A potential role of the JNK pathway in hyperoxia-induced cell death, myofibroblast transdifferentiation and TGF-β1-mediated injury in the developing murine lung

We used cultured human lung epithelial cells, fetal rat lung fibroblasts and a neonatal TGF-β1 transgenic mouse model. We demonstrate that hyperoxia inhibits cell proliferation, activates cell death mediators and causes cell death, and promotes myofibroblast transdifferentiation, in a dose-dependent manner. Except for fibroblast proliferation, the effects were mediated via the JNK pathway. In addition, since we observed increased expression of TGF-β1 by epithelial cells on exposure to hyperoxia, we used a TGF-β1 transgenic mouse model to determine the role of JNK activation in TGF-β1 induced effects on lung development and on exposure to hyperoxia. We noted that, in this model, inhibition of JNK signaling significantly improved the spontaneously impaired alveolarization in room air and decreased mortality on exposure to hyperoxia.When viewed in combination, these studies demonstrate that hyperoxia-induced cell death, myofibroblast transdifferentiation, TGF-β1- and hyperoxia-mediated pulmonary responses are mediated, at least in part, via signaling through the JNK pathway.Hyperoxia exposure to the developing lung is a critical factor in the occurrence of the most common chronic lung disease in neonates, namely bronchopulmonary dysplasia (BPD) [1]. This is especially important given the recent trend in non-invasive ventilation of preterm neonates; hence, bringing the role of hyperoxia (as opposed to endotracheal tube mechanical ventilation) to the forefront among the environmental factors contributing to "new" BPD [1-3]. While efforts have been made to decrease hyperoxia exposure to the developing lung, the incidence of BPD has actually increased [3]. An improved understanding of the mechanisms of hyperoxia-induced cell death and lung injury would be extremely helpful in formulating potential therapeutic strategies with the goal of ameliorating BPD [3,4].An important step in this direction would be to understand if varying levels of exposure to hyperoxia [5] have diff