ACE2 exhibits protective effects against LPS-induced acute lung injury in mice by inhibiting the LPS-TLR4 pathway
ACE2 exhibits protective effects against LPS-induced acute lung injury in mice by inhibiting the LPS-TLR4 pathway
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DOI：
10.1016/j.yexmp.2019.104350
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发表时间：
2020-04-01
影响因子：
3.6
通讯作者：
Liu, Zhenwei
中科院分区：
文献类型：
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作者：
Ye, Rensong;Liu, Zhenwei
本研究旨在探讨血管紧张素转换酶2（ACE 2）对脂多糖（LPS）诱导的急性肺损伤（ALI）的保护作用。在通过注射LPS产生ALI小鼠模型后，分析ACE 2、炎症因子和LPS-TLR 4通路的下游蛋白的水平。在体外建立LPS攻击的BEAS-2B细胞。其次，构建并验证了真核表达载体pm-ACE 2。转染含增强型绿色荧光蛋白的pm-ACE 2，或分别用D-Ala-Ang-（1-7）、血管紧张素转换酶抑制剂（ACEI）、血管紧张素受体阻滞剂（ARB）和LPS-TLR 4通路抑制剂富马酸二甲酯（DMF）处理细胞，分析上述因素对ACE 2调节的作用。随后评估了肾素、血管紧张素II、ACE和血管紧张素II 1型受体（AT 1 R）的表达。在ALI模型中，小鼠表现出ACE 2表达降低、肺病理损伤、炎性损伤和LPS-TLR 4通路的异常激活。LPS刺激的BEAS-2B细胞表现为肾素、血管紧张素II、ACE和AT 1 R的表达上调。注射ACE 2后，肺功能和肺病理损伤明显改善，炎症反应减轻，LPS-TLR 4通路失活。细胞研究显示了类似的结果。当用DMF和pm-ACE 2联合治疗时，上述观察结果进一步增强。D-Ala-Ang-（1-7）处理减弱了ACE 2的保护作用，而ACEI和ARB处理减轻了LPS诱导的肺损伤。总之，ACE 2在LPS诱导的ALI中以低水平表达。ACE 2过表达调节ACE 2/Ang-（1-7）/Mas和ACE/Ang II/AT 1轴，维持肾素-血管紧张素系统的动态平衡，减轻炎症反应。
This study aimed to investigate the protective effect of angiotensin converting enzyme 2 (ACE2) on lipopolysaccharide (LPS)-induced acute lung injury (ALI). After generating ALI mouse models by injecting LPS, the levels of ACE2, inflammatory factors, and downstream proteins of the LPS-TLR4 pathway were analyzed. LPS-challenged BEAS-2B cells were established in vitro. Next, a eukaryotic expression vector, pm-ACE2, was constructed and validated. Challenged cells were transfected with pm-ACE2 containing enhanced green fluorescent protein, or they were treated with D-Ala-Ang-(1-7), angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB) and the LPS-TLR4 pathway inhibitor dimethyl fumarate (DMF) for analysis of how the above factors contribute to ACE2 regulation. Expression of renin, Ang II, ACE and angiotensin II type 1 receptor (AT1R) was subsequently assessed. In the ALI model, mice exhibited decreased expression of ACE2, lung pathological injury, inflammatory injury, and abnormal activation of the LPS-TLR4 pathway. LPS-challenged BEAS-2B cells demonstrated upregulated expression of renin, Ang II, ACE and AT1R. After injection of ACE2, lung function and lung pathological injury were significantly improved, and that effect was accompanied by attenuated inflammation, and inactivation of the LPS-TLR4 pathway. Cell studies showed similar results. The above observations were further enhanced when there was a combined treatment with DMF and pm-ACE2. D-Ala-Ang-(1-7) treatment attenuated the protective effect of ACE2, while ACEI and ARB treatment alleviated LPS-induced pneumonic injury. In conclusion, ACE2 was expressed at low levels in response to LPS-induced ALI. Overexpression of ACE2 regulates the ACE2/Ang-(1-7)/Mas and ACE/Ang II/AT1 axes to maintain dynamic balance of the renin-angiotensin system, and attenuate inflammatory response.