A model of aspiration lung injury was developed in wildtype (WT) C57/BL6 mice in order to exploit genetically modified animals on this background, i.e., MCP-1 (-/-) mice. Mice were given intratracheal hydrochloric acid (ACID, pH = 1.25), small non-acidified gastric particles (SNAP), or combined acid plus small gastric particles (CASP). As reported previously in rats, lung injury in WT mice was most severe for 'two-hit' aspiration from CASP (40 mg/ml particulates) based on the levels of albumin, leukocytes, TNF, IL-1, IL-6, MCP-1, KC and MIP-2 in bronchoalveolar lavage (BAL) at 5, 24, and 48 hr. MCP-1 (-/-) mice given 40 mg/ml CASP had significantly decreased survival compared to WT mice (32% vs. 80% survival at 24 hrs and 0% vs. 72% survival at 48 hr). MCP-1 (-/-) mice also had decreased survival compared to WT mice for CASP aspirates containing reduced particulate doses of 10-20 mg/ml. MCP-1 (-/-) mice given 5 mg/ml CASP had survival similar to WT mice given 40 mg/ml CASP. MCP-1 (-/-) mice also had differing responses from WT mice for several inflammatory mediators in BAL (KC or IL-6 depending on the particle dose of CASP and the time of injury). Histopathology of WT mice with CASP (40 mg particles/ml) showed microscopic areas of compartmentalization with prominent granuloma formation by 24 hr, while lung tissue from MCP-1 (-/-) mice had severe diffuse pneumonia without granulomas. These results indicate that MCP-1 is important for survival in murine aspiration pneumonitis, and appears to act in part to protect uninjured lung regions by promoting the isolation and compartmentalization of tissue with active inflammation.