Therapeutic Effects of Nitric Oxide Inhibition during Experimental Fecal Peritonitis: Role of Interleukin-10 and Monocyte Chemoattractant Protein 1

ABSTRACT This study demonstrates that the therapeutic effect of a nitric oxide inhibitor in a murine model of fecal peritonitis is mediated in part by increased levels of interleukin-10 (IL-10) and monocyte chemoattractant protein 1 (MCP-1). Female CD1 mice were subjected to cecal ligation and puncture (CLP) with a 21-gauge needle and, immediately following surgery, were injected intraperitoneally with saline,N G-nitro-l-arginine methyl ester (l-NAME; 8 mg/kg), orN G-nitro-d-arginine methyl ester (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 received l-NAME were alive. To elucidate the effect of l-NAME treatment on chemokine and cytokine production during fecal peritonitis, the levels of macrophage inflammatory protein 2 (MIP-2), IL-10, and MCP-1 were measured in peritoneal washings from additional groups of mice 24 h after the CLP surgery. Peritoneal fluids froml-NAME-treated mice contained significantly higher levels of IL-10 and MCP-1 than did those from d-NAME-treated mice. To elucidate the effect of nitric oxide inhibition on potential cellular sources of IL-10 and MCP-1 in the CLP model, cultured alveolar and peritoneal macrophages were activated with bacterial lipopolysaccharide in the presence of l-NAME; these macrophages produced significantly more MCP-1 than did similarly activated macrophages in the presence of d-NAME. In the CLP surgery model, immunoneutralization of IL-10 alone or IL-10 and MCP-1 together with polyclonal antibodies prior to surgery significantly reduced the survival rates in l-NAME-treated groups compared with l-NAME-treated groups that received preimmune serum. Taken together, these data demonstrate that the inhibition of nitric oxide following experimental CLP fecal peritonitis is therapeutic, in part through the modulatory effect of this treatment on the synthesis of IL-10 and MCP-1.