Chemotactic cytokines mediate leukocyte recruitment in fibrotic lung disease

In rodents, bleomycin administration results in a route-, dose- and strain-dependent pulmonary inflammatory response. Given intratracheally, this response is characterized by increases in leukocyte accumulation, fibroblast proliferation, and collagen content. We believe that characterization of the cell types and soluble mediators present in the lesion will lend significant insight into the processes modulating pulmonary fibrosis. Recent studies have identified monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) as mediators of the inflammatory response in the lungs of human patients afflicted with idiopathic pulmonary fibrosis. Based on this compelling evidence for the involvement of C-C chemokines in fibrotic pathologies, we investigated the roles of MIP-1 alpha and MCP-1 protein in bleomycin-induced lung injury. In this study, we have established that neutralization of MIP-1 alpha and MCP-1 significantly reduces inflammatory cell accumulation. Further, we have shown that passive immunotherapy with either anti-MCP-1 or anti-MIP-1 alpha antibodies significantly reduced mononuclear phagocyte accumulation in bleomycin-challenged mice. These experiments strongly support the hypothesis that MIP-1 alpha and MCP-1 contribute to the recruitment of leukocytes during the pulmonary inflammatory response to bleomycin challenge.