-INDUCED LIVER-INJURY IN GALACTOSAMINE-SENSITIZED MICE

被引:47
作者
FISCHER, W
SCHUDT, C
WENDEL, A
机构
[1] UNIV CONSTANCE,POB 5560,W-7750 CONSTANCE,GERMANY
[2] BYK GULDEN LOMBERG CHEM FABRIK GMBH,W-7750 CONSTANCE,GERMANY
关键词
D O I
10.1016/0006-2952(93)90219-M
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Phosphodiesterase inhibitors were used as a tool to manipulate cellular nucleotide levels in vitro and in vivo. The lipopolysaccharide (LPS)-induced release of tumor necrosis factor alpha (TNF-alpha) from mouse peritoneal macrophages was inhibited by prostaglandin E2 with an IC50 of 0.05 muM and by dibutyryl-cAMP with an IC50 of 180 muM. In the presence of the phosphodiesterase inhibitors zardaverine or rolipram the intracellular cAMP concentration of LPS-stimulated macrophages was significantly increased. In these cells, LPS-inducible TNF release was inhibited by zardaverine (IC50 = 1.5 muM) or by rolipram (IC50 = 0.35 muM). In a model of septic shock, i.e. LPS challenge of galactosamine-sensitized mice, a dose-dependent protection against liver injury was observed following oral application of rolipram (ED50 = 0.55 mg/kg) or of zardaverine (ED50 almost-equal-to 30 mg/kg). The adenylate cyclase activator forskolin was also protective. Rolipram also protected against TNF-induced liver injury in mice while zardaverine failed to do so. It is concluded that the intracellular cAMP level of macrophages is a critical determinant of LPS-inducible TNF release and therefore modulates the susceptibility to septic shock.
引用
收藏
页码:2399 / 2404
页数:6
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