ACE2在慢性间歇低氧肺组织氧化应激损伤中的作用

寇育乐; 张盼盼; 王红阳等

ACE2在慢性间歇低氧肺组织氧化应激损伤中的作用

Protective Effect of angiotensin Converting Enzyme 2 (ACE2) Against Chronic Intermittent Hypoxia-induced Pulmonary Oxidative Stress Injury in Rats

摘要

摘要: 目的观察血管紧张素转换酶2(ACE2)在慢性间歇低氧(CIH)大鼠肺组织氧化应激损伤中的动态变化，探讨其在CIH肺损伤中可能的作用机制。方法 96只Wistar大鼠随机分为正常对照组（UC组）、CIH组、依达拉奉治疗组(NE组)、安慰剂（0.9%NaCl）治疗组(NS组)，并分为1周、2周、3周、4周4个时间亚组，每亚组6只大鼠。UC组暴露于空气中，CIH组、NE组及NS组分别暴露于CIH环境下，NE组每日给予依达拉奉注射液（3 mg/kg）尾静脉注射，NS组给予0.9%生理盐水（3 mg/kg）尾静脉注射。实验结束后，取各组大鼠肺组织标本，观察肺组织病理变化、应用免疫组化检测肺组织ACE2蛋白的表达，丙二醛（NDA）测定试剂盒检测MDA水平、实时荧光定量PCR法检测ACE2mRNA、血管紧张素Ⅱ（AngⅡ） mRNA的表达。结果 UC组未见明显病理损害，而CIH 组及NS组肺泡壁水肿增厚，肺泡萎缩不张，肺间质及支气管上皮内也可见中性粒细胞浸润，且随时间延长病理损伤逐渐加重，与NS相比NE组出现病理损伤的时间较晚且程度较轻；与UC组比较，CIH组及NS组MDA含量、AngⅡ mRNA表达在观察时间点内均逐渐增加（P<0.05），于4周达到高峰；而ACE2蛋白及ACE2 mRNA 1周、2周呈逐渐增高趋势（P<0.05），于2周时达到峰值，然后逐渐下降（P<0.05）；与NS组比较，NE组各指标升高幅度较低，依达拉奉能抑制CIH引起的各指标的的增加（P<0.05）；CIH组肺组织AngⅡ mRNA水平与MDA含量均呈正相关 (r=0.782， P<0.01)。结论提示ACE2对慢性间歇低氧大鼠肺组织氧化应激损伤有一定的保护作用，其机理可能与对AngⅡ降解作用增强有关。

Abstract: Objective To determine changes of angiotensin converting enzyme 2 (ACE2) in the development of chronic intermittent hypoxia (CIH)-induced pulmonary injury in rats and its mechanism. Methods 96 adult male Wistar rats were randomly allocated into four groups: control (UC) group, chronic intermittent hypoxia (CIH) group, normal saline treated CIH (NS) group, and edaravone treated CIH (NE) group. Each group contained four subgroups of rats (n=6) subjecting to 1 week, 2 weeks, 3 weeks, and 4 weeks experiment, respectively. No intervention was given to rats in the UC group. Rats in the experimental groups were exposed to alternating cycles of nitrogen and compressed air. Rats in the NS and NE groups received daily injection of 0.9% normal saline (3 mg/kg) and edaravone (3 mg/kg), respectively. Pulmonary sections were taken and stained with hematoxylin-eosin (HE). The levels of malondialdehyde (MDA), ACE2, ACE2mRNA, and angiotensin Ⅱ(AngⅡ) mRNA in the rat homogenate pulmonary samples were measured. Results Rats in the CIH and NS groups showed high levels of interstitial edema, alveolar atelectasis, and inflammatory cell infiltration in alveolar epithelial cells. The pulmonary injury got worse over time. Rats in the NE group showed later occurrence and milder pulmonary injury compared with those in the NS group. Rats in the CIH and NS groups had higher levels of and AngⅡ mRNA (which increased over time) than those in the UC group (P<0.05). The expression of ACE2 and the level of ACE2mRNA increased in rats in the CIH group (P<0.05), and peaked at 2 weeks (P<0.05). Rats in the NE group had moderately increased levels of MDA andAngⅡ mRNA compared with those in the NS group(P<0.05); moderately increased levels of expression of ACE2 and ACE2 mRNA compared with those in the UC and SC groups (P<0.05). The pulmonary level of AngⅡmRNA was positively correlated with MDA(r=0.782, P<0.01)in rats in the CIH group. Conclusion CIH can activate oxidation stress and AngⅡ, which maybe an important mechanism of CIH-induced pulmonary injury.

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