MCP-1 Causes Leukocyte Recruitment and Subsequently Endotoxemic Ileus in Rat

Endotoxemia causes an inflammatory response within the intestinal muscularis and gastrointestinal dysmotility. We hypothesize that the resident macrophage-derived chemokine monocyte chemoattractant protein-1 (MCP-1) plays a significant role in the recruitment of leukocytes into the lipopolysaccharide (LPS)-stimulated rat intestinal muscularis. MCP-1 mRNA expression was investigated by RT-PCR. Leukocyte extravasation and MCP-1 protein localization were determined by immunohistochemistry. Contractile activity was assessed by using a standard organ bath in rats that were treated with saline, recombinant MCP-1, LPS, LPS + nonspecific antibody, or LPS + MCP-1 antibody. Endotoxemia caused a significant 280-fold increase in MCP-1 mRNA expression in the muscularis, peaking at 3 h. MCP-1 protein was immunohistochemically located to muscularis macrophages. LPS application caused significant leukocyte recruitment into the muscularis and a 51% decrease in muscle contractility. MCP-1 antibody treatment significantly averted leukocyte recruitment and significantly prevented muscle dysfunction. These parameters were not significantly altered by the nonspecific antibody. Results show that resident muscularis macrophage-derived MCP-1 plays a major role in the recruitment of monocytes during endotoxemia, which then subsequently secrete kinetically active substances that cause ileus.