Aim: To explore the potential mechanism of the synergetic effect of alpha-lipoic acid with keratinocyte growth factor ( KGF) on protecting alveolar epithelial type II cells (ATIICs) from hyperoxia-induced injury. Methods: Primary culture of ATIICs from the Sprague-Dawley rat fetuses was examined under room air and 95% of O-2. Various KGF concentrations (0 to 100ng/ml) and 0.5 mM of alpha-lipoic were added into the cell culture. Levels of intracelluler reactive oxygen species, necrosisi, and proliferation of ATIICs were messured using flow cytometry, ELISA, and MTT assays, respectively. RT-PCR was performed to detect KGFR mRNA expression. Western blot was employed to detect the expression of KGFR, phospho-p53, HDAC1, and acetylated H3 and H4. Results: KGF promoted the proliferation and inhibited the apoptosis of ATIICs in room air or under temporary exposure to hyperoxia. However, the resistance of ATIICs to KGF was observed after prolonged exposure. Further investigation demonstrated that down-regulation of KGF receptor via activation of p53 and recruitment of HDAC1 induced by oxidative stress contributed to KGF resistance. This resistance could be attenuted by alpha-lipoic acid, a powerful antioxidant. Conclusion: Application of KGF comnined with alpha-lopoic acid could inhibit KGF resistance to provide maximum protection to ATIICs from hyperoxic injury. Copyright (C) 2014 S. Karger AG, Basel