Imatinib significantly reduces proinflammatory cytokines in SARS-CoV-2–affected endothelial cells
Researchers from The University of Hong Kong (HKU) have uncovered a novel mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced lung injury and vascular damage through epithelial–endothelial cell interaction and demonstrated the immunomodulatory role of imatinib, supporting its use for the treatment of coronavirus-19 (COVID-19).
“SARS-CoV-2 does not target and infect human lung vascular endothelial cells directly, but infects airway epithelial cells, which secrete cytokines through dysregulated immune responses, subsequently stimulating and injuring the endothelial cells to produce inflammation and vascular leakage factors,” explained Dr Michael Chan of the School of Public Health, HKU. “This is the most likely mechanism of how SARS-CoV-2–induced lung injury can lead to vascular diseases.”
The researchers used well differentiated human airway epithelial cells (HAECs) to explore the dynamics of cytokine and chemokine production following SARS-CoV-2 infection. Infection with SARS-CoV-2 led to the production of interleukin-6 (IL-6), interferon gamma–induced protein 10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1) in these cells. At the same time, while human pulmonary microvascular endothelial cells (HPMVECs) did not support productive replication of SARS-CoV-2, they produced proinflammatory cytokines, chemokines and vascular adhesion molecules when treated with the medium from the infected HAECs. [Clinical Infectious Diseases 2021;doi:10.1093/cid/ciab406]
“At HKU, we have been working since 2003 to understand the mechanisms of human respiratory disease caused by coronaviruses and to develop physiologically relevant models for these conditions. As one of the major complications of SARS-CoV-2 infection is endothelial cell damage, we sought to establish not only whether this damage is caused by viral infection, but also to evaluate whether already marketed therapeutic agents could dampen down this endothelial cell damage,” said Professor John Nicholls of the Department of Pathology, HKU.
Imatinib is a US FDA-approved cancer treatment with known efficacy against oedema, inflammation, and vascular leakage in mouse models of acute lung injury. [Am J Physiol Lung Cell Mol Physiol 2015;309:L1294-1304; Circulation 2012;126:2728-2738] Imatinib has also been shown to inhibit SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) replication with low cytotoxicity. [Antimicrob Agents Chemother 2014;58:4885-4893]
The HKU researchers evaluated the effect of imatinib on HPMVECs exposed to the conditioned medium from SARS-CoV-2–infected cells. Treatment with imatinib at non-cytotoxic concentrations led to significant suppression of IL-6, MCP-1, IP-10, vascular cell adhesion molecule-1 (VCAM-1) and E-selectin in these cells.
“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,” commented Dr Kenrie Hui of the School of Public Health, HKU.
“Imatinib is being studied in two phase III clinical trials [NCT04394416, NCT04422678] as a treatment for COVID-19 patients. However, there has been limited information on the mechanism of imatinib in modulating SARS-CoV-2 infection. Apart from antiviral effects, our study finds that imatinib can act as an immunomodulator as it significantly reduced the induction of proinflammatory cytokines, chemokines and leukocyte adhesion molecules in endothelial cells treated with conditioned medium from SARS-CoV-2–infected airway cells,” concluded the researchers.