Gadolinium chloride inhibits lipopolysaccharide-induced mortality and in vivo prostaglandin E-2 release by splenic macrophages

The monocytic phagocytic system, consisting primarily of tissue macrophages of the liver and spleen, produces prostaglandin E-2 (PGE(2)), a modulator of the septic response, Macrophages are known to internalize gadolinium chl oride (GD), a lanthanide metal, which inhibits phagocytic function. Thus we studied the effect of in vivo GD on lipopolysacchride (LPS)-induced mortal ity and on LPS-stimulated PGE2 release by cultured splenic macrophages. GD (7 mg/kg intravenously) given on the two days prior to LPS challenge (30 mg /kg int ravenously) completely prevented the uniform mortality in rats. Thi s protective effect was transient since rechallenge with LPS 10 days later was uniformly lethal. Previous work in this laboratory has established a cr itical role of arginine concentration on macrophage behavior in vitro. Ther efore, to establish culture conditions reflective of the milieu within the portal venous system, alanine and arginine levels were measured in the port al and hepatic veins of normal and endotoxemic (LPS, 10 mg/kg intraperitone ally) rats. Ln contrast to alanine levels, which were not altered by endoto xemia, there was a reduction of arginine concentrations from a range of 50 to 250 mu mol/L in normal rats to a range of 10 to 50 mu mol/L after LPS ch allenge. Consequently subsequent in vitro assays of splenic macrophage secr etory behavior were performed in concentrations of 1200 mu mol/L arginine ( in standard RPMI-1640), as well as in concentrations reflective of physiolo gic arginine levels (10 and 100 mu mol/L in modified RPMI-1640). Rat spleni c macrophages harvested after two consecutive days of either in vivo saline or GD injection (7 mg/kg intravenously) were stimulated with LPS (0.025 to 2.5 mu g/ml). At 72 hours of culture, the release of PGE2 by splenic macro phages from GD-treated rats was significantly (P <0.0001) reduced at all LP S concentrations. Increased PGE2 production was not present when the spleni c macrophages were cultured in the supraphysiologic arginine (1200 mu mol/L ) concentration The results demonstrate the relevance of physiologic argini ne concentrations in cell culture studies and suggest that the protection c onferred by GD against septic mortality may be related to downregulation of the release of immunosuppressive PGE(2) by the monocytic phagocytic system .