Liu Ji-Qiang, Zhang Li, Yao Ji, Yao Shuo, Yuan Ting
Department of Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, China.
Department of Respiratory Medicine, Third Xiangya Hospital, Central South University, Changsha, China.
Biochem Biophys Res Commun. 2018 Mar 4;497(2):564-570. doi: 10.1016/j.bbrc.2018.02.095. Epub 2018 Feb 12.
Chronic obstructive pulmonary disease (COPD), is characterized by inflammation of airways accompanied by a progressive destruction of lung parenchyma. This process is initiated in most cases by cigarette smoking. In this study we investigated the role of AMP activated protein kinase (AMPK) in cigarette smoke extract (CSE)-induced airway epithelial cell apoptosis as a consequence of endoplasmic reticulum stress (ER stress). Exposure of human bronchial epithelial cells (HBEpC) to CSE resulted in apoptosis as detected using Annexin V-PI flow cytometry. However, co-treatment with N-(β-d-ribofuranosyl)-5-aminoimidazole-4-carboxamide (AICAR), a pharmacological activator of AMPK, significantly increased cell protection against ER stress-induced apoptosis by upregulating the 150 kDa oxygen-regulated protein (ORP150), which functions as an ER-associated chaperone, with concomitant elevation of FOXO1, a critical transcription factor regulating ORP150 expression. Lentiviral silencing of AMPK or FOXO1 using short hairpin (sh) RNA resulted in a significant decrease of ORP150 and an elevation of CCAAT/enhancer-binding protein-homologous protein (CHOP) resulting in ER stress and apoptosis of HBEpC. Together, our results strongly suggest that AMPK can activate ORP150 through FOXO1 pathway and confer protection against ER stress-induced apoptosis of airway epithelial cells following exposure to CSE. Thus, AMPK may serve as a likely therapeutic target for clinical and sub-clinical interventions in COPD.
慢性阻塞性肺疾病（COPD）的特征是气道炎症并伴有肺实质的进行性破坏。在大多数情况下，这个过程是由吸烟引发的。在本研究中，我们调查了AMP激活蛋白激酶（AMPK）在香烟烟雾提取物（CSE）诱导的内质网应激（ER应激）导致的气道上皮细胞凋亡中的作用。使用Annexin V-PI流式细胞术检测发现，人支气管上皮细胞（HBEpC）暴露于CSE会导致细胞凋亡。然而，与AMPK的药理学激活剂N-（β-D-呋喃核糖基）-5-氨基咪唑-4-甲酰胺（AICAR）共同处理，通过上调150 kDa氧调节蛋白（ORP150）（一种作为内质网相关伴侣蛋白发挥作用），并伴随关键转录因子FOXO1（调节ORP150表达）的升高，显著增强了细胞对ER应激诱导凋亡的保护作用。使用短发夹（sh）RNA对AMPK或FOXO1进行慢病毒沉默，导致ORP150显著减少以及CCAAT/增强子结合蛋白同源蛋白（CHOP）升高，从而导致HBEpC的ER应激和凋亡。总之，我们的结果强烈表明，AMPK可通过FOXO1途径激活ORP150，并在暴露于CSE后赋予气道上皮细胞对ER应激诱导凋亡的保护作用。因此，AMPK可能是COPD临床和亚临床干预的一个潜在治疗靶点。
