Alveolar macrophage stimulation of lung fibroblast growth in asbestos-induced pulmonary fibrosis

Abstract

Asbestotic lesions are characterized by macrophagic accumulation, fibroblast proliferation, and collagen deposition. To evaluate the potential involvement of alveolar macrophages in the subsequent fibrogenic reaction, the authors studied the effects of macrophages from normal and asbestos-treated rats upon lung fibroblast proliferation in vitro. Culture supernatants from bronchoalveolar (BAL) cells (99% macrophages) of normal rats stimulated lung fibroblast DNA synthesis and growth in a dose-dependent manner. Fibroblast growth factor (FGF) release by alveolar macrophages (AMs) was rapid (within 1 hour of incubation) and dependent on the number of AMs in culture. Moreover, culture supernatants from BAL cells of animals exposed to asbestos (single intratracheal injection) stimulated fibroblast proliferation to a greater degree than culture supernatants from BAL cells of control animals. Enhanced FGF production occurred 1 week after asbestos instillation and persisted up to 24 weeks. This change was accompanied in the early stages (1-4 weeks) by an increase in the total number of BAL cells which returned to control values by 12 weeks. Differential analysis of BAL cell populations showed a transient infiltration of neutrophils in the bronchoalveolar compartment followed by a significant accumulation of macrophages which persisted up to 1 month. Furthermore, lungs of asbestos-treated animals showed evidence of pathologic alterations characterized by fibroblast proliferation and collagen deposition. This study demonstrates that increased production of fibroblast growth factor by alveolar macrophages in vitro coincides with the development of asbestos-induced fibrosis. Prolonged stimulation of FGF release may contribute to excessive fibroblast proliferation and fibrosis.