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Novel therapeutic targets for SARS-CoV-2-induced acute lung injury: Targeting a potential IL-1β/neutrophil extracellular traps feedback loop.
Med Hypotheses. 2020 Oct; 143:109906.MH

Abstract

Most COVID-19 infected individuals present with mild flu-like symptoms; however, 5-10% of cases suffer from life-threatening pneumonia and respiratory failure. The pathogenesis of SARS-CoV-2 and its pathology of associated acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis, coagulopathy and multiorgan failure is not known. SARS-CoV-2 is an envelope virus with S (spike), M (membrane), N (nucleocapsid) and E (envelop) proteins. In a closely related coronavirus (SARS-CoV), the transmembrane E protein exerts an important role in membrane-ionic transport through viroporins, deletion of which reduced levels of IL-1β and a remarkably reduced lung edema compared to wild type. IL-1β is generated by macrophages upon activation of intracellular NLRP3 (NOD-like, leucine rich repeat domains, and pyrin domain-containing protein 3), part of the functional NLRP3 inflammasome complex that detects pathogenic microorganisms and stressors, while neutrophils are enhanced by increasing levels of IL-1β. Expiring neutrophils undergo "NETosis", producing thread-like extracellular structures termed neutrophil extracellular traps (NETs), which protect against mild infections and microbes. However, uncontrolled NET production can cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), coagulopathy, multiple organ failure, and autoimmune disease. Herein, we present arguments underlying our hypothesis that IL-1β and NETs, mediated via NLRP3 inflammasomes, form a feed-forward loop leading to the excessive alveolar and endothelial damage observed in severe cases of COVID-19. Considering such assertions, we propose potential drug candidates that could be used to alleviate such pathologies. Considering that recent efforts to ascertain effective treatments of COVID-19 in severe patients has been less than successful, investigating novel avenues of treating this virus are essential.

Authors+Show Affiliations

College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. Electronic address: ayaqinuddin@alfaisal.edu.College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Department of Comparative Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32505910

Citation

Yaqinuddin, Ahmed, and Junaid Kashir. "Novel Therapeutic Targets for SARS-CoV-2-induced Acute Lung Injury: Targeting a Potential IL-1β/neutrophil Extracellular Traps Feedback Loop." Medical Hypotheses, vol. 143, 2020, p. 109906.
Yaqinuddin A, Kashir J. Novel therapeutic targets for SARS-CoV-2-induced acute lung injury: Targeting a potential IL-1β/neutrophil extracellular traps feedback loop. Med Hypotheses. 2020;143:109906.
Yaqinuddin, A., & Kashir, J. (2020). Novel therapeutic targets for SARS-CoV-2-induced acute lung injury: Targeting a potential IL-1β/neutrophil extracellular traps feedback loop. Medical Hypotheses, 143, 109906. https://doi.org/10.1016/j.mehy.2020.109906
Yaqinuddin A, Kashir J. Novel Therapeutic Targets for SARS-CoV-2-induced Acute Lung Injury: Targeting a Potential IL-1β/neutrophil Extracellular Traps Feedback Loop. Med Hypotheses. 2020;143:109906. PubMed PMID: 32505910.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel therapeutic targets for SARS-CoV-2-induced acute lung injury: Targeting a potential IL-1β/neutrophil extracellular traps feedback loop. AU - Yaqinuddin,Ahmed, AU - Kashir,Junaid, Y1 - 2020/05/30/ PY - 2020/04/27/received PY - 2020/05/17/revised PY - 2020/05/28/accepted PY - 2020/6/9/pubmed PY - 2020/10/21/medline PY - 2020/6/8/entrez KW - COVID19 KW - Coronavirus KW - Inflammasomes KW - Neutrophil extracellular traps (NETs) KW - SARS SP - 109906 EP - 109906 JF - Medical hypotheses JO - Med Hypotheses VL - 143 N2 - Most COVID-19 infected individuals present with mild flu-like symptoms; however, 5-10% of cases suffer from life-threatening pneumonia and respiratory failure. The pathogenesis of SARS-CoV-2 and its pathology of associated acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis, coagulopathy and multiorgan failure is not known. SARS-CoV-2 is an envelope virus with S (spike), M (membrane), N (nucleocapsid) and E (envelop) proteins. In a closely related coronavirus (SARS-CoV), the transmembrane E protein exerts an important role in membrane-ionic transport through viroporins, deletion of which reduced levels of IL-1β and a remarkably reduced lung edema compared to wild type. IL-1β is generated by macrophages upon activation of intracellular NLRP3 (NOD-like, leucine rich repeat domains, and pyrin domain-containing protein 3), part of the functional NLRP3 inflammasome complex that detects pathogenic microorganisms and stressors, while neutrophils are enhanced by increasing levels of IL-1β. Expiring neutrophils undergo "NETosis", producing thread-like extracellular structures termed neutrophil extracellular traps (NETs), which protect against mild infections and microbes. However, uncontrolled NET production can cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), coagulopathy, multiple organ failure, and autoimmune disease. Herein, we present arguments underlying our hypothesis that IL-1β and NETs, mediated via NLRP3 inflammasomes, form a feed-forward loop leading to the excessive alveolar and endothelial damage observed in severe cases of COVID-19. Considering such assertions, we propose potential drug candidates that could be used to alleviate such pathologies. Considering that recent efforts to ascertain effective treatments of COVID-19 in severe patients has been less than successful, investigating novel avenues of treating this virus are essential. SN - 1532-2777 UR - https://www.unboundmedicine.com/medline/citation/32505910/Novel_therapeutic_targets_for_SARS_CoV_2_induced_acute_lung_injury:_Targeting_a_potential_IL_1β/neutrophil_extracellular_traps_feedback_loop_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-9877(20)31021-5 DB - PRIME DP - Unbound Medicine ER -