Production and function of macrophage inflammatory protein-1 alpha in bleomycin-induced lung injury.

Since the initial characterization of the rodent model in 1974, many laboratories have investigated the pathophysiology of the response to intratracheal bleomycin challenge. 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 hypothesized that an unremitting profibrotic inflammatory response is a cause of dysregulated fibrogenesis. Further, 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 (IPF). 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. We have identified two C-C chemokines that mediate, in part, the profibrotic pulmonary inflammatory response to bleomycin challenge. We have established that MIP-1$\alpha$ and MCP-1 are both present in the lesion and promote inflammatory cell accumulation. Further, we have shown that neutralization of MIP-1$\alpha$ significantly attenuates fibrosis. Finally, we have identified IL-6 and bleomycin as stimuli for MIP-1$\alpha$ production in the acute lesion, and TNF as a stimulus for MIP-1$\alpha$ production in the chronic lesion. These findings establish that MIP-1$\alpha$ protein is expressed in the lungs of bleomycin-challenged mice, promotes leukocyte accumulation, and is part of an important cytokine network in the lungs. These experiments strongly support the hypothesis that MIP-1$\alpha$ and MCP-1 participate in the processes which link leukocyte accumulation and activation to pulmonary fibrosis.PhDHealth and Environmental SciencesImmunologyPathologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/130364/2/9722094.pd