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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IL-6 is a major player in chronic inflammatory diseases, autoimmune diseases, cancer and cytokine storm.
“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]
The ACE/Angiotensin II/AT1R axis section describes IL-6 signaling as part of a mechanism that induces cytokine storm in severe COVID-19. The Introduction also reports higher IL-6 levels in patients who died of COVID-19 than in those who recovered. These passages support the cytokine-storm part of the claim, but the paper does not establish IL-6 as a major player in chronic inflammatory diseases, autoimmune diseases, or cancer. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSARS-CoV-1 and SARS-CoV-2 infection activate both NF-κB and STAT3, key elements of the IL-6 Amp, to cause cytokine storm.
“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]
The ACE/Angiotensin II/AT1R axis section describes SARS-CoV-2 activating NF-κB and STAT3, with their simultaneous activation driving the IL-6 amplifier and cytokine storm. The copy does not extend that mechanism to SARS-CoV-1; its Introduction mentions SARS-CoV in connection with immune responses, not this pathway. Page numbers were not provided. (LLM, conf=0.88)
Experimental — accuracy not yet measuredARDS in COVID-19 is considered the result of cytokine storm, resembling the disease caused by SARS-CoV-1 and Middle East respiratory syndrome coronavirus.
“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]
Severe COVID-19 is a cytokine storm syndrome.
“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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InfluentialBeyond lysis: how complement influences cell fate
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InfluentialThe Role of the Complement System in Virus Infections
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BackgroundHow COVID-19 induces cytokine storm with high mortality
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Flavonoids against the SARS-CoV-2 induced inflammatory storm
Líšková, A., Samec, M., Koklesová, L., Samuel, S. M., Zhai, K., AL-Ishaq, R. K., Abotaleb, M., Nosáľ, V., Kajo, K., Ashrafizadeh, M., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111430 · Cited by 144 · see citing works
“vation can promote proinflammatory responses through AT1R in kidney and vascular system [16].”
InfluentialCytokine storm in COVID-19: from viral infection to immune responses, diagnosis and therapy
Jiang, Y.-Z., Rubin, L., Peng, T., Liu, L., Xing, X., Lazarovici, P., & Zheng, W. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.59272 · Cited by 141 · see citing works
“Moreover, SARS-COV-2 infection could also result in cytokine production by activating complement pathways such as the C3a-C3aR/ C5a-C5aR axis [71].”
BackgroundCurcumin as a Potential Treatment for COVID-19
Rattis, B. A. D. C., Ramos, S. G., & Celes, M. R. N. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.675287 · Cited by 143 · see citing works
“…addressed in this and other reviews, it has been reinforced that curcumin could serve as an adjuvant drug in COVID-19 treatment (Babaei et al., 2020; Manoharan et al., 2020; Roy et al., 2020; Soni et al., 2020; Zahedipour et al., 2020; Saeedi-Boroujeni et al., 2021; Thimmulappa et al., 2021).”
BackgroundAnnasamy, G., Kumar, N. A., & Anand, S. (2021) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2021.116205 · Cited by 129 · see citing works
Liu, B., Martins, T. B., Peterson, L. K., & Hill, H. R. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155478 · Cited by 126 · see citing works
Islam, M. M., & Takeyama, N. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242115805 · Cited by 130 · see citing works
Molecular pathways involved in COVID-19 and potential pathway-based therapeutic targets
Farahani, M., Niknam, Z., Amirabad, L. M., Dashatan, N. A., Koushki, M., Nemati, M., Pouya, F. D., Rezaei–Tavirani, M., Rasmi, Y., & Tayebi, L. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112420 · Cited by 125 · see citing works
“Also, AT1R-mediated inflammatory response is accompanied by the activation of the complement system, MAPK, and NF-kB in the lungs lead to a cytokine storm, followed by ARDS, which has been detected in COVID-19 patients with severe conditions [33,34].”
