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 proliferation, and increased extracellular matrix production. Previous studies of models of pulmonary fibrosis have investigated the role of cytokines in the evolution of the fibrotic response. The involvement of tumor necrosis factor and interleukin‐1 in bleomycin‐induced lung injury, 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 alone cannot account for the recruitment and activation of specific leukocyte populations found in the bleomycin model. Recently, a family of novel proinflammatory cytokines (chemokines) was cloned and characterized, yielding many putative mediators of leukocyte functions. Macrophage inflammatory protein‐1α (MIP‐1α) and monocyte chemoattractant protein‐1 (MCP‐1) belong to the C‐C chemotactic cytokine family, a group of low‐molecular‐weight peptides. These molecules modulate chemotaxis, proliferation, and cytokine expression in leukocyte subsets. Our group has investigated the roles of MCP‐1 and MIP‐1α in the bleomycin model. Both MCP‐1 and MIP‐1α are expressed in a time‐dependent manner after bleomycin challenge, and passive immunization of these animals with either anti‐MIP‐1α or anti‐MCP‐1 antibodies attenuated leukocyte accumulation. In addition, we have identified specific cell types expressing MCP‐1 or MIP‐1α by in situ hybridization and immunohistochemical localization, respectively. Furthermore, our results indicate that MIP‐1α expression is mediated by alveolar macrophage‐derived tumor necrosis factor, identifying an important cytokine pathway in the initiation of pulmonary fibrosis. Finally, anti‐MIP‐1α therapy attenuated fibrosis, providing direct evidence for its involvement in fibrotic pathology. Our work has clearly established that the C‐C chemokines MCP‐1 and MIP‐1α are expressed and contribute to the initiation and maintenance of the bleomycin‐induced pulmonary lesion. J. Leukoc. Biol. 57: 782–787; 1995.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141648/1/jlb0782.pd