BLEOMYCIN STIMULATION OF CYTOKINE SECRETION BY THE HUMAN ALVEOLAR MACROPHAGE

Bleomycin (BLM) is a very effective antineoplastic drug for many gynecologic and urinary tract carcinomas. However, its use, e.g., cumulative dosage, often is limited by the pulmonary fibrosis that it causes. The mechanism by which BLM causes fibrosis is not understood but is proposed to involve the pulmonary macrophage, a central cell in the cytokine network of the lung. To examine the direct effects of this drug on the human alveolar macrophage, we have treated human alveolar macrophages (isolated from normal subjects by bronchoalveolar lavage) with BLM in vitro and examined resultant macrophage secretory products that have importance for inflammatory and fibrotic processes. A 24-h treatment with BLM (0.5-100 mU/ml) was found to result in 1) a concentration-dependent decrease in the ability of the macrophage to produce superoxide anion in response to phorbol 12,13-dibutyrate, 2) an increase in secreted interleukin-1-beta (IL-1-beta), and 3) a decrease in intracellular levels of adenosine 3',5'-cyclic monophosphate. Kinetic studies revealed a time-dependent appearance of BLM-induced cytokines; tumor necrosis factor-alpha could be detected as early as 4 h after stimulation, followed by IL-1-beta at 8 h. The secretion of these cytokines was found to precede the release of prostaglandin E2, which became significant only at 24 h. Taken together, the present results imply that the human alveolar macrophage does not contribute to BLM-induced oxidant injury of the lung but that it may contribute to the development of BLM-induced pulmonary fibrosis.