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

Phosphodiesterase inhibitors were used as a tool to manipulate cellula r 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 pre sence of the phosphodiesterase inhibitors zardaverine or rolipram the intracellular cAMP concentration of LPS-stimulated macrophages was sig nificantly increased. In these cells, LPS-inducible TNF release was in hibited by zardaverine (IC50 = 1.5 muM) or by rolipram (IC50 = 0.35 mu M). In a model of septic shock, i.e. LPS challenge of galactosamine-se nsitized mice, a dose-dependent protection against liver injury was ob served following oral application of rolipram (ED50 = 0.55 mg/kg) or o f zardaverine (ED50 almost-equal-to 30 mg/kg). The adenylate cyclase a ctivator forskolin was also protective. Rolipram also protected agains t 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 modula tes the susceptibility to septic shock.