Int J Biol Sci 2020; 16(13):2382-2391. doi:10.7150/ijbs.47652

Research Paper

Glucocorticoids improve severe or critical COVID-19 by activating ACE2 and reducing IL-6 levels

Zhen Xiang1#, Jialin Liu2#, Dake Shi3#, Wei Chen4, Jun Li1, Ranlin Yan1, Yufang Bi5, Weiguo Hu1, Zhenggang Zhu1✉, Yingyan Yu1✉, Zhitao Yang6✉

1. Department of General Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
2. Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025, Shanghai, China.
3. Department of Infection Control, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025, Shanghai, China.
4. Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025, Shanghai, China.
5. Department of Endocrinology and Metabolism Disease, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025, Shanghai, China.
6. Emergency Department, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025, Shanghai, China.
#Equal contributions

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Citation:
Xiang Z, Liu J, Shi D, Chen W, Li J, Yan R, Bi Y, Hu W, Zhu Z, Yu Y, Yang Z. Glucocorticoids improve severe or critical COVID-19 by activating ACE2 and reducing IL-6 levels. Int J Biol Sci 2020; 16(13):2382-2391. doi:10.7150/ijbs.47652. Available from http://www.ijbs.com/v16p2382.htm

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Abstract

COVID-19 is a public health emergency that has rapidly spread to over 200 countries and regions, and no effective treatment has been established to date. Severe and critical cases have been associated with higher mortality due to acute respiratory distress syndrome (ARDS) and cytokine storm. Based on the novelty and recent emergence of COVID-19, no effective treatment regimen has been identified, thus prompting clinicians to engage in drug repurposing to address the immediate therapeutic need. This study focused on the molecular target angiotensin-converting enzyme 2 (ACE2) of SARS-CoV-2 and screened a group of ACE2 agonists by bioinformatics. Glucocorticoids are a type of ACE2 activator. We verified the efficacy of nine chemicals on regulating ACE2 expression in human GES-1, an upper digestive tract epithelial cell line, and THP-1, a human monocyte cell line, and found that several glucocorticoids imparted activating effects on ACE2 in both cell lines. The drugs triciribine and kinetin riboside activate ACE2 expression or inhibit IL-6 production in macrophages to some extent. In addition, we compared the efficacies of several glucocorticoids. Hydrocortisone showed the strongest effect on ACE2 activation, followed by prednisolone, dexamethasone, and methylprednisolone. We retrospectively analyzed the therapeutic efficacy of nine severe or critical patients from a cohort of 90 COVID-19 cases, who received medium to small doses of glucocorticoids from our integrated medical team in Wuhan. Seven out of nine patients revealed significant improvement in clinical parameters and chest CT images. This study provides experimental and clinical evidence that medium-to-low-dose glucocorticoids may play a protective role in the respiratory and digestive systems by activating ACE2 and suppressing cytokine storm.

Keywords: COVID-19, SARS-CoV-2, ACE2, Glucocorticoids, Drug repurposing