A ROLE FOR C-C CHEMOKINES IN FIBROTIC LUNG-DISEASE

Pulmonary fibrosis is the end point of a chronic inflammatory process characterized by leukocyte recruitment and activation, fibroblast prol iferation, and increased extracellular matrix production, Previous stu dies of models of pulmonary fibrosis have investigated the role of cyt okines in the evolution of the fibrotic response, The involvement of t umor necrosis factor and interleukin-1 in bleomycin-induced lung injur y, a model of idiopathic pulmonary fibrosis, has been well established , suggesting that cytokines mediate the initiation and maintenance of chronic inflammatory lesions, However, the aforementioned cytokines al one cannot account for the recruitment and activation of specific leuk ocyte populations found in the bleomycin model, Recently, a family of novel proinflammatory cytokines (chemokines) was cloned and characteri zed, yielding many putative mediators of leukocyte functions, Macropha ge inflammatory protein-1 alpha (MIP-1 alpha) and monocyte chemoattrac tant protein-1 (MCP 1) belong to the C-C chemotactic cytokine family, a group of low-molecular-weight peptides, These molecules modulate che motaxis, proliferation, and cytokine expression in leukocyte subsets, Our group has investigated the roles of MCP-1 and MIP-1 alpha in the b leomycin model, Both MCP-1 and MIP-1 alpha are expressed in a time-dep endent manner after bleomycin challenge, and passive immunization of t hese animals with either anti-MIP-1 alpha or anti-MCP-1 antibodies att enuated leukocyte accumulation, In addition, we have identified specif ic cell types expressing MCP-1 or MIP-1 alpha by in situ hybridization and immunohistochemical localization, respectively, Furthermore, our results indicate that MIP-1 alpha expression is mediated by alveolar m acrophage-derived tumor necrosis factor, identifying an important cyto kine pathway in the initiation of pulmonary fibrosis, Finally, anti-MI P-1 alpha therapy attenuated fibrosis, providing direct evidence for i ts involvement in fibrotic pathology, Our work has clearly established that the C-C chemokines MCP-1 and MIP-1 alpha are expressed and contr ibute to the initiation and maintenance of the bleomycin-induced pulmo nary lesion.