Immunohistochemical localization of transforming growth factor-β and insulin-like growth factor-I in asbestosis in the sheep model

Abstract

Asbestosis is characterized by increased collagen deposition along the walls of terminal respiratory bronchioles that extends into the alveolar ducts and septae. Alveolar macrophages are activated and release growth factors that stimulate mesenchymal cell proliferation and enhanced formation of extracellular matrix. Both insulin-like growth factor-I (IGF-I), and transforming growth factor beta (TGF-beta) regulate cellular growth and promote matrix accumulation and are hypothesized to play important roles in asbestosis. We performed immunohistochemistry using 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 asbestos. All three TGF-beta isoforms were found in bronchial and bronchiolar epithelium, macrophages, and bronchial and vascular smooth muscle in control lungs. The distribution of TGF-beta was increased in these lung constituents as fibrotic lesions developed. Fibrotic lesions additionally 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, bronchial 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 lesions. Our data demonstrate different immunostaining patterns for IGF-I and 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.

Aberrant Expression of the Insulin-Like Growth Factor-1 Receptor by T Cells from Patients with Graves’ Disease May Carry Functional Consequences for Disease Pathogenesis

“…Expression of IGF-1R by submucosal fibroblasts and adipocytes is confined to areas of fibrosis and inflammation. This is also true in chronic inflammatory lung diseases where increased numbers of IGF-1R ϩ and IGF-1 ϩ fibroblasts and infiltrating macrophages are found in pulmonary fibrosis and systemic sclerosis (45,46). IGF-1 generated by infiltrating cells promotes lung fibroblast proliferation (47).…”

Immunohistochemical Localization of Transforming Growth Factor Beta Isoforms in Asbestos-Related Diseases

“…Therefore, we propose that TGF-1 may be present to stimulate collagen production. We previously showed that TGF-,1, -42, and -43 are intensely localized to extracellular matrix zones of early and developing fibrotic lesions in the lungs of sheep treated intratracheally with chrysotile asbestos (11). In the nodular lesions of silicosis, we reported that central hyalinized areas showed the maximum immunostaining for TGF-4 (12).…”

Interstitial fibrosis and growth factors.

“…This is consistent with the concept that TNF-ax upregulates the expression of TGF-,1, an important idea to consider in those systems in which multiple factors are active simultaneously during disease development. In other modes, immunohistochemical localization of TGF-,1 in an ovine model of asbestos-induced lung fibrosis demonstrated increased staining for TGF-I1 within the interstitial matrix (186). Investigation into mediators of airway wall fibrosis induced by mineral dusts (asbestos, iron oxide, titanium dioxide) in rat tracheal explants demonstrates increases in TGF-1 gene expression, which is localized to both the epithelium and subepithelial space (130).…”