PRODUCTION AND FUNCTION OF MURINE MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA IN BLEOMYCIN-INDUCED LUNG INJURY

We investigated the role of macrophage inflammatory protein-1 alpha (M IP-1 alpha) in bleomycin-induced lung injury, a model of interstitial lung disease. Bleomycin stimulates a T cell-dependent pulmonary inflam matory response characterized by an increase in leukocyte infiltration , fibroblast proliferation, and collagen synthesis. Intratracheal chal lenge of CBA/J mice with bleomycin resulted in a significant time-depe ndent increase in MIP-1 alpha protein levels both in whole-lung homoge nates and bronchoalveolar lavage fluid. The kinetics of MIP-1 alpha ex pression were biphasic, with the first peak occurring at 2 days postin stillation and the second peak at 16 days. These levels of Ag expressi on temporally correlated with the accumulation of granulocytes, lympho cytes, and mononuclear phagocytes in the lung. In addition, immunohist ochemical staining identified alveolar macrophages and bronchial epith elial cells as the primary cellular sources of MIP-1 alpha production. Interestingly, passive immunization of bleomycin-challenged mice with anti-MIP-1 alpha Abs significantly reduced pulmonary mononuclear phag ocyte accumulation and fibrosis. These experiments establish that MIP- 1 alpha protein is expressed in the lungs of bleomycin-treated mice an d provide evidence that MIP-1 alpha promotes leukocyte accumulation an d activation. Furthermore, these findings support the notion that leuk ocyte accumulation and activation are linked to fibrosis.