Acid and particulate-induced aspiration lung injury in mice: importance of MCP-1

Raghavendran, Krishnan, Bruce A. Davidson, Barbara A. Mullan, Alan D. Hutson, Thomas A. Russo, Patricia A. Mander-scheid, James A. Woytash, Bruce A. Holm, Robert H. Notter, and Paul R Knight. Acid and particulate-induced aspiration lung injury in mice: importance of MCP-1. Am J Physiol Lung Cell Mol Physiol 289: L134-L143, 2005. First published March 18, 2005; doi:10.1152/ajplung.00390.2004.-A model of aspiration lung injury was developed in WT C57BL/6 mice to exploit genetically modified animals on this background, i.e., MCP-1(-/-) mice. Mice were given intratracheal hydrochloric acid ( ACID, pH 1.25), small nonacidified 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-alpha, IL-1 beta, IL-6, MCP-1, KC, and MIP-2 in bronchoalveolar lavage (BAL) at 5, 24, and 48 h. MCP- 1(-/-) mice given 40 mg/ml CASP had significantly decreased survival compared with WT mice (32% vs. 80% survival at 24 h and 0% vs. 72% survival at 48 h). MCP-1(-/-) mice also had decreased survival compared with 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 time of injury). Histopathology of WT mice with CASP ( 40 mg particles/ml) showed microscopic areas of compartmentalization with prominent granuloma formation by 24 h, whereas 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 partly to protect uninjured lung regions by promoting isolation and compartmentalization of tissue with active inflammation.