Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jan 7;24(2):1187.
doi: 10.3390/ijms24021187.

Severe COVID-19-A Review of Suggested Mechanisms Based on the Role of Extracellular Matrix Stiffness

Garry Kerch  1
Affiliations
Review

Severe COVID-19-A Review of Suggested Mechanisms Based on the Role of Extracellular Matrix Stiffness

Garry Kerch. Int J Mol Sci. .

Abstract

The severity of COVID-19 commonly depends on age-related tissue stiffness. The aim was to review publications that explain the effect of microenvironmental extracellular matrix stiffness on cellular processes. Platelets and endothelial cells are mechanosensitive. Increased tissue stiffness can trigger cytokine storm with the upregulated expression of pro-inflammatory cytokines, such as tumor necrosis factor alpha and interleukin IL-6, and tissue integrity disruption, leading to enhanced virus entry and disease severity. Increased tissue stiffness in critically ill COVID-19 patients triggers platelet activation and initiates plague formation and thrombosis development. Cholesterol content in cell membrane increases with aging and further enhances tissue stiffness. Membrane cholesterol depletion decreases virus entry to host cells. Membrane cholesterol lowering drugs, such as statins or novel chitosan derivatives, have to be further developed for application in COVID-19 treatment. Statins are also known to decrease arterial stiffness mitigating cardiovascular diseases. Sulfated chitosan derivatives can be further developed for potential use in future as anticoagulants in prevention of severe COVID-19. Anti-TNF-α therapies as well as destiffening therapies have been suggested to combat severe COVID-19. The inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells pathway must be considered as a therapeutic target in the treatment of severe COVID-19 patients. The activation of mechanosensitive platelets by higher matrix stiffness increases their adhesion and the risk of thrombus formation, thus enhancing the severity of COVID-19.

Keywords: COVID-19; cardiovascular diseases; mechanosensitive platelets; stiffness; thrombotic complications.

PubMed Disclaimer

Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Platelet activation leading to thrombus formation can be caused by increased arterial stiffness in COVID-19 patients or by cytokine storm also induced by increased arterial stiffness. Patients with hypertension, diabetes, and obesity are more often severely ill with COVID-19 probably because of higher old age-related tissue stiffness in various organs. Partly the increased tissue stiffness can be explained by increased aging cholesterol content in cell membranes and the related increase of virus entry in cells.
Figure 2
Figure 2
Increase of ECM stiffness results in increased COVID-19 severity. Curcumin decreases arterial stiffness and COVID-19 severity due to decrease of inflammation, cytokine storm, blood coagulation, and platelet activation.
Figure 3
Figure 3
The transcription factor NF-κB has links to thrombotic processes and inflammation.
See this image and copyright information in PMC

References

    1. Wang H., Paulson K.R., Pease S.A., Watson S., Comfort H., Zheng P., Aravkin A.Y., Bisignano C., Barber R.M., Alam T., et al. Estimating excess mortality due to the COVID-19 pandemic: A systematic analysis of COVID-19-related mortality, 2020–2021. Lancet. 2022;399:1513–1536. doi: 10.1016/S0140-6736(21)02796-3. - DOI - PMC - PubMed
    1. Tong M., Jiang Y., Xia D., Xiong Y., Zheng Q., Chen F., Zou L., Xiao W., Zhu Y. Elevated Expression of Serum Endothelial Cell Adhesion Molecules in COVID-19 Patients. J. Infect. Dis. 2020;222:894–898. doi: 10.1093/infdis/jiaa349. - DOI - PMC - PubMed
    1. Kerch G. Tissue Integrity and COVID-19. Encyclopedia. 2021;1:20. doi: 10.3390/encyclopedia1010020. - DOI
    1. Szeghy R.E., Stute N.L., Province V.M., Augenreich M.A., Stickford J.L., Stickford A.S.L., Ratchford S.M. Six-month longitudinal tracking of arterial stiffness and blood pressure in young adults following SARS-CoV-2 infection. J. Appl. Physiol. 2022;132:1297–1309. doi: 10.1152/japplphysiol.00793.2021. - DOI - PMC - PubMed
    1. Kumar S., Singh V., Kumar A., Kumar A., Singh P.K., Bhushan D., Kumar N., Kumar A. The COSEVAST Study Outcome: Evidence of COVID-19 Severity Proportionate to Surge in Arterial Stiffness. Indian J. Crit. Care Med. 2021;25:1113–1119. doi: 10.5005/jp-journals-10071-24000. - DOI - PMC - PubMed

MeSH terms