Morais, A. H. D. A., Aquino, J. D. S., da Silva-Maia, J. K., Vale, S. H. D. L., Maciel, B. L. L., & Passos, T. S. (2020) · British Journal Of Nutrition · doi:10.1017/s0007114520003311 · Cited by 123 · see citing works
Muñoz, F. M., Cramer, J. P., Dekker, C. L., Dudley, M. Z., Graham, B. S., Gurwith, M., LAW, B. J., Perlman, S. M., Polack, F. P., Spergel, J. M., et al. (2021) · Vaccine · doi:10.1016/j.vaccine.2021.01.055 · Cited by 115 · see citing works
“ADE has only been convincingly demonstrated in coronavirus infections in cats that were previously seropositive from infection or vaccination and immunized with S protein expressing vectors followed by challenge with feline infectious peritonitis virus [73].”
Haematological manifestations of COVID‐19: From cytopenia to coagulopathy
Agbuduwe, C., & Basu, S. (2020) · European Journal Of Haematology · doi:10.1111/ejh.13491 · Cited by 110 · see citing works
JAK-STAT Pathway: A Novel Target to Tackle Viral Infections
Ezeonwumelu, I. J., García-Vidal, E., & Ballana, E. (2021) · Viruses · doi:10.3390/v13122379 · Cited by 109 · see citing works
Behl, T., Kaur, I., Aleya, L., Sehgal, A., Singh, S., Sharma, N., Bhatia, S., Al‐Harrasi, A., & BUNGAU, S. G. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2021.152072 · Cited by 101 · see citing works
“This condition of hypercytokinemia is uncontrolled release of cytokines, which is observed in cases of infectious and non-infectious disorders, facilitating a hyperinflammatory state in the host organism (Mahmudpour et al., 2020).”
Calming the Storm: Natural Immunosuppressants as Adjuvants to Target the Cytokine Storm in COVID-19
Peter, A. E., Sandeep, B. V., Rao, B. G., & Kalpana, V. L. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.583777 · Cited by 99 · see citing works
“…II following the disruption of the rennin-angiotensin system; caused when S1 subunit of spike protein binds to hACE2 in the alveolar macrophages (Acharya et al., 2020; Fu et al., 2020b; Golonka et al., 2020; Iwasaki et al., 2020; Lee and Shin, 2020; Lee et al., 2020; Mahmudpour et al., 2020).”
BackgroundLiu, Y., Shi, L., Qiu, W., & Shi, Y. (2022) · Molecular & Cellular Toxicology · doi:10.1007/s13273-021-00219-5 · Cited by 108 · see citing works
“Generally speaking, the release of these inflammatory mediators is beneficial to the body, but excessive release of inflammatory mediators is harmful to the body, and is even closely related to a variety of inflammation-related diseases (Back et al. 2019; Mahmudpour et al. 2020).”
BackgroundSignificance of NETs Formation in COVID-19
Janiuk, K., Jabłońska, E., & Garley, M. (2021) · Cells · doi:10.3390/cells10010151 · Cited by 100 · see citing works
Liu, B., & Hill, H. R. (2020) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2020.0210 · Cited by 98 · see citing works
Overview of COVID-19 inflammatory pathogenesis from the therapeutic perspective
Lee, C.-H., & Choi, W. J. (2021) · Archives of Pharmacal Research · doi:10.1007/s12272-020-01301-7 · Cited by 91 · see citing works
“Pathologically, this could lead to increased angioedema, blood coagulation, and complementary pathway stimulation, all of which can further aggravate the proinflammation conditions induced by SARS-CoV-2 infection (Mahmudpour et al. 2020).”
BackgroundAhmad, S., Manzoor, S., Siddiqui, S., Mariappan, N., Zafar, I., Ahmad, A., & Ahmad, A. M. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.01.003 · Cited by 89 · see citing works
“Targeting therapeutics against these cytokine mediators, complement systems as well as ACE2 upregulation can potentially attenuate the injury and reduce mortality [48,49].”
