Attenuation of acute lung injury in transgenic mice expressing human transforming growth factor-alpha

Transforming growth factor-alpha (TGF-alpha) is produced in the lung in exp erimental and human lung diseases; however, its physiological actions after lung injury are not understood. To determine the influence of TGF-alpha on acute lung injury, transgenic mouse lines expressing differing levels of h uman TGF-alpha in distal pulmonary epithelial cells under control of the su rfactant protein C gene promoter were generated. TGF-alpha transgenic and n ontransgenic control mice were exposed to polytetrafluoroethylene (PTFE; Te flon) fumes to induce acute lung injury. Length of survival of four separat e TGF-alpha transgenic mouse lines was significantly longer than that of no ntransgenic control mice, and survival correlated with the levels of TGF-al pha expression in the lung. The transgenic line expressing the highest leve l of TGF-alpha (line 28) and nontransgenic control mice were then compared at time intervals of 2, 4, and 6 h of PTFE exposure for differences in pulm onary function, lung histology, bronchoalveolar lavage fluid protein and ce ll differential, and lung homogenate proinflammatory cytokines. Line 28 TGF -alpha transgenic mice demonstrated reduced histological changes, decreased bronchoalveolar lavage fluid total protein and neutrophils, and delayed al terations in pulmonary function measures of airway obstruction compared wit h those in nontransgenic control mice. Both line 28 and nontransgenic contr ol mice had similar increases in interleukin-1 beta protein levels in lung homogenates. In contrast, interleukin-6 and macrophage inflammatory protein -2 levels were significantly reduced in line 28 transgenic mice compared wi th those in nontransgenic control mice. In the transgenic mouse model, TGF- alpha protects against PTFE-induced acute lung injury, at least in part, by attenuating the inflammatory response.