Cell proliferation during the process of bleomycin-induced pulmonary fibrosis in rats

To elucidate the relationship between cell proliferation and structural remodeling in pulmonary fibrosis, light and electron microscopy with immunohistochemistry for bromodeoxyuridine (BrdU) and morphometry for BrdU-positive cells were performed following a single intratracheal instillation of bleomycin in rats. The results showed that terminal bronchiolar epithelial cells, Type II alveolar epithelial cells and interstitial cells began to proliferate 2 days after the injury. Then each cell type showed a different style of proliferation. Interstitial cells which were located in the interstitium and migrated into intraalveolar spaces proliferated, then produced intra-alveolar fibrosis. Terminal bronchiolar epithelial cells proliferated rapidly and formed alveolar bronchiolization with squamous metaplasia in areas where alveoli were severely damaged and intraalveolar fibrosis was formed, and thereafter the proliferation ceased within 2 weeks. The degree of proliferation of type II alveolar epithelial cells and interstitial cells was rather slight, but continued constantly until the later stage. In addition, intraalveolar macrophages were BrdU-positive from an early stage. Endothelial cell proliferation was observed in small vessels and alveolar capillaries at 1 week after bleomycin instillation. Rapidly proliferating bronchiolar epithelial cells which formed alveolar bronchiolization with squamous metaplasia were important in preventing the progress of intraalveolar fibrosis, because the proliferation of type II alveolar epithelial cells was limited.