Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York, USA.
Division of Allergy, Immunology, and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA; and.
FASEB J. 2018 Sep;32(9):4955-4971. doi: 10.1096/fj.201701518R. Epub 2018 Apr 9.
Histone deacetylase 2 (HDAC2), a critical determinant of chromatin remodeling, is reduced as a consequence of oxidative stress-mediated DNA damage and impaired repair. Cigarette smoke (CS) exposure causes DNA damage and cellular senescence. However, no information is available on the role of HDAC2 in CS-induced DNA damage, stress-induced premature senescence (SIPS), and senescence-associated secretory phenotype (SASP) during the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema. We hypothesized that CS causes persistent DNA damage and cellular senescence via HDAC2-dependent mechanisms. We used HDAC2 global knockout (KO) and HDAC2 lung epithelial cell-specific KO [Clara cell-specific HDAC2 deletion (HDAC2 CreCC10)] mice to determine whether HDAC2 is a major player in CS-induced oxidative stress, SIPS, and SASP. HDAC2 KO mice exposed to CS show exaggerated DNA damage, inflammatory response, and decline in lung function leading to airspace enlargement. Chronic CS exposure augments lung senescence-associated β-galactosidase activity in HDAC2 KO, but not in HDAC2 CreCC10 mice. HDAC2 lung epithelial cell-specific KO did not further augment CS-induced inflammatory response and airspace enlargement but instead caused an increase in lymphoid aggregate formation. Our study reveals that HDAC2 is a key player regulating CS-induced DNA damage, inflammatory response, and cellular senescence leading to COPD/emphysema.-Sundar, I. K., Rashid, K., Gerloff, J., Rangel-Moreno, J., Li, D., Rahman, I. Genetic ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema.
组蛋白去乙酰化酶 2（HDAC2）是染色质重塑的关键决定因素，由于氧化应激介导的 DNA 损伤和修复受损而减少。香烟烟雾（CS）暴露会导致 DNA 损伤和细胞衰老。然而，目前尚不清楚 HDAC2 在 CS 诱导的 DNA 损伤、应激诱导的过早衰老（SIPS）和衰老相关分泌表型（SASP）在慢性阻塞性肺疾病（COPD）/肺气肿发病机制中的作用。我们假设 CS 通过 HDAC2 依赖性机制引起持续的 DNA 损伤和细胞衰老。我们使用 HDAC2 全局敲除（KO）和 HDAC2 肺上皮细胞特异性 KO [Clara 细胞特异性 HDAC2 缺失（HDAC2 CreCC10）]小鼠来确定 HDAC2 是否是 CS 诱导的氧化应激、SIPS 和 SASP 的主要参与者。暴露于 CS 的 HDAC2 KO 小鼠显示出更严重的 DNA 损伤、炎症反应和肺功能下降，导致气腔扩大。慢性 CS 暴露增加了 HDAC2 KO 小鼠的肺衰老相关β-半乳糖苷酶活性，但在 HDAC2 CreCC10 小鼠中则没有增加。HDAC2 肺上皮细胞特异性 KO 并没有进一步增加 CS 诱导的炎症反应和气腔扩大，而是导致淋巴样聚集形成增加。我们的研究表明，HDAC2 是调节 CS 诱导的 DNA 损伤、炎症反应和细胞衰老导致 COPD/肺气肿的关键因素。-Sundar, I. K., Rashid, K., Gerloff, J., Rangel-Moreno, J., Li, D., Rahman, I. 组蛋白去乙酰化酶 2 基因敲除导致 COPD/肺气肿中的肺细胞衰老和淋巴滤泡形成。
