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.
Subject(s)
Hyperoxia/complications , Lung Injury/metabolism , Lung Injury/prevention & control , Proto-Oncogene Proteins c-akt/metabolism , Androstadienes/pharmacology , Animals , Animals, Newborn , Apoptosis , Bronchopulmonary Dysplasia/etiology , Bronchopulmonary Dysplasia/metabolism , Cell Line , Disease Models, Animal , Gene Transfer Techniques , Humans , Hyperoxia/metabolism , Hyperoxia/pathology , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/prevention & control , In Vitro Techniques , Infant, Newborn , Lung Injury/etiology , Oxygen/toxicity , Oxygen Inhalation Therapy/adverse effects , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/genetics , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/growth & development , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/pathology , Rats , WortmanninABSTRACT
Strategic prioritization of research agendas to address health problems with a large social and economic burden has increased the demand for interdisciplinary research. Universities have addressed the need for interdisciplinary research in their strategic documents. However, research training to equip graduates for careers in interdisciplinary research teams has not kept pace. We offer recommendations to graduate students, universities, health services organizations, and health research funders designed to increase the capacity for interdisciplinary research team training, and provide an example of an existing training program.
