Abstract
BackgroundTransforming growth factor-beta 1 (TGF-β1) has been implicated in hyperoxia-induced cell death and impaired alveolarization in the developing lung. In addition, the c-JunNH2-terminal kinase (JNK) pathway has been shown to have a role for TGF-β1-mediated effects. We hypothesized that the JNK pathway is an important regulator of hyperoxia-induced pulmonary responses in the developing murine lung.ResultsWe 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.ConclusionsWhen 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.
Highlights
Transforming growth factor-beta 1 (TGF-b1) has been implicated in hyperoxia-induced cell death and impaired alveolarization in the developing lung
Hyperoxia-induced A549 cell death and its mediators are dependent on the JunNH2-terminal kinase (JNK) pathway We initially exposed A549 and MLE cells to varying levels of hyperoxia (40%, 60% and 95% O2) for 24 h and noted increased cell death, compared to 21% O2, at 24 h
Hyperoxia-induced alveolar interstitial fibroblasts (AIFs) cell proliferation is not dependent on the JNK pathway We examined the effect of hyperoxia on AIF proliferation and whether this was modulated via JNK activation
Summary
Transforming growth factor-beta 1 (TGF-b1) has been implicated in hyperoxia-induced cell death and impaired alveolarization in the developing lung. We hypothesized that the JNK pathway is an important regulator of hyperoxia-induced pulmonary responses in the developing murine lung. 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; bringing the role of hyperoxia (as opposed to endotracheal tube mechanical ventilation) to the forefront among the environmental factors contributing to “new” BPD [1,2,3]. JNK signaling has been implicated in hyperoxia-induced pulmonary injury responses [6,7,8,9,10]
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