BackgroundVitamin D and COVID‐19: Role of ACE2, age, gender, and ethnicity
Getachew, B., & Tizabi, Y. (2021) · Journal of Medical Virology · doi:10.1002/jmv.27075 · Cited by 88 · see citing works
Rowaiye, A. B., Okpalefe, O. A., Onuh, O. A., Ogidigo, J. O., Oladipo, O. H., Ogu, A. C., Oli, A. N., Olofinsae, S. A., Onyekwere, O., Abubakar, A. R., et al. (2021) · Journal of Inflammation Research · doi:10.2147/jir.s301784 · Cited by 85 · see citing works
Acute Infection of Viral Pathogens and Their Innate Immune Escape
Rai, K. R., Shrestha, P., Yang, B., Chen, Y., Liu, S., Maarouf, M., & Chen, J. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.672026 · Cited by 87 · see citing works
Cytokine storm induced by SARS-CoV-2 infection: The spectrum of its neurological manifestations
Thepmankorn, P., Bach, J. R., Lasfar, A., Zhao, X., Souayah, S., Chong, Z. Z., & Souayah, N. (2020) · Cytokine · doi:10.1016/j.cyto.2020.155404 · Cited by 86 · see citing works
Oxidative Stress‐Related Mechanisms in SARS‐CoV‐2 Infections
Wieczfińska, J., Kleniewska, P., & Pawliczak, R. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/5589089 · Cited by 86 · see citing works
“Importantly, “ cytokine storm ” may occur, responsible for lung tissue damage during viral respiratory infections [46, 47].”
Innate lymphoid cell composition associates with COVID‐19 disease severity
García, M., Kokkinou, E., García, A. C., Parrot, T., Medina, L. M. P., Maleki, K. T., Christ, W., Varnaitė, R., Filipovic, I., Ljunggren, H., et al. (2020) · Clinical & Translational Immunology · doi:10.1002/cti2.1224 · Cited by 83 · see citing works
Impact of aging on immunity in the context of COVID-19, HIV, and tuberculosis
Grifoni, A., Alonzi, T., Alter, G., Noonan, D. M., LANDAY, A. L., Albini, A., & Goletti, D. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1146704 · Cited by 87 · see citing works
Modulation of Macrophage Polarization by Viruses: Turning Off/On Host Antiviral Responses
Yu, S., Ge, H., Su, L., & Qiu, H. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.839585 · Cited by 73 · see citing works
Potential Detrimental Role of Soluble ACE2 in Severe COVID-19 Comorbid Patients
Rahman, M., Hasan, M., & Ahmed, A. (2020) · Reviews in Medical Virology · doi:10.1002/rmv.2213 · Cited by 72 · see citing works
Haghpanah, A., Masjedi, F., Alborzi, S., Hosseinpour, A., Dehghani, A., Malekmakan, L., & Roozbeh, J. (2020) · Andrologia · doi:10.1111/and.13883 · Cited by 69 · see citing works
“…overproduction of cytokines which regulate immune response such as IL-6 induced by a viral infection can result in leucocyte infiltration in testis interstitium and consequently cause an autoimmune response and form ASA (Hedger & Meinhardt, 2003; Mahmudpour et al., 2020; Rival et al., 2006).”
BackgroundSelf-citationAugusti, P. R., Conterato, G. M. M., Denardin, C. C., Prazeres, I. D., Serra, T., Bronze, M. R., & Emanuelli, T. (2021) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2021.108787 · Cited by 69 · see citing works
“causes an inflammatory cytokine storm, an out-of-control cytokine release, leading to a hyperinflammatory condition in the host [96] .”
Rahman, M. A., Shanjana, Y., Tushar, M. I., Mahmud, T., Rahman, G. M. S., Milan, Z. H., Sultana, T., Chowdhury, A. M. L. H., Bhuiyan, M. A., Islam, M. R., et al. (2021) · PLoS ONE · doi:10.1371/journal.pone.0255379 · Cited by 71 · see citing works
“It is well established that cytokine storm causes to increase several inflammatory biomarker’s levels in SCP [52, 53].”
