An animal model for studying angiotensin-converting enzyme type 2 (ACE2) on the pathogenic process in acute lung injury

Cheng-Han Lin* (林承翰), Yi-Ju Chen* (陳怡洳), Ho-Ju Chang, Chih-Sheng Lin1

National Yang Ming Chiao Tung University 

Background: The ongoing COVID-19 pandemic has highlighted Angiotensin converting enzyme type 2 (ACE2) is critical in SARS-CoV-2 infection. ACE2. In the renin angiotensin system (RAS), ACE2 play a protective role by cleaving angiotensin II (Ang II) to generate angiotensin 1-7 (Ang 1-7). In the study, we aimed to investigate ACE2 in acid-induced acute lung injury (ALI), the mouse with genetic modifications of hACE2(+)/mACE2(-) were performed to explore the effects of ACE2 in ALI pathogenesis.

Animal and Treatments: The wild-type (WT) and genetic modifications mice, including hACE2 transgenic (K18-hACE2 TG) and mACE2 knockout (mACE2 KO) mice were used in this study. The mice were treated intratracheal instillation of HCl once every three days, twice in total (2 ml/g, 0.1 N) and then sacrificed after 4 days and 11 days of acid treatment for pathological examination of the lungs. Bronchoalveolar lavage fluid (BALF) of the mice were collected for inflammatory cytokines assay.

Results: The results show that the significant injury and serious inflammation in the lungs of the mice by acid intratracheal instillation. It is identified that the acid-induced ALI was successfully established in the mice. Inflammation in the ALI was determined by white blood cells infiltration and the increased expression of inflammatory factor, TNF-a, IL-6 and TGF-ß1. Compared with the hACE2 TG mice, the inflammation and tissue injury were substantially pronounced in the lungs of WT and mACE2 KO mice after 4 days of acid treatment. However, the pathological damages in the lung of hACE2 TG mice significantly recovered compared to those in the WT mice after 11 days of acid treatment. Among the WT, hACE2 TG and mACE2 KO mice, the lung injury and inflammation induced by acid treatment were severe to recover in the mACE2 KO mice.

Conclusion: Our results indicate that in the absence of ACE2, the cell and tissue injury of acid-induced ALI is more severe, and the repair process in the injured lungs is slower and ACE2 could attenuate the lung damages of ALI.