Activation of Akt Protects Alveoli from Neonatal Oxygen-Induced Lung Injury

Abstract

Bronchopulmonary dysplasia (BPD) is the main complication of extreme prematurity, resulting in part from mechanical ventilation and oxygen therapy. Currently, no specific treatment exists for BPD. BPD is characterized by an arrest in alveolar development and increased apoptosis of alveolar epithelial cells (AECs). Type 2 AECs are putative distal lung progenitor cells, capable of regenerating alveolar homeostasis after injury. We hypothesized that the protection of AEC2 death via the activation of the prosurvival Akt pathway prevents arrested alveolar development in experimental BPD. We show that the pharmacologic inhibition of the prosurvival factor Akt pathway with wortmannin during the critical period of alveolar development impairs alveolar development in newborn rats, resulting in larger and fewer alveoli, reminiscent of BPD. Conversely, in an experimental model of BPD induced by oxygen exposure of newborn rats, alveolar simplification is associated with a decreased activation of lung Akt. In vitro studies with rat lung epithelial (RLE) cells cultured in hyperoxia (95% O(2)) showed decreased apoptosis and improved cell survival after the forced expression of active Akt by adenovirus-mediated gene transfer. In vivo, adenovirus-mediated Akt gene transfer preserves alveolar architecture in the newborn rat model of hyperoxia-induced BPD. We conclude that inhibition of the prosurvival factor Akt disrupts normal lung development, whereas the expression of active Akt in experimental BPD preserves alveolar development. We speculate that the modulation of apoptosis may have therapeutic potential in lung diseases characterized by alveolar damage.

Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage

“…However, the restoration of Akt just to the "normal" level after cessation of cigarette smoking does not appear sufficient for repair of damaged lung because the significant emphysematous change was still observed in the SM rat lungs in our previous study (18). Consistent with this idea, forced expression of active Akt in vivo resumed alveolar development in a bronchopulmonary dysplasia model caused by hyperoxia, which resulted in p-Akt reduction (2).…”

“…It also promotes cell proliferation by inhibiting interaction of p21 with PCNA and promoting assembly of cyclin D1:cyclin-dependent kinase 4 complex. Of note, a pathological significance of Akt in maintenance of alveolar architecture is evidenced by the findings that inhibition of the PI3K/Akt pathway by wortmannin aggravated hyperoxia-induced bronchopulmonary dysplasia, and forced expression of constitutively active Akt attenuated hyperoxia-induced airspace enlargement with suppression of apoptosis (2). However, although the authors showed that adenoviral expression of Akt attenuated hyperoxia-induced lung injury and rescued type 2 alveolar epithelial cells from hyperoxia-induced apoptosis, it remains unknown whether Akt may play a critical role in survival, proliferation, and function in other cell types including lung fibroblasts for successful alveolarization.…”

Hyperoxia and Interferon-γ–Induced Injury in Developing Lungs Occur via Cyclooxygenase-2 and the Endoplasmic Reticulum Stress–Dependent Pathway

“…important aspect of this pathological process involves cell death secondary to hyperoxia (6,28,29). Although a variety of mechanisms account for cell death in the lung (30), we decided to focus on the ER stress pathway, because limited information is available on this process in the context of BPD.…”

Cigarette Smoke Induces Akt Protein Degradation by the Ubiquitin-Proteasome System

“…Thus, TTC3 appears to play an important role in cigarette smoke-mediated lung injury, possibly via Akt degradation, which may induce cell death and prevent lung repair through inhibition of cell proliferation. It is of note that patients with Down syndrome have alveolar hypoplasia (30) and that impaired alveolar development is associated with decreased Akt activation in a hyperoxia-induced bronchopulmonary dysplasia model (31).…”