Involvement of B-cell CLL/lymphoma 2 promoter methylation in cigarette smoke extract-induced emphysema

Abstract

Abnormal apoptotic events play an important role in the pathogenesis of emphysema. The B-cell CLL/lymphoma 2 (Bcl-2) family proteins are essential and critical regulators of apoptosis. We determined whether the anti-apoptotic Bcl-2 play a role in the cigarette smoke extract (CSE)-induced emphysema. Furthermore, given the involvement of epigenetics in chronic obstructive pulmonary disease, we hypothesized that the deregulation of Bcl-2 might be caused by gene methylation. The emphysema in BALB/C mice was established by intraperitoneally injection of CSE. 5-aza-2 0 -deoxycytidine (AZA; a demethylation reagent) and phosphate-buffered saline were also administered intraperitoneally as CSE. TUNEL assay was used to assess apoptotic index of pulmonary cells. The methylation status of CpG dinucleotides within the Bcl-2 promoter was observed in all groups by bisulfite sequencing PCR. Pulmonary expression of Bcl-2, Bax, and cytochrome C were measured after four weeks of treatment. The apoptotic index of pulmonary cells in CSE injection group was much higher than control ((25.88 AE 7.55)% vs. (6.28 AE 2.96)%). Compared to control mice, decreased expression of Bcl-2 and high methylation of Bcl-2 promoter was observed in CSE injected mice (0.88 AE 0.08 vs. 0.49 AE 0.11, (3.82 AE 1.34)% vs. (35.68 AE 5.99)%, P < 0.01).CSE treatment induced lung cell apoptosis and decreased lung function. AZA treatment increased Bcl-2 expression with Bcl-2 promoter demethylation. AZA also alleviated the lung cell apoptosis and function failure caused by CSE treatment. The decreased expression of antiapoptotic Bcl-2 might account for the increased apoptosis in CSE induced-emphysema. Apparently, epigenetic alternation played a role in this deregulation of Bcl-2 expression, and it might support the involvement of epigenetic events in the pathogenesis of emphysema.

Notch1 regulates endothelial apoptosis via the ERK pathway in chronic obstructive pulmonary disease

“…Due to a decrease in cell maintenance factors, it has been proposed that epithelial and endothelial cell death may be responsible for the development of emphysema ( 18 ). Consistent with this notion, our previous studies have confirmed that CS exposure induces endothelial cell apoptosis and small vascular injury in both animal models and human lungs ( 4 , 18 , 37 , 38 ). An increase in pulmonary endothelial cell apoptosis induced by CSE in vitro was also reported ( 4 , 36 ).…”

“…Recent data suggested that abnormal apoptosis serves as a significant factor contributing to the destruction of pulmonary tissue in COPD ( 28 ). Studies from both animal model and human confirmed that endothelial apoptosis plays an important role in the pathogenesis of emphysema and COPD ( 4 , 14 , 26 , 36 , 37 ).…”

Differential coexpression networks in bronchiolitis and emphysema phenotypes reveal heterogeneous mechanisms of chronic obstructive pulmonary disease

“…The present study identified coexpression of several B cell–related genes enriched in the tan module, which positively correlate with emphysema, which is consistent with the work of Faner et al and other groups that implicates antigen and immune processes in COPD pathogenesis . Moreover, we also identified other vital genes using gene interaction network analysis (Supplementary Figure ).…”

“…The present study identified coexpression of several B cell-related genes enriched in the tan module, which positively correlate with emphysema, which is consistent with the work of Faner et al 15 and other groups that implicates antigen and immune processes in COPD pathogenesis. 25,26 Moreover, we also identified other vital genes using gene interaction network analysis (Supplementary Figure S3). For example, CD79A increases with increasing emphysema severity, 27 and targeting the CD79A interacting genes CXCL13 and CXCR5 causes a decrease in the immune responses of allergic airway inflammatory process.…”

Prohibitin Protects Against Cigarette Smoke Extract-Induced Cell Apoptosis in Cultured Human Pulmonary Microvascular Endothelial Cells

“…In the present study, we have investigated the protective ability of prohibitin overexpression in CSE exposure associated mitochondrial dysfunction, ROS generation, oxidative DNA damage and apoptosis in HPMECs. CSE may induce apoptosis in bronchial epithelial cells, endothelial cells and human airway smooth muscle cells (ASMCs) [11][12][13][14] CSE may cause injury in mitochondrial morphology and function and induce apoptosis via an intrinsic apoptotic pathway, which involves mitochondrial fragmentation and the disruption of mitochondrial membrane integrity, inhibit of mitochondrial respiration and release of cytochrome c, as well as changed expression levels of pro-apoptotic and anti-apoptotic molecules [13,[15][16][17][18]. A previous study has demonstrated that prohibitin decrease the apoptosis of endothelial cells in response to glyLDL [19].…”