The Role of Tripartite Motif Protein 72 in the Regulation of Irs and Pi3k/Akt/Mtor Pathway in Experimental Bronchopulmonary Dysplasia: in Vitro and in Vivo Assessment

Bronchopulmonary dysplasia (BPD) is a major cause of early death. BPD results from ongoing lung injury and simultaneous repair; inflammation related to chorioamnionitis, postnatal infections, or iatrogenic causes (such as the use of ventilation or oxygen). It is well known that hyperoxia causes lung injury in animal models, and pulmonary injury in infants receiving supplemental oxygen therapy is similar. The lung of neonatal rats exposed to hyperoxic environment was found to present as impaired alveolarization and septation in our previous study. However, the molecular mechanisms responsible for oxygen toxicity are not completely understood. The phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway is an intracellular signaling pathway important in regulating the cell cycle. During the septation and alveolarization of neonatal lungs on the late canalicular through alveolar stage of lung development, the PI3K/AKT/mTOR pathway acts as protective roles in distal lung development and hyperoxia defense. The expression of active AKT in experimental BPD preserves alveolar development. The roles have been known as antiapoptotic regulator responsible for maintaining cell viability. Tripartite motif protein 72 (TRIM72, also referred to as mitsugumin 53) TRIM72 is abundantly expressed in striated muscle tissues and has been shown to function as a mediator for degradation of the insulin receptor and insulin receptor substrate 1 (IRS1). Overexpression of TRIM72 degrades IRS1 and down regulates insulin-like growth factor (IGF)-1 dependent PI3K/AKT/mTOR signal pathway in previous studies. Despite an extensive literature relating to BPD, no specific therapies are available to correct the BPD with hyperoxic environment on neonatal period, thus it is important to investigate the mechanisms by which neonatal lung respond to hyperoxia. Our preliminary study revealed that hyperoxia increases the alveolar volume, decreases the width of alveolar wall and enhanced neonatal lung tissue TRIM72 expression. We hypothesized that the overexpressed TRIM72 would down regulate the IRS1 PI3K/AKT/mTOR signal pathway and disrupt the effects of alveolar protection during hyperoxic environment. Thus, the downstream effects of TRIM72 would be reversed by active IRS1 PI3K/AKT/mTOR signal pathway. The aims of this study are: 1) to establish a cell and animal model of hyperoxia; 2) to investigate the effects of hyperoxia on neonatal rat lung morphology; 3) to evaluate the effects of hyperoxia on TRIM72 and IRS1 PI3K/AKT/mTOR signal pathway in alveolar cells; 4) to evaluate hyperoxia on TRIM72 and IRS1 PI3K/AKT/mTOR signal pathway in neonatal rat lung tissues. These results might provide useful therapeutic strategies for BPD induced by hyperoxia.