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    The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach

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    Author
    Morris, G; Bortolasci, CC; Puri, BK; Olive, L; Marx, W; O'Neil, A; Athan, E; Carvalho, AF; Maes, M; Walder, K; ...
    Date
    2020-10-01
    Source Title
    Life Sciences
    Publisher
    PERGAMON-ELSEVIER SCIENCE LTD
    University of Melbourne Author/s
    O'Neil, Adrienne; Berk, Michael; WALDER, KENNETH
    Affiliation
    Psychiatry
    Melbourne School of Population and Global Health
    Academic Services and Registrar
    Metadata
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    Document Type
    Journal Article
    Citations
    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, https://doi.org/10.1016/j.lfs.2020.118166.
    Access Status
    Access this item via the Open Access location
    URI
    http://hdl.handle.net/11343/254383
    DOI
    10.1016/j.lfs.2020.118166
    Open Access URL
    https://europepmc.org/articles/PMC7392886?pdf=render
    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.

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