Patients with hypoxemia require high-concentration oxygen therapy. However, prolonged exposure to oxygen concentrations 21% higher than physiological concentrations (hyperoxia) may cause oxidative cellular damage. Pulmonary alveolar epithelial cells are major targets for hyperoxia-induced oxidative stress. In this study, we evaluated the therapeutic potential of the antioxidant N-acetyl-L-cysteine (NAC) for preventing hyperoxia-induced cell death. In vitro experiments were performed using the human lung cancer cell line A549. In brief, NAC-treated and untreated cells were exposed to various concentrations of oxygen (hyperoxia) for different durations. The results indicated that hyperoxia inhibited proliferation and caused cell cycle arrest in A549 cells. It also induced necrosis and autophagy. Furthermore, hyperoxia increased intracellular reactive oxygen species levels and altered mitochondrial membrane potential. Co-treatment with NAC improved the survival of cells exposed to 95% oxygen for 24 h. Experiments performed using a neonatal rat model of acute lung injury confirmed that hyperoxia induced an autophagic response. This study provides evidence for hyperoxia-induced autophagy both in vitro and in vivo. NAC can protect A549 cells from death induced by short-term hyperoxia. Our findings may inform protective strategies against hyperoxia-induced injury in developing lungs-for example, bronchopulmonary dysplasia in premature infants.
Keywords: N-acetyl-L-cysteine; autophagy; cell death; hyperoxia; pulmonary epithelial cell.
Hyperoxia reduced proliferation, induced cell cycle arrest and necrosis, and increased ROS levels in A549 cells.Hyperoxia led to time- and oxygen concentration–dependent hyperpolarization or depolarization of the mitochondrial membrane in A549 cells.Hyperoxia induced autophagy in both A549 cells and a rat model of acute lung injury.The antioxidant N-acetyl-L-cysteine (at concentrations of 1 and 5 mM) considerably protected A549 cells exposed to hyperoxia for 24 h, but not those exposed to hyperoxia for 72 h.