Bleomycin-induced
fibrosis in rodents has been used extensively as a model of human
pulmonary fibrosis. The influx of monocytes observed during the early stages of
fibrosis is at least partially regulated by the elaboration of
chemotactic factors in the lung. Exposure of alveolar macrophages (AM phi) to
bleomycin either in vivo or in vitro stimulated secretion of monocyte chemotactic activity (MCA). This MCA has been previously characterized as being primarily due to
fibronectin fragments. The present experiments revealed that
bleomycin also induced AM phi to secrete a second
chemotactic factor,
transforming growth factor-beta (
TGF-beta). However, the
TGF-beta secreted by macrophages was in latent form, since no
TGF-beta activity was detected unless AM phi
conditioned medium (CM) was
acid-activated. After acidification, chemotactic activity in CM from AM phi stimulated with
bleomycin in vitro was increased by 3.6, whereas activity in AM phi CM from fibrotic rats increased by 2 and that of a
bleomycin-stimulated AM phi cell line increased by 1.6. This
acid-activatable chemotactic activity was inhibited by antibody to
TGF-beta.
Bleomycin-stimulated AM phi s secreted significantly more
TGF-beta than did unstimulated controls. Further, in vitro exposure of AM phi to
bleomycin induced
TGF-beta mRNA expression in a time- and concentration-dependent manner, with maximal
mRNA being detected following a 16-h incubation with 1 microgram/ml
bleomycin.