BackgroundAn update review of emerging small-molecule therapeutic options for COVID-19
Tian, D., Liu, Y., Liang, C., Xin, L., Xie, X., Zhang, D., Wan, M., Li, H., Fu, X., Liu, H., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111313 · Cited by 68 · see citing works
Saravi, B., Li, Z., Lang, C. N., Schmid, B., Lang, F. K., Grad, S., Alini, M., Richards, R. G., Schmal, H., Südkamp, N. P., et al. (2021) · Cells · doi:10.3390/cells10030650 · Cited by 68 · see citing works
Elucidating the Neuropathologic Mechanisms of SARS-CoV-2 Infection
Pacheco‐Herrero, M., Soto-Rojas, L. O., Harrington, C. R., Flores-Martinez, Y. M., Villegas-Rojas, M. M., León-Aguilar, A. M., Martínez-Gómez, P. A., Campa-Córdoba, B. B., Apátiga-Pérez, R., Corniel-Taveras, C. N., et al. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.660087 · Cited by 69 · see citing works
Cooper, S. L., Boyle, E., Jefferson, S. R., Heslop, C., Mohan, P., Mohanraj, G. G. J., Sidow, H. A., Tan, R. C. P., Hill, S. J., & Woolard, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158255 · Cited by 67 · see citing works
“It is possible that in addition to a virus-mediated cytokine storm, dysregulation of the RAAS and KKS by SARS-CoV-2/ACE2 contribute to the hyper-inflammation observed in severe cases of COVID-19 and to the development of CVCs [113].”
BackgroundThe anaphylatoxin C5a: Structure, function, signaling, physiology, disease, and therapeutics
Ghosh, M., & Rana, S. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110081 · Cited by 64 · see citing works
Chang, Y., Bai, M., & You, Q. (2022) · BioMed Research International · doi:10.1155/2022/2755246 · Cited by 63 · see citing works
Activation of TLR4 by viral glycoproteins: A double-edged sword?
Halajian, E. A., LeBlanc, E. V., Gee, K., & Colpitts, C. C. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.1007081 · Cited by 63 · see citing works
“During the COVID-19 pandemic, a common feature of many severe SARS-CoV-2 cases has been an aggressive inflammatory response characterized by the uncontrollable release of high levels of proinflammatory cytokines, increased activation of immune cells, and harmful hyperinflammation (Mahmudpour et al., 2020; Ragab et al.…”
BackgroundFerraro, E., Germanò, M., Mollace, R., Mollace, V., & Malara, N. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/8841911 · Cited by 62 · see citing works
Pazır, Y., Eroğlu, T., Kose, A., Bulut, T. B., Genc, C., & Kadıhasanoğlu, M. (2021) · Andrologia · doi:10.1111/and.14157 · Cited by 62 · see citing works
“In addition, excessive production of proinflammatory cytokines induced by SARSCoV- 2 infection may adversely affect spermatogenesis by increasing autoimmune response and leucocyte infiltration in the testis (Hedger & Meinhardt, 2003; Mahmudpour et al., 2020; Rival et al., 2006; Xu et al., 2006).”
BackgroundBrain Mechanisms of COVID-19-Sleep Disorders
Semyachkina-Glushkovskaya, O. V., Тофик-Кызы, М. А., Telnova, V., Klimova, M., Saranceva, E. I., Ageev, V., Yu, T., Zhu, D. Y., Penzel, T., & Kurths, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136917 · Cited by 62 · see citing works
Mechanisms of COVID-19-induced kidney injury and current pharmacotherapies
Faour, W. H., Choaib, A., Issa, E., Choueiry, F. E., Shbaklo, K., Alhajj, M., Sawaya, R. T., Harhous, Z., Alefishat, E. A., & Nader, M. (2021) · Inflammation Research · doi:10.1007/s00011-021-01520-8 · Cited by 59 · see citing works
Role of ACE2 in pregnancy and potential implications for COVID-19 susceptibility
Cruz, N. A. N., Stoll, D., Casarini, D. E., & Bertagnolli, M. (2021) · Clinical Science · doi:10.1042/cs20210284 · Cited by 64 · see citing works
Applications of Non-invasive Neuromodulation for the Management of Disorders Related to COVID-19
Baptista, A. F., Baltar, A., Okano, A. H., Moreira, A., Campos, A. C. P., Fernandes, A. M., Brunoni, A. R., Badran, B. W., Tanaka, C., de Andrade, D. C., et al. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.573718 · Cited by 59 · see citing works
“Systemic issues such as coagulation disturbances/thrombosis (10, 11) and cytokine storm (12, 13) are also relevant, especially to understand how COVID-19 would be associated with nervous system pathology.”
