A study led by researchers from the LKS Faculty of Medicine at The University of Hong Kong (HKUMed) discovered the mechanisms of how infection with SARS-CoV-2 virus can lead to lung injury and vascular damage. It is the first study worldwide to demonstrate such mechanism. In addition, the research team found that Imatinib, an FDA-approved oral targeted therapy drug, may work as a potential treatment for COVID-19 induced vascular diseases by modulating the dysregulated immune responses induced by SARS-CoV-2 in endothelial cells. The results from this study are now published in a leading international journal Clinical Infectious Diseases. [link to the publication]

Mechanism on how SARS-CoV-2 induces lung injury and vascular diseases 

It is now well established that many COVID-19 patients develop problems with clotting in their blood, leading to occlusion of vessels by aggregates of cells and proteins called thrombi. What has not been clear is whether this damage to the cells lining the vessels (endothelial cells) leading to thrombus formation is caused by direct virus infection, or as a result of chemicals released by damaged SARS-CoV-2 infected cells near the vessels. 

Dr Michael Chan Chi-wai, Associate Professor of School of Public Health, HKUMed and his research team investigated the mechanisms of the pathogenesis of COVID-19 in lung injury and vascular diseases. They found that SARS-CoV-2 induced lung injury and vascular diseases through cross-talk between airway epithelial cells and lung microvascular endothelial cells.   

Dr Chan elaborated, “SARS-CoV-2 does not target and infect human lung vascular endothelial cells directly, but infects airway epithelial cells to secrete cytokines through dysregulated immune responses, which subsequently stimulate and injure endothelial cells to produce inflammation and vascular leakage factors. This is the most likely mechanism how SARS-CoV-2 induced lung injury can lead to vascular diseases.”

Imatinib protects endothelial cells to prevent vascular diseases

Severe COVID-19 patients develop life-threatening acute respiratory failure and acute respiratory distress syndrome (ARDS), which is caused by dysregulation of host inflammatory responses. Apart from severe lung injury, hyper-induction of cytokines leads to multi-organ failure including liver, heart, kidney damage and vascular diseases. 

Imatinib, also known as Gleevec or Glivec, is an FDA-approved drug for the treatment of patients with various types of leukaemia and tumours. It is a tyrosine kinase inhibitor and entry inhibitor of SARS-CoV-2 in cell models. The research team found that treatment of endothelial cells with Imatinib have dual functions — suppressing the SARS-CoV-2 infection and inflammatory responses, and the vascular damage that is induced by SARS-CoV-2 infection in respiratory tract.   
  
Dr Kenrie Hui Pui-yan, Assistant Professor of School of Public Health, HKUMed said, “We evaluated the role of Imatinib in treating severe COVID-19 diseases, particularly those related with vascular diseases and acute lung injury. Our findings not only show that Imatinib can target adverse host responses, but also provide mechanistic insights into the interplay between the cells within our respiratory tract, giving rise to additional directions into fighting the virus through immune-regulation.” 

Professor John Nicholls, Clinical Professor of Department of Pathology, HKUMed expressed, “At HKUMed we have been working since 2003 to understand the mechanisms of human respiratory disease caused by coronaviruses, including SARS-CoV-1 and MERS-CoV, and to develop physiologically relevant models for these conditions. As one of the major complications of SARS-CoV-2 infection has been damage to endothelial cells, we sought to establish not only whether this damage is caused by viral infection, but also to evaluate whether therapeutic agents which are already marketed could dampen down this endothelial cell damage. Having these results will help bring our findings from the bench to the bedside.” 

About the research team
The research was conducted by a team led by Dr Michael Chan Chi-wai, Associate Professor, School of Public Health, HKUMed. The research team included Dr Kenrie Hui Pui-yan, Assistant Professor, School of Public Health, HKUMed; Professor Malik Peiris, Tam Wah-Ching Professor in Medical Science and Chair Professor of Virology, School of Public Health, HKUMed; and Professor John Nicholls, Clinical Professor, Department of Pathology, HKUMed. 

This work was supported by grants from the National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Surveillance (CEIRS) (contract HHSN272201400006C), Research Grant Council of Hong Kong (T11-712/19-N) and the Health and Medical Research Fund (COVID190202 and 15141022).

About the School of Public Health, HKUMed 
The School of Public Health, LKS Faculty of Medicine of The University of Hong Kong has a long and distinguished history in public health education and high impact research. With world leading research in infectious diseases as well as on non-communicable diseases of both local and global importance, the School has made significant contributions through its research and advocacy to improve the health of populations and individuals, both locally and globally. The School is a leading research and teaching hub in public health on influenza and other emerging viruses, control of non-communicable and infectious diseases, tobacco control, air pollution, psycho-oncology, behavioural sciences, exercise science, life-course epidemiology, and health economics, health services planning and management. This work has informed international (e.g. the US Food and Drug Administration, Health Canada, the World Health Organization), national and local public health policies.

For the latest update from HKUMed on COVID-19:
http://www.med.hku.hk/en/covid-19 

HKUMed demonstrates the mechanisms of vascular damage in SARS-CoV-2 infection, and shows how Imatinib may be a potential treatment for COVID-19 induced lung injury and vascular diseases. Members of the research team include: (from left to right) Dr Michael Chan Chi-wai, Associate Professor, School of Public Health; Dr Kenrie Hui Pui-yan, Assistant Professor, School of Public Health; and Professor John Nicholls, Clinical Professor, Department of Pathology.