Protection by phosphodiesterase inhibitors against endotoxin-induced liver injury in galactosamine-sensitized mice.
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 microM and by dibutyryl-cAMP with an IC50 of 180 microM. 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 microM) or by rolipram (IC50 = 0.35 microM). 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 approximately 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.
University of Konstanz, Germany.
W
W
Fischer
C
C
Schudt
A
A
Wendel
D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis; D015232:Dinoprostone / Q000494:pharmacology; D005688:Galactosamine / Q000008:administration & dosage*; D006505:Hepatitis / Q000378:metabolism / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D012772:Shock, Septic / Q000378:metabolism / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011760:Pyrrolidinones; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D005688:Galactosamine; D000242:Cyclic AMP; D020889:Rolipram; D015232:Dinoprostone; C066436:zardaverine