The DOI matches its Crossref record; 130 of the 140 references it cites were found in a registry or an index.
COVID-19 cytokine storm: The anger of inflammation
Open accessAbstract
Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.
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“Among them, IL-6 is a major player in chronic inflammatory diseases, autoimmune diseases, cancer and cytokine storm (1, 3, 10–26).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Therefore, SARS-CoV-1 and SARS-CoV-2 infection activate both NF-κB and STAT3, key elements of the IL-6 Amp, to cause cytokine storm (12, 13, 15, 349, 350).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [13]
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“ARDS in COVID-19 is considered the result of cytokine storm (12–17), resembling the disease caused by SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) (335).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [13]
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“Consistent with the notion that severe COVID-19 is a cytokine storm syndrome (12–17, 336), the severity of COVID-19 is associated with an increased level of inflammatory cytokines, such as IL-6, granulocyte macrophage colony-stimulating factor (GM-CSF) and TNFα (333, 337).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [13]
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Cites
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30183-5 · Cited by 48,884
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“An increment of the highly pro-inflammatory CCR6+ Th17 in CD4 T cells was reported in COVID-19 associated with ARDS [9].”
InfluentialStructure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor
Lan, J., Ge, J., Yu, J., Shan, S., Zhou, H., Fan, S., Zhang, Q., Shi, X., Wang, Q., Zhang, L., et al. (2020) · Nature · doi:10.1038/s41586-020-2180-5 · Cited by 5,983 · cited 3×
“These severe cases that develop respiratory failure show a series of pathological findings such as hyaline membrane formation, inflammatory infiltration with multinucleated syncytial cells in their lung pathology and a burst of cytokine release leading to morbidity and mortality [6,12].”
Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study
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Angiotensin-converting enzyme 2 protects from severe acute lung failure
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“The protective effect of ACE2 in severe acute lung failure has been shown in animal models [40].”
Ziegler, C. G. K., Allon, S. J., Nyquist, S. K., Mbano, I. M., Miao, V. N., Tzouanas, C. N., Cao, Y., Yousif, A. S., Bals, J., Hauser, B. M., et al. (2020) · Cell · doi:10.1016/j.cell.2020.04.035 · Cited by 2,284 · cited 2×
“ACE2 enzyme is expressed in the heart, kidneys, testes, gastrointestinal tract and lungs [15,31].”
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Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19
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Cited by
Sorted by citations
IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453
“Therefore, SARS-CoV-1 and SARS-CoV-2 infection activate both NF-κ B and STAT3, key elements of the IL-6 Amp, to cause cytokine storm (12, 13, 15, 349, 350).”
BackgroundHow COVID-19 induces cytokine storm with high mortality
Hojyo, S., Uchida, M., Tanaka, K., Hasebe, R., Tanaka, Y., Murakami, M., & Hirano, T. (2020) · Inflammation and Regeneration · doi:10.1186/s41232-020-00146-3 · Cited by 663
Rouzé, A., Martín‐Loeches, I., Póvoa, P. M. S. R., Makris, D. A., Artigas, A., Bouchereau, M., Lambiotte, F., Metzelard, M., Cuchet, P., Geronimi, C. B., et al. (2021) · Intensive Care Medicine · doi:10.1007/s00134-020-06323-9 · Cited by 388
Systemic racism, chronic health inequities, and COVID ‐19: A syndemic in the making?
Gravlee, C. C. (2020) · American Journal of Human Biology · doi:10.1002/ajhb.23482 · Cited by 390
Najjar, S., Najjar, A., Chong, D. J., Pramanik, B. K., Kirsch, C., Kuzniecky, R., Pacia, S. V., & Azhar, S. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01896-0 · Cited by 292
Metadata
- Authors
- Mahmudpour, M., Roozbeh, J., Keshavarz, M., Farrokhi, S., & Nabipour, I.
- Affiliations
- Bushehr University of Medical Sciences (IR)
- Shiraz University of Medical Sciences (IR)
- Iranian Academy of Medical Sciences (IR)
- Corresponding author
- Nabipour, Iraj
- Venue
- Cytokine
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 133
- Pages
- 155151
- ISSN
- 1043-4666 (ISSN-L)
- PMC
- PMC7260598
- OpenAlex
- W3030136428
- Cited by
- 461
- References
- 140
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 47 · 2023: 61 · 2022: 104 · 2021: 168 · 2020: 52
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cytokine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bushehr University of Medical Sciences
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- COVID-19 pandemic, cytokine storm, SARS-CoV-2, hyperinflammation, ACE2, renin-angiotensin-aldosterone system, Mas receptor, bradykinin B1 receptor, complement system, C5a, membrane attack complex, acute respiratory distress syndrome, intensive care unit patients, treatment options
- MeSH terms
- Betacoronavirus, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Proto-Oncogene Mas, Bradykinin, Humans, Inflammation, Peptidyl-Dipeptidase A, Models, Molecular, Pneumonia, Viral, Proto-Oncogene Proteins, Renin-Angiotensin System, Complement C5a, Cytokines, Coronavirus Infections, Receptors, G-Protein-Coupled, Complement C5b, Pandemics, Spike Glycoprotein, Coronavirus
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