Department of Respiratory Medicine, Shanghai First People's Hospital, Shanghai Jiaotong University , Shanghai , China and.
Inhal Toxicol. 2014 Jan;26(1):14-22. doi: 10.3109/08958378.2013.850563.
To investigate the anti-inflammatory effects of angiotensin-converting enzyme 2 (ACE2) overexpression on rat model of chronic obstructive pulmonary disease (COPD), and explore underlying mechanism.
The rat COPD model was established by cigarette smoking using a total body exposure method. A total of 64 male Wistar rats were randomly divided into four groups: normal, COPD, Ad-ACE2 and Ad-EGFP groups. The COPD model rats (including COPD, Ad-ACE2 and Ad-EGFP groups) received an intratracheal injection of normal saline, Ad-ACE2 and Ad-EGFP, respectively. The normal group underwent the same procedure but received an intratracheal injection of normal saline only. Pulmonary function tests, lung histopathology analysis, malondialdehyde (MDA) and reactive oxygen species (ROS) level, ACE2 mRNA and protein expression level, inflammatory cytokines and related signaling pathway proteins were measured.
COPD rats showed impairment of lung function as evidenced by decreased ratio of forced expiratory volume at 0.3 s and forced vital capacity (FEV0.3/FVC) and dynamic lung compliance (Cldyn), increased resistance inspiration (Ri) and resistance expiration (Re) as compared with the normal group, accompanying with reduced ACE2 mRNA expression, elevated ROS and MDA, elevated inflammatory cytokines levels (tumor necrosis factor α, TNF-α; interleukin-8, IL-8; IL-2 and IL-1β) and activation of nuclear factor-κB (NF-κB) and p38 MAPK (mitogen activated protein kinases) pathway in lung tissues. ACE2 overexpression through Ad-ACE2 infusion significantly attenuated the inflammatory response in lung tissues of COPD model rats.
ACE2 could attenuate COPD inflammatory process induced by cigarette smoke through reduction of oxidative stress and inhibition of NF-κB and p38 MAPK pathway activation.
探讨血管紧张素转换酶 2（ACE2）过表达对慢性阻塞性肺疾病（COPD）大鼠模型的抗炎作用，并探讨其潜在机制。
采用全身暴露法吸烟建立大鼠 COPD 模型。将 64 只雄性 Wistar 大鼠随机分为 4 组：正常组、COPD 组、Ad-ACE2 组和 Ad-EGFP 组。COPD 模型大鼠（包括 COPD 组、Ad-ACE2 组和 Ad-EGFP 组）分别接受生理盐水、Ad-ACE2 和 Ad-EGFP 气管内注射，正常组接受相同操作，但仅接受生理盐水气管内注射。测量肺功能、肺组织病理学分析、丙二醛（MDA）和活性氧（ROS）水平、ACE2mRNA 和蛋白表达水平、炎症细胞因子及相关信号通路蛋白。
与正常组相比，COPD 组大鼠表现出肺功能受损，第 0.3 秒用力呼气容积与用力肺活量之比（FEV0.3/FVC）和动态肺顺应性（Cldyn）降低，吸气阻力（Ri）和呼气阻力（Re）增加，同时 ACE2mRNA 表达降低，ROS 和 MDA 升高，炎症细胞因子水平（肿瘤坏死因子-α，TNF-α；白细胞介素-8，IL-8；白细胞介素-2 和白细胞介素-1β）升高，核因子-κB（NF-κB）和丝裂原激活蛋白激酶（MAPK）通路中 p38MAPK 激活。通过 Ad-ACE2 输注过表达 ACE2 可显著减轻 COPD 模型大鼠肺组织中的炎症反应。
ACE2 可通过减少氧化应激和抑制 NF-κB 和 p38MAPK 通路的激活来减轻香烟烟雾引起的 COPD 炎症过程。
