Role of Growth Factors and Cytokines on Bleomycin Induced Pulmonary Fibrosis

Abstract

BACKGROUND: It is now thought that the earliest manifestation of idiopathic pulmonary fibrosis is alveolitis, that is, an accumulation of inflammatory and immune effector cells within alveolar walls and spaces. Inflammatory cells including alveolar macrophages and resident normal pulmonary tissue cells participate through the release of many variable mediators such as inflammatory growth factors and cytokines, which contribute to tissue damage and finally cause chronic pulmonary inflammation and fibrosis. This study was performed to investigate the source and distribution pattern of transforming growth factor-beta1(TGF-beta1), platelet derived growth factor(PDGF), basic fibroblast growth factor(bFGF), interleukin 1(IL-1), interleukin 6(IL-6), tumor necrosis factor-alpha(TNF-alpha) and the role of these mediators on bleomycin(BLM)-induced pulmonary injury and fibrosis in rats. METHOD: Wistar rats were divided into three groups(control group, BML treated group, BML and vitamine E treated group). Animals were sacrifices periodically at 1, 2, 3, 4, 5, 7, 14, 21, 28 days after saline or BLM administration. The effects were compared to the results of bronchoalveolar lavage fluid analysis, light microscopic findings, immunohistochemical stains for six defferent mediators(TGF-beta1, PDGF, bFGF, IL-1, IL-6 and TNF-alpha) and mRNA in situ hybridization for TGF-beta1. RESULTS: IL-1 and IL-6 are maximally expressed at postbleomycin 1~7th day which are mainly produced by neutrophils and bronchiolar epithelium. It is thought that they induce recruitment of inflammatory cells at the injury site. The expression of IL-1 and IL-6 at the bronchiolar epithelium within 7th day is an indirect evidence of contribution of bronchiolar epithelial cells to promote and maintain the inflammatory and immune responses adjacent to the airways. TNF-alpha is mainly produced by neutrophils and bronchiolar epithelial cells during 1~5th day, alveolar macrophages during 7~28th day. At the earlier period, TNF-alpha causes recruitment of inflammatory cells at the injury site and later stimulates pulmonary fibrosis. The main secreting cells of TGF-beta1 are alveolar macrophages and bronchiolar epithelium and the target is pulmonary fibroblasts and extracellular matrix. TGF-beta1 and PDGF stimulate proliferation of pulmonary fibroblasts and TGF-beta1 and bFGF incite the fibroblasts to produce extracellular matrix. The vitamine E and BLM treated group shows few positive cells(p<0.05). CONCLUSION: After endothelial and epithelial injury, the neutrophils and bronchiolar epithelium secrete IL-1, IL-6, TNF-alpha which induce infiltration of many neutrophils. It is thought that variable enzymes and O2 radicals released by these neutrophils cause destruction of normal lung architecture and progression of pulmonary fibrosis. At the 7~28th day, TGF-beta1, PDGF, bFGF, TNF-alpha secreted by alveolar macrophages sting pulmonary fibroblasts into proliferating with increased production of extracellular matrix and finally, they make progression of pulmonary fibrosis. TNF-alpha compares quite important with TGF-beta1 to cause pulmonary fibrosis. Vitamine E seems to decrease the extent of BLM induced pulmonary fibrosis.