BackgroundInflammatory and Prothrombotic Biomarkers Associated With the Severity of COVID-19 Infection
Castañeda, S. E. L., García‐Larragoiti, N., Cano‐Méndez, A., Blancas-Ayala, K., Damian-Vázquez, G., Perez-Medina, A. I., Chora-Hernández, L. D., Arean-Martínez, C. A., & Viveros‐Sandoval, M. E. (2021) · Clinical and Applied Thrombosis/Hemostasis · doi:10.1177/1076029621999099 · Cited by 58 · see citing works
Zhou, Y., Shi, X., Fu, W., Xiang, F., He, X., Yang, B., Wang, X., & Ma, W. (2021) · Journal of Inflammation Research · doi:10.2147/jir.s311518 · Cited by 58 · see citing works
A Review on the Neurological Manifestations of COVID-19 Infection: a Mechanistic View
Zangbar, H. S., Gorji, A., & Ghadiri, T. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02149-0 · Cited by 57 · see citing works
Ramos, S. G., Rattis, B. A. D. C., Giulia Ottaviani, M., Celes, M. R. N., & Dias, E. P. (2021) · American Journal Of Pathology · doi:10.1016/j.ajpath.2021.04.010 · Cited by 57 · see citing works
“0 DTD AJPA3566_proof overactivation, and inflammation.(12,15,65) In addition, after AT1R activation, Ang II can activate the NF-kB pathway(66,67) via stimulation of the phosphorylation of the p65 subunit of NF-kB.”
The pivotal link between ACE2 deficiency and SARS-CoV-2 infection: One year later
Angeli, F., Zappa, M., Reboldi, G., Trapasso, M., Cavallini, C., Spanevello, A., & Verdecchia, P. (2021) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2021.09.007 · Cited by 56 · see citing works
“of Ang II develop an abnormal activation of the Ang II/Ang II type 1 receptor (AT1R) component of the RAAS, producing end-organ damage through the activation of pro-inflammatory cascade (also enhanced by the activation of the complement system by pattern recognition receptors [PRRs]), pro-fibrotic cascade, pro-coagula…”
SARS-CoV-2 involvement in central nervous system tissue damage
Sabra, M., Kobeissy, F. H., Bizri, M., Haidar, M. A., Shakkour, Z., Reslan, M. A., Al-Haj, N., Chamoun, P., Habashy, K. J., Kaafarani, H., et al. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.327323 · Cited by 57 · see citing works
“Furthermore, immobilization, which is known to increase the risk of thrombus formation, is another factor that contributes to blood stasis in hospitalized COVID-19 patients (Maier et al., 2020).”
BackgroundInfluentialAltered gut microbial metabolites could mediate the effects of risk factors in Covid‐19
Chen, J., Hall, S., & Vitetta, L. (2021) · Reviews in Medical Virology · doi:10.1002/rmv.2211 · Cited by 55 · see citing works
“Activation of the complements C5a and C5b‐9 is also involved in SARS‐CoV‐2‐caused inflammation.(25) Guo et al.”
