Dose-dependent lung remodeling in transgenic mice expressing transforming growth factor-alpha

Transgenic mice overexpressing human transforming growth factor-alpha (TGF- alpha) develop emphysema and fibrosis during postnatal alveologenesis. To a ssess dose-related pulmonary alterations, four distinct transgenic lines ex pressing different amounts of TGF-alpha in the distal lung under control of the surfactant protein C (SP-C) promoter were characterized. Mean lung hom ogenate TGF-alpha levels ranged from 388 +/- 40 pg/ml in the lowest express ing line to 1,247 +/- 33 pg/ml in the highest expressing line. Histological assessment demonstrated progressive alveolar airspace size changes that we re more severe in the higher expressing TGF-alpha lines. Pleural and parenc hymal fibrosis were only detected in the highest expressing line (line 28), and increasing terminal airspace area was associated with increasing TGF-a lpha expression. Hysteresis on pressure-volume curves was significantly red uced in line 28 mice compared with other lines of mice. There were no diffe rences in bronchoalveolar lavage fluid cell count or differential that woul d indicate any evidence of lung inflammation among all transgenic lines. Pr oliferating cells were increased in line 28 without alterations of numbers of type II cells. We conclude that TGF-alpha lung remodeling in transgenic mice is dose dependent and is independent of pulmonary inflammation.