The function role of ubiquitin proteasome pathway in the ER stress-induced AECII apoptosis during hyperoxia exposure

Abstract

Background Bronchopulmonary dysplasia (BPD) is a major cause of mortality and morbidity in premature infants, characterized by alveolar dysplasia and pulmonary microvascular remodeling. In the present study, we have investigated the functional roles of ubiquitin proteasome pathway (UPP) in BPD, and its relationship with endoplasmic reticulum stress (ERS) mediated type II alveolar epithelial cell (AECII) apoptosis. Methods A hyperoxia-induced BPD rat model was constructed and the pathologic changes of lung tissues were evaluated by hematoxylin–eosin staining. Cell apoptosis and protein expression were determined by TUNEL assay and Western blotting, respectively. Further reagent kit with specific fluorescent substrate was utilized to measure the activity of 20 s proteasome. Meanwhile, AECII were cultured in vitro and exposed to hyperoxia. AECII apoptosis were measured by flow cytometry. In contrast, MG132 treatment was induced to explore UPP during hyperoxia exposure on AECII apoptosis and ERS sensors expression. Results A significant increase in apoptosis and total ubiquitinated proteins expression were observed in BPD rats and AECII culture, and the change of UPP was associated with ERS. In order to confirm the role of UPP in AECII apoptosis of BPD, AECII cells were treated by MG132 with the concentration of 10 μmol/L under hyperoxia exposure. We found that the proteins expression of glucose-regulated protein 78 (GRP-78), PKR-like ER kinase (PERK), activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6) and C/EBP homologous protein (CHOP), as well as AECII apoptosis were increased following MG132 treatment. Furthermore, the relatively up-regulated in the levels of total ubiquitinated proteins expression and 20 s proteasome activity were correlated with increased ERS sensors expression. Conclusions Our findings indicate that UPP may participate in the ERS-induced AECII apoptosis under hyperoxia condition.

LncRNA gadd7 promotes mitochondrial membrane potential decrease and apoptosis of alveolar type II epithelial cells in hyperoxia-induced lung injury by promoting MFN1

“… 25 In the early stage of hyperoxia exposure, unfolded protein response is activated in rat lung tissue and starts the apoptosis process in AECII. 30 Hyperoxia exposure is positively correlated with the apoptosis of alveolar epithelial cells. 31 Hyperoxic conditions decreased Bcl-2 level and increased Bax level, which induced proliferation restriction and apoptosis of AECIIs.…”

Comprehensive analysis of characteristic genes of inflammation-related bronchopulmonary dysplasia based on bioinformatics methods

“…The imbalance of BPD in ammatory response regulation is the cause of BPD progression [12]. The levels of Th17 cells and Th17 cell-related cytokines were signi cantly increased in BPD mice, which may be related to the regulation of hyperoxia-induced lung injury by type 2 innate lymphocytes by targeting the regulation of Th17 cell response in BPD [13] The PI3K − Akt signaling pathway is associated with alveolar epithelial type II cell apoptosis, and alveolar epithelial type II cells also play a key role in the development of BPD [14] This study predicts that the predicted biological pathways or pathways are consistent with the existing results.…”

ILC2 regulates hyperoxia-induced lung injury via an enhanced Th17 cell response in the BPD mouse model

“…UJS-IACUC-AP-2,020,030,304). C57BL/6 mice were provided by the Animal Center of Jiangsu University (Zhenjiang, China), and the BPD mice model was established according to previous studies [ 20 , 21 ]. The lung development of neonatal mice is equivalent to that of human lungs gestational age of 28 weeks, which can well simulate the lung development of human preterm infants.…”