BackgroundEndotheliopathy in Acute COVID-19 and Long COVID
Vassiliou, A. G., Vrettou, C. S., Keskinidou, C., Dimopoulou, I., Kotanidou, Α., & Orfanos, S. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098237 · Cited by 55 · see citing works
AlKhafaji, D., Argan, R. A., Albaker, W., Elq, A. A., Al-Hariri, M., AlSaid, A., Alwaheed, A., Alqatari, S. G., Alzaki, A., Alwarthan, S., et al. (2022) · International Journal of General Medicine · doi:10.2147/ijgm.s346169 · Cited by 54 · see citing works
“One of the hallmarks of COVID-19 infection severity is the huge secretion of inflammatory cytokines known as a “cytokine storm”.(43) According to a previous report showing that respiratory illnesses are associated with dysregulated Vit D metabolism, suggesting the possibility of Vit D deficiency as a consequence of pu…”
BackgroundOkagu, I. U., Ezeorba, T. P. C., Aham, E. C., Aguchem, R. N., & Nechi, R. N. (2022) · Food Chemistry Molecular Sciences · doi:10.1016/j.fochms.2022.100078 · Cited by 54 · see citing works
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Dynamic Changes of Lymphocyte Subsets in the Course of COVID-19
Rezaei, M. S., Marjani, M., Mahmoudi, S., Mortaz, E., & Mansouri, D. (2021) · International Archives of Allergy and Immunology · doi:10.1159/000514202 · Cited by 51 · see citing works
Neutrophil Extracellular Traps in Fatal COVID-19-Associated Lung Injury
Obermayer, A., Jakob, L.-M., Haslbauer, J. D., Matter, M. S., Tzankov, A., & Stoiber, W. (2021) · Disease Markers · doi:10.1155/2021/5566826 · Cited by 51 · see citing works
“A copious release of proinflammatory peptides causing a cytokine storm, as seen in COVID-19 [9], has long been regarded as a potent inductor of NETosis (e.”
BackgroundNashiry, M. A., Sumi, S. S., Islam, S., Quinn, J. M. W., & Moni, M. A. (2020) · Briefings in Bioinformatics · doi:10.1093/bib/bbaa426 · Cited by 50 · see citing works
Lordan, R. (2021) · Nutrients · doi:10.3390/nu13030740 · Cited by 50 · see citing works
Autoinflammatory Diseases and Cytokine Storms—Imbalances of Innate and Adaptative Immunity
Marcuzzi, A., Melloni, E., Zauli, G., Romani, A., Secchiero, P., Maximova, N., & Rimondi, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011241 · Cited by 49 · see citing works
Depressive and Neurocognitive Disorders in the Context of the Inflammatory Background of COVID-19
Dąbrowska, E., Galińska-Skok, B., & Waszkiewicz, N. (2021) · Life · doi:10.3390/life11101056 · Cited by 47 · see citing works
A double edged-sword - The Complement System during SARS-CoV-2 infection
Santiesteban-Lores, L. E., Amamura, T. A., da Silva, T. F., Midon, L. M., Carneiro, M. C., Isaac, L., & Bavia, L. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119245 · Cited by 47 · see citing works
Are Nutraceuticals Effective in COVID-19 and Post-COVID Prevention and Treatment?
Catalano, A. A., Iacopetta, D., Ceramella, J., Maio, A. C. D., Basile, G., Giuzio, F., Bonomo, M. G., Aquaro, S., Walsh, T. J., Sinicropi, M. S., et al. (2022) · Foods · doi:10.3390/foods11182884 · Cited by 47 · see citing works
Complement Activation via the Lectin and Alternative Pathway in Patients With Severe COVID-19
Niederreiter, J., Eck, C., Ries, T., Hartmann, A., Märkl, B., Büttner-Herold, M. J., Amann, K., & Daniel, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.835156 · Cited by 47 · see citing works
Gasparello, J., Finotti, A., & Gambari, R. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.110415 · Cited by 46 · see citing works
“In COVID-19 cytokine storm, this perturbation is initiated via attachment of the SARS-CoV-2 spike protein to ACE2 receptor, followed by the ACE/Ang II/AT1R axis activation leading to hyperactivation of NF-κB by IL-6/STATs axis [3].”
