Abstract
Background: In our previous studies, angiotensin-converting enzyme 2 (ACE2) was shown to alleviate the severity of acute lung injury (ALI), 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 lung were studied. The role of epithelial-mesenchymal transition (EMT) and that of the transforming growth factor-beta1 (TGF-β1)/Smad2/Smad3 pathway in LPS-induced fibrosis in 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 α-SMA expression, collagen I, hydroxyproline, and TGF-β1 in the lung. DIZE significantly decreased TGF-β1 expression and the activation of Smad2 and Smad3. ACE2 overexpression inhibited the LPS-induced EMT in MLE-12 cells (lung epithelial cells) and siRNA treatment of ACE2 stimulated EMT. ACE2 overexpression also inhibited TGF-β1 expression and activation of Smad2 and Smad3 in MLE-12 cells. Finally, after MLE-12 cells were treated with both ACE2 and TGF-β1 plasmid, TGF-β1 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-β1/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 Our results revealed that ACE2 can inhibit the TGF-β1/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-induced pulmonary fibrosis treatment and clarifies the intervention mechanism of ACE2 in pulmonary fibrosis, which has potential value for clinical application.
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