ACE2 and a Traditional Chinese Medicine Formula NRICM101 Could Alleviate the Inflammation and Pathogenic Process of Acute Lung Injury

Cheng-Han Lin, Yi-Ju Chen, Ho-Ju Chang, Xin-Rui Yang, Meng-Wei Lin

Chih-Sheng Lin

Department of Biological Science and Technology, National Yang Ming Chiao Tung University,

Purpose

The COVID-19 is a highly transmittable respiratory illness caused by SARS-CoV-2, and acute lung injury (ALI) is the major complication of COVID-19. The challenge in studying SARS-CoV-2 pathogenicity is the limited availability of animal models. Therefore, it is necessary to establish animal models that can reproduce multiple characteristics of ALI to study therapeutic applications.

Materials and Methods

The present study established a mouse model that has features of ALI similar to COVID-19 syndrome. The role of human angiotensin-converting enzyme type II (ACE2) and administration of the Chinese herbal prescription NRICM101 were investigated in the pathogenic process of ALI. Mice with ACE2 genetic modifications, including the overexpression of human ACE2 (K18-hACE2 TG) and the absence of ACE2 (mACE2 KO), were intratracheally instillated with hydrochloric acid to induce ALI.

Results

The acid intratracheal instillation induced the imbalance between angiotensin-converting enzyme I (ACE) and ACE2, severe immune cell infiltration, inflammation, and pulmonary disease. Compared with K18-hACE2 TG mice, mACE2 KO mice exhibited dramatically increased levels of inflammatory cytokines (IL-6 and TNF-α) in bronchoalveolar lavage fluid and histological evidence of lung injury. The results indicated that the overproduction of ACE2 and induction of the ACE2-Ang-(1-7)/Mas axis could counteract the proinflammatory effect of acid-induced ALI. Therefore, p-ERK1/2 and p-STAT3 signaling pathways, and MMP-2/MMP-9 activities were regulated to alleviate the pathogenic process of ALI. In addition, NRICM101, which is an effective TCM that has both antiviral and anti-inflammatory effects against COVID-19, shows potential for treating acid-induced ALI. NRICM101 could ameliorate the disease progression of acid-induced ALI by suppressing IL-6 and TNF-α production in alveoli.

Conclusion

In conclusion, the established mouse model provided an effective platform for researchers to investigate the role of ACE2 on pathological mechanisms and develop therapeutic strategies for ALI, including COVID-19-related ALI. The effects of NRICM101 administration was a potential strategy for curing acid-induced ALI.

Keywords: Angiotensin-converting enzyme type II (ACE2), Acute lung injury (ALI), Animal model, Traditional Chinese medicine