IL 33 Correlates With COVID-19 Severity, Radiographic and Clinical Finding
Marković, S. S., Jovanovic, M., Gajović, N., Jurišević, M., Arsenijević, N., Jovanović, M., Jovanovic, M., Mijailović, Ž., Lukić, S., Zornić, N., et al. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.749569 · Cited by 45 · see citing works
Du, H., Hou, X., Yujie, G., Le, C., Yu-Huan, M., Dahui, L., & Luqi, H. (2022) · Animal Models and Experimental Medicine · doi:10.1002/ame2.12224 · Cited by 45 · see citing works
Prognostic bioindicators in severe COVID-19 patients
Bergantini, L., Bargagli, E., d’Alessandro, M., Refini, R. M., Cameli, P., Galasso, L., Scapellato, C., Montagnani, F., Scolletta, S., Franchi, F., et al. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155455 · Cited by 44 · see citing works
“The severe pneumonia-associated respiratory syndrome caused by the new coronavirus shows different clinical phenotypes, varying from mild-moderate to severe and critical with acute respiratory distress syndrome, requiring hospitalization and mechanical ventilation [5,6,44].”
BackgroundRavichandran, R., Surapaneni, K. M., Sukumaran, S. K., Kamaraj, D., Daivasuga, S. S., Ravi, S. O. A. S., Vijayaraghavalu, S., & Kumar, R. K. (2022) · Scientific Reports · doi:10.1038/s41598-022-10370-1 · Cited by 44 · see citing works
Vetrici, M. A., Mokmeli, S., Bohm, A. R., Monici, M., & Sigman, S. A. (2021) · Journal of Inflammation Research · doi:10.2147/jir.s301625 · Cited by 44 · see citing works
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Role of Kinins in Hypertension and Heart Failure
Hamid, S., Rhaleb, I. A., Kassem, K. M., & Rhaleb, N. (2020) · Pharmaceuticals · doi:10.3390/ph13110347 · Cited by 43 · see citing works
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Chomiak, A. A., Tiedemann, R. L., Liu, Y., Kong, X., Cui, Y., Wiseman, A. K., Thurlow, K. E., Cornett, E. M., Topper, M. J., Baylin, S. B., et al. (2024) · Science Advances · doi:10.1126/sciadv.adk4423 · Cited by 42 · see citing works
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“Moreover, Ang (1–7) seems to have anti-inflammatory effects through suppressing the NF-κB pathway and cytokines such as IL-6, tumor necrosis factor (TNF)-α, and IL-8 [41, 42].”
BackgroundSelf-citationCommonalities Between COVID-19 and Radiation Injury
Rios, C. I., Cassatt, D. R., Hollingsworth, B. A., Satyamitra, M. M., Tadesse, Y., Taliaferro, L. P., Winters, T. A., & DiCarlo, A. L. (2020) · Radiation Research · doi:10.1667/rade-20-00188.1 · Cited by 43 · see citing works
The Immunopathological and Histological Landscape of COVID-19-Mediated Lung Injury
Zarrilli, G., Angerilli, V., Businello, G., Sbaraglia, M., Traverso, G., Fortarezza, F., Rizzo, S., Gaspari, M. D., Basso, C., Calabrese, F., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020974 · Cited by 46 · see citing works
Air Pollution and COVID-19: A Possible Dangerous Synergy for Male Fertility
Montano, L., Donato, F., Bianco, P. M., Lettieri, G., Guglielmino, A., Motta, O., Bonapace, I. M., & Piscopo, M. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18136846 · Cited by 41 · see citing works
“One of these, IL-6, induced by Sars-CoV-2, can cause leukocyte infiltration into the testis with disruption of the testis−blood barrier that can lead to an autoimmune response with potential formation of antisperm antibodies (ASA) [80,81].”
