血管紧张素转化酶 2 通过下调转化生长因子-β1/ Smad2/Smad3 通路抑制脂多糖诱导的肺纤维化。
Angiotensin-Converting Enzyme 2 Inhibits Lipopolysaccharide-Caused Lung Fibrosis via Downregulating the Transforming Growth Factor -1/Smad2/Smad3 Pathway.
机构信息
Department of Intensive Care Unit, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fujian, China (X.L., Y.Z.); Department of Clinical Medicine, Shengli Clinical Medical College, Fujian Medical University, Fujian, China (W.L.); and Department of Respiratory Medicine, Shanghai Construction Group Hospital, Shanghai, China (F.G.)
Department of Intensive Care Unit, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fujian, China (X.L., Y.Z.); Department of Clinical Medicine, Shengli Clinical Medical College, Fujian Medical University, Fujian, China (W.L.); and Department of Respiratory Medicine, Shanghai Construction Group Hospital, Shanghai, China (F.G.).
出版信息
J Pharmacol Exp Ther. 2022 Jun;381(3):236-246. doi: 10.1124/jpet.121.000907. Epub 2022 Mar 28.
BACKGROUND
In our previous studies, angiotensin-converting enzyme 2 (ACE2) was shown to alleviate the severity of acute lung injury, but its effects on the development of lung injury-caused lung fibrosis have not been studied.
METHODS
In the present study, the effects of ACE2 on lipopolysaccharide (LPS)-induced fibrosis in the lung were studied. The role of epithelial-mesenchymal transition (EMT) and that of the transforming growth factor -1 (TGF-1)/Smad2/Smad3 pathway in LPS-induced fibrosis in the lung were investigated.
RESULTS
ACE2 expression in the mouse model of LPS-induced lung fibrosis was significantly increased. ACE2 activator diminazene aceturate (DIZE) significantly reduced pulmonary fibrosis, decreased alpha-smooth muscle actin expression, collagen I, hydroxyproline, and TGF-1 in the lung. DIZE significantly decreased TGF-1 expression and the activation of Smad2 and Smad3. ACE2 overexpression inhibited the LPS-induced EMT in MLE-12 cells (lung epithelial cells) and small interfering RNA treatment of ACE2 stimulated EMT. ACE2 overexpression also inhibited TGF-1 expression and activation of Smad2 and Smad3 in MLE-12 cells. Finally, after MLE-12 cells were treated with both ACE2 and TGF-1 plasmid, TGF-1 plasmid significantly abolished the effect of ACE2 plasmid on the EMT in MLE-12 cells.
CONCLUSION
Combined with the in vivo study, it was revealed that ACE2 can suppress the TGF-1/Smad2/Smad3 pathway in lung type II epithelial cells, thus reversing their EMT and lung fibrosis. The present study provides basic research data for the application of ACE2 in lung injury-caused lung fibrosis treatment and clarifies the intervention mechanism of ACE2 in pulmonary fibrosis, which has potential value for clinical application.
SIGNIFICANCE STATEMENT
Angiotensin-converting enzyme 2 (ACE2) can inhibit the epithelial-mesenchymal transition (EMT) in lung type II epithelial cells and lung fibrosis. ACE2 can regulate the transforming growth factor -1/Smad2/Smad3 pathway in lung type II epithelial cells, which may be the underlying mechanism of ACE2's effect on EMT and lung fibrosis.
背景
在我们之前的研究中，血管紧张素转换酶 2（ACE2）被证明可以减轻急性肺损伤的严重程度，但它对肺损伤引起的肺纤维化发展的影响尚未得到研究。
方法
本研究旨在研究 ACE2 对脂多糖（LPS）诱导的肺纤维化的影响。研究了上皮-间充质转化（EMT）和转化生长因子-β1（TGF-β1）/Smad2/Smad3 途径在 LPS 诱导的肺纤维化中的作用。
结果
在 LPS 诱导的肺纤维化小鼠模型中，ACE2 的表达明显增加。ACE2 激活剂地昔尼尔（DIZE）显著减轻肺纤维化，减少肺中α-平滑肌肌动蛋白表达、胶原 I、羟脯氨酸和 TGF-β1。DIZE 显著降低 TGF-β1 表达和 Smad2 和 Smad3 的激活。ACE2 过表达抑制 LPS 诱导的 MLE-12 细胞（肺上皮细胞）中的 EMT，并且 ACE2 的小干扰 RNA 处理刺激 EMT。ACE2 过表达还抑制 MLE-12 细胞中 TGF-β1 表达和 Smad2 和 Smad3 的激活。最后，在用 ACE2 和 TGF-β1 质粒处理 MLE-12 细胞后，TGF-β1 质粒显著消除了 ACE2 质粒对 MLE-12 细胞 EMT 的影响。
结论
结合体内研究，揭示 ACE2 可以抑制肺 II 型上皮细胞中的 TGF-β1/Smad2/Smad3 途径，从而逆转 EMT 和肺纤维化。本研究为 ACE2 在肺损伤引起的肺纤维化治疗中的应用提供了基础研究数据，并阐明了 ACE2 在肺纤维化中的干预机制，具有潜在的临床应用价值。
意义陈述
血管紧张素转换酶 2（ACE2）可抑制肺 II 型上皮细胞中的上皮-间充质转化（EMT）和肺纤维化。ACE2 可调节肺 II 型上皮细胞中的转化生长因子-β1/Smad2/Smad3 途径，这可能是 ACE2 对 EMT 和肺纤维化影响的潜在机制。
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