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The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach.
Life Sci. 2020 Oct 01; 258:118166.LS

Abstract

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed.

Authors+Show Affiliations

Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia.Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Deakin University, Centre for Molecular and Medical Research, School of Medicine, Geelong, Australia. Electronic address: chiara.b@deakin.edu.au.C.A.R., Cambridge, UK.Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; School of Psychology, Deakin University, Geelong, Australia.Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia.Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Barwon Health, Geelong, Australia.Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, University of Toronto, Toronto, Canada; Centre for Addiction and Mental Health (CAMH), Toronto, Canada.Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, King Chulalongkorn University Hospital, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria.Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Deakin University, Centre for Molecular and Medical Research, School of Medicine, Geelong, Australia.Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

32739471

Citation

Morris, Gerwyn, et al. "The Pathophysiology of SARS-CoV-2: a Suggested Model and Therapeutic Approach." Life Sciences, vol. 258, 2020, p. 118166.
Morris G, Bortolasci CC, Puri BK, et al. The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach. Life Sci. 2020;258:118166.
Morris, G., Bortolasci, C. C., Puri, B. K., Olive, L., Marx, W., O'Neil, A., Athan, E., Carvalho, A. F., Maes, M., Walder, K., & Berk, M. (2020). The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach. Life Sciences, 258, 118166. https://doi.org/10.1016/j.lfs.2020.118166
Morris G, et al. The Pathophysiology of SARS-CoV-2: a Suggested Model and Therapeutic Approach. Life Sci. 2020 Oct 1;258:118166. PubMed PMID: 32739471.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach. AU - Morris,Gerwyn, AU - Bortolasci,Chiara C, AU - Puri,Basant K, AU - Olive,Lisa, AU - Marx,Wolfgang, AU - O'Neil,Adrienne, AU - Athan,Eugene, AU - Carvalho,Andre F, AU - Maes,Michael, AU - Walder,Ken, AU - Berk,Michael, Y1 - 2020/07/31/ PY - 2020/06/18/received PY - 2020/07/23/revised PY - 2020/07/25/accepted PY - 2020/8/3/pubmed PY - 2020/9/30/medline PY - 2020/8/3/entrez KW - COVID-19 KW - Respiratory infection KW - SARS-CoV-2 KW - Treatment SP - 118166 EP - 118166 JF - Life sciences JO - Life Sci VL - 258 N2 - In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed. SN - 1879-0631 UR - https://www.unboundmedicine.com/medline/citation/32739471/The_pathophysiology_of_SARS_CoV_2:_A_suggested_model_and_therapeutic_approach_ DB - PRIME DP - Unbound Medicine ER -