Macrophage production of transforming growth factor β and fibroblast collagen synthesis in chronic pulmonary inflammation

Abstract

A rat model of bleomycin-induced pulmonary inflammation and fibrosis was used to examine the relationship between collagen synthesis and transforming growth factor β (TGF-β) production, and cellular distribution. Total lung TGF-β was elevated within 2 h of intratracheal bleomycin administration and peaked 7 d later at levels 30-fold higher than controls. This was followed by a gradual decline with lower but persistent levels of production in the late phase of the response between 21 and 28 d later. The peak TGF-β levels preceded the maximum collagen and noncollagen protein synthesis measured by [3H]proline incorporation into lung fibroblast explants of bleomycin-treated rats. The pattern of immunohistochemical staining localized TGF-β initially in the cytoplasm of bronchiolar epithelium cells and subepithelial extracellular matrix. The peak of lung TGF-β levels at 7 d coincided with intense TGF-β staining of macrophages dispersed in the alveolar interstitium and in organized clusters. Later in the course of the response, TGF-β was primarily associated with extracellular matrix in regions of increased cellularity and tissue repair, and coincided with the maximum fibroblast collagen synthesis. This temporal and spatial relationship between collagen production and TGF-β production by macrophages suggests an important if not primary role for TGF-β in the pathogenesis of the pulmonary fibrosis.