Abstract
BackgroundBronchopulmonary 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.MethodsA 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.ResultsA 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.ConclusionsOur findings indicate that UPP may participate in the ERS-induced AECII apoptosis under hyperoxia condition.
Highlights
Bronchopulmonary dysplasia (BPD) was defined as the need for mechanical ventilation and oxygen supplementation at 28 days of life and at 36 weeks of gestation [1]
Apoptosis and Total ubiquitinated proteins expression in BPD model rats Lung histology of the rats exposed to hyperoxia was characterized by decreased septation, distal air space enlargement and a reduction in complexity, which was similar to the histology observed in human infants with BPD [22]
Compared with the rats exposed to room air, Radial alveolar counts (RACs) were lower in the rats exposed to hyperoxia (Fig. 1A)
Summary
Bronchopulmonary dysplasia (BPD) was defined as the need for mechanical ventilation and oxygen supplementation at 28 days of life and at 36 weeks of gestation [1]. Type II alveolar epithelial cell (AECII) is the main stem cells in the lung, which maintains normal pulmonary function. Zhu et al BMC Pulmonary Medicine (2021) 21:379 induce excessive apoptosis in AECII, which play an important role of the BPD development [2,3,4]. Prolonged exposure to hyperoxia results in the accumulation of misfolded proteins in the ER, and activation of unfolded protein response (UPR) [4,5,6,7,8]. 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
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