THERAPEUTIC EFFECTS OF NITRIC-OXIDE INHIBITION DURING EXPERIMENTAL FECAL PERITONITIS - ROLE OF INTERLEUKIN-10 AND MONOCYTE CHEMOATTRACTANT PROTEIN-1

This study demonstrates that the therapeutic effect of a nitric oxide inhibitor in a murine model of fecal peritonitis is mediated in part b y increased levels of interleukin-10 (IL-10) and monocyte chemoattract ant protein 1 (MCP-1), Female CD1 mice were subjected to cecal ligatio n and puncture (CLP) with a 21-gauge needle and, immediately following surgery, were injected intraperitoneally with saline, N-G-nitro-L-arg inine methyl ester (L-NAME; 8 mg/kg), or N-G-nitro-D-arginine methyl e ster (D-NAME; 8 mg/kg), At 96 h after surgery and drug treatment, 20% of mice that received D-NAME had survived whereas 60% of mice that rec eived L-NAME were alive, To elucidate the effect of L-NAME treatment o n chemokine and cytokine production during fecal peritonitis, the leve ls of macrophage inflammatory protein 2 (MIP-2), IL-10, and MCP 1 were measured in peritoneal washings from additional groups of mice 24 h a fter the CLP surgery, Peritoneal fluids from L-NAME-treated mice conta ined significantly higher levels of IL-10 and MCP-I than did those fro m D-NAME-treated mice, To elucidate the effect of nitric oxide inhibit ion on potential cellular sources of IL-IO and MCP-1 in the CLP model, cultured alveolar and peritoneal macrophages were activated with bact erial lipopolysaccharide in the presence of L-NAME; these macrophages produced significantly more MCP-I than did similarly activated macroph ages in the presence of D-NAME, In the CLP surgery model, immunoneutra lization of IL-10 alone or IL-10 and MCP-1 together with polyclonal an tibodies prior to surgery significantly reduced the survival rates in L-NAME-treated groups compared with L-NAME-treated groups that receive d preimmune serum, Taken together, these data demonstrate that the inh ibition of nitric oxide following experimental CLP fecal peritonitis i s therapeutic, in part through the modulatory effect of this treatment on the synthesis of IL-10 and MCP-1.