IMMUNOHISTOCHEMICAL LOCALIZATION OF TRANSFORMING GROWTH-FACTOR-BETA AND INSULIN-LIKE GROWTH-FACTOR-I IN ASBESTOSIS IN THE SHEEP MODEL

Asbestosis is characterized by increased collagen deposition along the walls of terminal respiratory bronchioles that extends into the alveo lar ducts and septae. Alveolar macrophages are activated and release g rowth factors that stimulate mesenchymal cell proliferation and enhanc ed formation of extracellular matrix. Both insulin-like growth factor- I (IGF-I), and transforming growth factor beta (TGF-beta) regulate cel lular growth and promote matrix accumulation and are hypothesized to p lay important roles in asbestosis. We performed immunohistochemistry u sing polyclonal antibodies to specific synthetic peptides of the three mammalian isoforms of TGF-beta (TGF-beta 1, -beta 2, -beta 3) and to IGF-I on lungs of sheep treated intratracheally with chrysotile asbest os. All three TGF-P isoforms were found in bronchial and bronchiolar e pithelium, macrophages, and bronchial and vascular smooth muscle in co ntrol lungs. The distribution of TGF-beta was increased in these lung constituents as fibrotic lesions developed. Fibrotic lesions additiona lly demonstrated intense immunostaining of all three TGF-beta isoforms that localized to the extracellular matrix zones with little staining of interstitial cells. In the control sheep lungs, IGF-I staining was detected in bronchial and bronchiolar epithelium, bronchial glands, b ronchial and vascular smooth muscle, endothelium and macrophages. IGF- I immunostaining was detected in macrophages in peribronchial fibrosis and in fibroblasts along the periphery of and within lesions, but not in the extracellular matrix. Metaplastic proliferating epithelium and macrophages were strongly immunoreactive for IGF-I in advanced lesion s. Our data demonstrate different immunostaining patterns for IGF-I an d TGF-beta in asbestosis, with IGF-I in the cellular periphery and TGF -beta in the extracellular matrix consistent with a complementary role in stimulating interstitial fibroblast proliferation and new collagen deposition in areas of active fibrosis.