Ischemic Postconditioning Attenuates Myocardial Ischemia-Reperfusion-Induced Acute Lung Injury by Regulating Endoplasmic Reticulum Stress-Mediated Apoptosis

ABSTRACT Objective: To explore the effect of ischemic postconditioning on myocardial ischemia-reperfusion-induced acute lung injury (ALI). Methods: Forty adult male C57BL/6 mice were randomly divided into sham operation group (SO group), myocardial ischemia-reperfusion group (IR group), ischemic preconditioning group (IPRE group) and ischemic postconditioning group (IPOST group) (10 mice in each group). Anterior descending coronary artery was blocked for 60 min and then reperfused for 15 min to induce myocardial IR. For the IPRE group, 3 consecutive cycles of 5 min of occlusion and 5 minutes of reperfusion of the coronary arteries were performed before ischemia. For the IPOST group, 3 consecutive cycles of 5 min reperfusion and 5 minutes of occlusion of the coronary arteries were performed before reperfusion. Pathological changes of lung tissue, lung wet-to-dry (W/D) weight ratio, inflammatory factors, oxidative stress indicators, apoptosis of lung cells and endoplasmic reticulum stress (ERS) protein were used to evaluate lung injury. Results: After myocardial IR, lung injury worsened significantly, manifested by alveolar congestion, hemorrhage, structural destruction of alveolar septal thickening, and interstitial neutrophil infiltration. In addition, lung W/D ratio was increased, plasma inflammatory factors, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-17A, were increased, malondialdehyde (MDA) activity of lung tissue was increased, and superoxide dismutase (SOD) activity was decreased after myocardial IR. It was accompanied by the increased protein expression levels of ERS-related protein glucose regulatory protein 78 (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), and caspase-12, and the increased apoptotic indices of lung tissues. Conclusion: IPOST can effectively improve myocardial IR-induced ALI by inhibiting ERS-induced apoptosis of alveolar epithelial cells.

摘要
目的：探讨缺血后处理（ischemic postconditioning）对心肌缺血再灌注诱导的急性肺损伤（acute lung injury, ALI）的影响。
方法：将40只成年雄性C57BL/6小鼠随机分为假手术组（SO组）、心肌缺血再灌注组（IR组）、缺血预处理（ischemic preconditioning）组（IPRE组）及缺血后处理组（IPOST组），每组10只。通过阻断冠状动脉前降支（anterior descending coronary artery）60 min后再灌注15 min构建心肌缺血再灌注模型。其中IPRE组于缺血前连续实施3个周期的冠状动脉阻断5 min、再灌注5 min的预处理操作；IPOST组于再灌注前连续进行3个周期的冠状动脉再灌注5 min、阻断5 min的后处理操作。采用肺组织病理形态变化、肺湿干重比（wet-to-dry weight ratio, W/D）、炎症因子水平、氧化应激指标、肺细胞凋亡情况及内质网应激（endoplasmic reticulum stress, ERS）蛋白表达水平评估肺损伤程度。
结果：心肌缺血再灌注造模后，小鼠肺损伤显著加重，表现为肺泡充血、出血，肺泡间隔增厚伴结构破坏，以及肺间质中性粒细胞浸润。同时，肺湿干重比升高，血浆炎症因子包括白细胞介素（interleukin, IL）-6、肿瘤坏死因子（tumor necrosis factor, TNF）-α及IL-17A水平上调，肺组织丙二醛（malondialdehyde, MDA）活性升高、超氧化物歧化酶（superoxide dismutase, SOD）活性降低。此外，内质网应激相关蛋白葡萄糖调节蛋白78（glucose regulatory protein 78, GRP78）、CCAAT/增强子结合蛋白同源蛋白（CCAAT/enhancer-binding protein homologous protein, CHOP）及caspase-12的蛋白表达水平上调，肺组织凋亡指标亦显著升高。
结论：缺血后处理可通过抑制内质网应激介导的肺泡上皮细胞凋亡，有效改善心肌缺血再灌注诱导的急性肺损伤。