UP-REGULATED EXPRESSION OF TRANSFORMING GROWTH-FACTOR-ALPHA IN THE BRONCHIOLAR-ALVEOLAR DUCT REGIONS OF ASBESTOS-EXPOSED RATS

It has become apparent that numerous growth factors and cytokines are produced during the development of fibroproliferative lung disease. In vestigators must sort out which combinations of these factors are play ing mechanistic roles in the disease process. Here we demonstrate that transforming growth factor (TGF)-alpha, a potent epithelial and mesen chymal cell mitogen, is up-regulated specifically at the sites of asbe stos fiber deposition in the lungs of rats exposed for 5 hours. Unexpo sed animals and those exposed to high concentrations of iron spheres e xhibited no increase in TGF-alpha expression at any time during the ex periment. Inhaled asbestos fibers deposit initially at the bronchiolar -alveolar duct regions and alveolar macrophages accumulate at these si tes within hours. Non-isotopic in situ hybridization and immunohistoch emistry were used to show that the mRNA that codes for TGF-alpha along with the peptide were clearly up-regulated at the bronchiolar-alveola r duct regions by 24 hours after the single asbestos exposure. The num bers of labeled cells demonstrated that expression of the mRNA and pro tein remained significantly above background for at least 2 weeks afte r exposure along with increased cell proliferation assessed by stainin g for proliferating cell nuclear antigen. This, to our knowledge, is t he first demonstration of TGF-alpha expression at sites of lung injury in developing fibroproliferative disease. This finding supports the h ypothesis that the growth factor is involved in the dramatic epithelia l and mesenchymal proliferation we documented previously, although add itional experiments will be essential to establish the precise role of TGF-alpha.