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

Transforming growth factor alpha (TGFalpha) stimulates type II alveolar epithelial cell proliferation and also is associated with fibrosis. We studied the changes in bronchoalveolar lavage (BAL) TGFalpha 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 TGFalpha protein and delayed the appearance of mature lower molecular weight (AM) TGFa 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 TGFalpha 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 TGFalpha. Intratracheal KGF instillation into adult wild-type and TGFalpha-null mice demonstrated that the KGF induced equivalent robust levels of proliferation in both TGFalpha deficient and wild-genotype mice. In conclusion, there are both quantitative and qualitative changes in TGFalpha protein in a hyperoxia-induced fibrosis neonatal rabbit model during periods of type 17 cell proliferation and fibrosis.