Keratinocyte growth factor protects alveolar epithelium and endothelium from oxygen-induced injury in mice

Keratinocyte growth factor (KGF) has been used successfully to prevent alve olar damage induced by oxygen exposure in rodents. However, this treatment was used intratracheally and before oxygen exposure, which limited its clin ical application. In the present study, mice were treated with the recombin ant human KGF intravenously before (days -2 and -1) or during (days 0 and 1) oxygen exposure. In both cases, lung damage was attenuated. KGF increase d the number of cells incorporating bromodeoxyuridine (BrdU) in the septa a nd in bronchial epithelium of air-breathing mice but not of oxygen-exposed mice, indicating that the protective effect of KGF is not necessarily assoc iated with proliferation. Oxygen-induced damage of alveolar epithelium and, unexpectedly, of endothelium was prevented by KGF treatment as seen by ele ctron microscopy, We investigated the effect of KGF on different mechanisms known to be involved in oxygen toxicity. The induction of p53, Bar, and Bc l-x mRNAs during hyperoxia was to a large extent prevented by KGF, Surfacta nt proteins A and B mRNAs were not markedly modified by KGF. The anti-fibri nolytic activity observed in the alveoli during hyperoxia was to a large ex tent prevented by KGF, most probably by suppressing the expression of plasm inogen activator inhibitor-1 (PAI-1) mRNA and protein. As PAI-1 -/- mice ar e more resistant to hyperoxia, KGF might act, at least in part, by decreasi ng the expression of this protease inhibitor and by restoring the fibrinoly tic activity into the lungs.