BackgroundMahmud, M. S., Hossain, M. S., Ahmed, A. T. M. F., Islam, M. Z., Sarker, M. E., & Islam, M. R. (2021) · Molecules · doi:10.3390/molecules26237216 · Cited by 43 · see citing works
Lumbers, E. R., Head, R. J., Smith, G. R., Delforce, S. J., Jarrott, B., Martin, J. H., & Pringle, K. G. (2022) · Pharmacology Research & Perspectives · doi:10.1002/prp2.917 · Cited by 38 · see citing works
SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets
Li, Y., Duche, A., Sayer, M. R., Roosan, D., Khalafalla, F. G., Ostrom, R. S., Totonchy, J. E., & Roosan, M. R. (2021) · BMC Genomics · doi:10.1186/s12864-021-07433-4 · Cited by 39 · see citing works
Dysregulated Bradykinin: Mystery in the Pathogenesis of COVID-19
Tabassum, A., Iqbal, M. S., Sultan, S., Alhuthali, R. A., Alshubaili, D. I., Sayyam, R. S., Abyad, L. M., Qasem, A. H., & Arbaeen, A. F. (2022) · Mediators of Inflammation · doi:10.1155/2022/7423537 · Cited by 38 · see citing works
“Many complex inflammatory molecular pathways of downregulation of angiotensin-converting enzyme 2 (ACE2) in relation to SARS-CoV-2 have been proposed, like the complement system pathway, dysregulated bradykinin pathway, angiotensin-converting enzyme/angiotensin-II/ angiotensin receptor 1 (ACE2/Ang-II/ATR1), and ACE2/…”
BackgroundKong, L., You, R., Zhang, D., Yuan, Q., Xiang, B., Liang, J., Lin, Q., Ding, C., Liao, M., Chen, L., et al. (2022) · Frontiers in Veterinary Science · doi:10.3389/fvets.2021.824179 · Cited by 38 · see citing works
Zheng, J., Lu, C., Ding, Y., Zhang, J., Tan, F., Liu, J., Yang, G., Wang, Y., Li, Z., Yang, M., et al. (2022) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2022.121719 · Cited by 37 · see citing works
“Coronavirus infectious disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an increasingly prevalent viral contagion at the global scale, causes acute respiratory distress syndrome (ARDS)(Mahmudpour et al., 2020; Mohanty et al., 2021).”
Functional and druggability analysis of the SARS-CoV-2 proteome
Cavasotto, C. N., Sánchez‐Lamas, M., & Maggini, J. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173705 · Cited by 37 · see citing works
Chaves, O. A., Lima, C. R., Rodrigues, N. F., Sacramento, C. Q., de Freitas, C. S., Vázquez, L., Temerozo, J. R., Rocha, M. E. N., Dias, S. D. S. G., Carels, N., et al. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.09.204 · Cited by 37 · see citing works
“Severe cases of COVID-19 have been characterized by developing cytokine storm [35], therefore, the discovery of antivirals that also might inhibit the hyperinflammatory response and/or regulate the immune responses is an interesting strategy to better attenuate illness in patients infected with SARS-CoV-2.”
BackgroundTurrubiates‐Hernández, F. J., Sánchez‐Zuno, G. A., González-Estévez, G., Hernández‐Bello, J., Ojeda, G. M., & Muñóz-Valle, J. F. (2021) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2021.4865 · Cited by 37 · see citing works
Sex-Related Overactivation of NLRP3 Inflammasome Increases Lethality of the Male COVID-19 Patients
Zhang, H., Tang, Y., & Tao, J. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.671363 · Cited by 37 · see citing works
“Both renin-angiotensinaldosterone system (RAAS) and complement cascade are involved in SARS-CoV-2-induced overproduction of inflammatory cytokines (Mahmudpour et al., 2020), and this overproduction is caused by NLRP3 inflammasome (Ratajczak and Kucia, 2020).”
BackgroundHyperbaric oxygen treatment for long coronavirus disease-19: a case report
Bhaiyat, A. M., Sasson, E., Wang, Z., Khairy, S., Ginzarly, M., Qureshi, U., Fikree, M., & Efrati, S. (2022) · Journal of Medical Case Reports · doi:10.1186/s13256-022-03287-w · Cited by 37 · see citing works
Saleki, K., Banazadeh, M., Miri, N. S., & Azadmehr, A. (2021) · Reviews in the Neurosciences · doi:10.1515/revneuro-2021-0047 · Cited by 36 · see citing works
“…G-CSF, TNF, CXCL10, MCP1, and MIP1α (Huang et al. 2020; Yongzhi 2021), highlighting that critical COVID-19 might be implicated as a cytokine release syndrome (CRS), a disease developed through cytokine storm (Hirano and Murakami 2020; Mahmudpour et al. 2020; McGonagle et al. 2020; Yongzhi 2021).”
Background
- 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 · 2018: 2
- 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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