REGULATION OF TYPE-II ALVEOLAR EPITHELIAL-CELL PROLIFERATION BY TGF-BETA DURING BLEOMYCIN-INDUCED LUNG INJURY IN RATS

Three isoforms of transforming growth factor-beta (TGF-beta) are found in mammalian cells and are potent regulators of inflammation, connect ive tissue synthesis, cellular proliferation, and differentiation. To determine the distribution and regulation of TGF-beta isoforms during pulmonary injury, a rat model of bleomycin induced lung inflammation a nd repair was used. Using immunohistochemistry, we demonstrate that TG F-beta 2 and TGF-beta 3 were localized to alveolar macrophages as well as epithelial and smooth muscle cells of both normal rat lungs and ra t lungs obtained at all time intervals after bleomycin administration. Early in bleomycin-induced lung injury, when there is active prolifer ation of type II alveolar epithelial cells, there was an increase in t he number of type II alveolar epithelial cells isolated per lung and a n increase in DNA synthesis by explanted type II alveolar epithelial c ells. At this time, the secretion of biologically active TGF-beta 1-3, which are potent inhibitors of epithelial cell proliferation, was dec reased. However, the secretion of TGF-beta 1-3 activity was markedly i ncreased later in the injury response and coincided with a reduction i n the number of type II alveolar epithelial cells isolated per lung an d DNA synthesis in vitro. Furthermore, the addition of TGF-beta 1, 2, and 3 to cultures of actively proliferating type II alveolar epithelia l cells resulted in inhibition of [H-3]thymidine incorporation, wherea s, in the presence of anti-TGF-beta 1-3 antibody, there was an increas e in [H-3]thymidine incorporation. Our findings suggest that altered s ecretion of TGF-beta 1-3 activity by type II alveolar epithelial cells during bleomycin-induced lung injury may regulate pulmonary alveolar epithelial cell proliferation during injury and repair phases.