Biphasic response of checkpoint control proteins in hyperoxia: exposure to lower levels of oxygen induces genome maintenance genes in experimental baboon BPD

Abstract

Breathing high concentrations of oxygen (hyperoxia) causes lung injury and is associated with lung diseases such as bronchopulmonary dysplasia (BPD), respiratory distress syndrome (RDS) and persistent pulmonary hypertension of the newborns (PPHN). Hyperoxia (95–100%O2) causes DNA damage and growth arrest of lung cells and consequently cells die by apoptosis or necrosis. Although supplemental oxygen therapy is clinically important, the level and duration of hyperoxic exposure that would allow lung cells to reenter the cell cycle remains unclear. We hypothesized that cells exposed lower concentrations of hyperoxia will retain the capacity to enter cell cycle when recovered in room air. We employed varying concentrations of oxygen (21–95%) to determine the response of lung cells to hyperoxia. Our results indicate that cells were growth arrested and failed to reenter the cell cycle when exposed to greater than 60% oxygen. Cell cycle checkpoint proteins were increased in a biphasic manner, increasing until 70% oxygen, but declined in greater than 90% oxygen. Microarray analysis shows that there is significant decrease in the abundance of Cdks 6–8 and retinoblastoma protein (Rb), p107 and p130 in exposure to 90% oxygen for 48 hours. We further tested the effect of clinically relevant as needed oxygen [(pro-re-nada (prn)] in premature infant (125d and 140d) baboon model of bronchopulmonary dysplasia (BPD). The microarray results show that 6 or 14d PRN oxygen exposed animals had induced expression of chromosomal maintenance genes (MCMs), genes related to anti-inflammation, proliferation and differentiation.

Effect of Montelukast on Bronchopulmonary Dysplasia (BPD) and Related Mechanisms

“…Previous studies have reported the critical roles of lung cell apoptosis in the occurrence and development of BPD [ 29 , 30 ]. In this study, we also investigated whether montelukast had an effect on lung cell apoptosis in vitro , and human type II alveolar epithelial cell line A549 was used in the present study to establish the lung cell injury model induced by hyperoxia.…”

Long non-coding RNA MALAT1 protects preterm infants with bronchopulmonary dysplasia by inhibiting cell apoptosis

“…Recent studies have found that CDC6 itself has a role in inhibiting apoptosis, complex CDC6 through its ATPase domain and apoptosis protease activating factor Apaf-1 to form stable, blocking the formation of apoptotic bodies [ 25 ]. Previous study indicated that cell apoptosis plays an important role in the occurrence and development process of premature BPD [ 26 ]. Our study showed that MALAT1 depletion in WI-38 cells induces cell apoptosis.…”

Update on Molecular Biology of Lung Development—Transcriptomics

“…Validation studies clearly demonstrated a robust, albeit with variable magnitude, accumulation of CTMC in the airspaces in BPD lung tissue. In a preterm baboon model of hyperoxia-induced lung injury leading to BPD-like phenotypes, microarray analysis of lung tissue identified increased expression of genes related to chromosomal maintenance, proliferation, and differentiation [50]. Additionally, and of note, in this model there appeared to be an increase in genes associated with the inhibition of inflammation.…”