MOLECULAR PATHOGENESIS OF INTERSTITIAL PNEUMONITIS WITH TNF-ALPHA TRANSGENIC MICE

Tumour necrosis factor alpha (TNF-alpha)transgenic mice, which overexp ress TNF-alpha only in the lungs, develop interstitial pneumonitis res embling idiopathic pulmonary fibrosis (IPF) in humans, Transgenic mice were used to study molecular pathogenesis of interstitial pneumonitis with regard to sequential histological changes and cytokine network i nduced by TNF-alpha, The authors divided the histological process of i nterstitial pneumonitis into three stages: early stage with lymphocyti c infiltration in alveolar septa, middle stage with recruitment of mac rophages, and late stage with hyperplasia of epithelial cells and mild fibrosis, As for cytokine network, prolonged overexpression of TNF-a along with increasing interleukin 6 (IL-6) were associated with the pr ogression of interstitial pneumonitis, Increasing IL-1 was found only in the early stage, the beginning of lymphocyte proliferation, The mRN A level of an anti-inflammatory cytokine, IL-10, was constantly enhanc ed in the lungs of transgenic mice, However, transforming growth facto r beta 1 (TGF-beta 1) protein decreased, which is closely associated w ith prolonged TNF-alpha synthesis, resulting in development of chronic inflammation and less severe fibrosis in the lungs of this animal mod el, analogous to inflammatory stage of human IPF, TNF-alpha transgenic mice enabled the analysis of the sequential process of interstitial p neumonitis as a model of IPF pathogenesis in humans, the results of wh ich will give rise to new therapeutic measures for human IPF. (C) 1998 Academic Press Limited.