Transforming growth factor alpha (TGF(alpha)) is increased during hyperoxia and fibrosis

Transforming growth factor alpha (TGF(alpha)) stimulates type II alveolar epithelial cell proliferation and also is associated with fibrosis. We studied the changes in bronchoalveolar lavage (BAL) TGF(alpha) protein in a neonatal rabbit hyperoxia-fibrosis model (100% O(2) for 8 to 9 days, followed by 60% O(2) to 36 days of age). Hyperoxia increased TGF(alpha) protein and delayed the appearance of mature lower molecular weight (MW) TGF(alpha) isoforms at postnatal days 6 and 8 during the acute injury period. At 3 and 5 weeks, after chronic hyperoxia exposure, there was an increase in lower MW TGF(alpha) peptides during the fibrotic period. Keratinocyte growth factor (KGF) is also a type II cell mitogen. In vitro studies of keratinocytes suggest that KGF-induced proliferation is mediated through TGF(alpha). Intratracheal KGF instillation into adult wild-type and TGF(alpha)-null mice demonstrated that the KGF induced equivalent robust levels of proliferation in both TGF(alpha) deficient and wild-genotype mice. In conclusion, there are both quantitative and qualitative changes in TGF(alpha) protein in a hyperoxia-induced fibrosis neonatal rabbit model during periods of type II cell proliferation and fibrosis.