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

LIFE SCIENCES

卷:258

Review

Morris, Gerwyn¹  Bortolasci, Chiara C.^1,2  Puri, Basant K.³  Olive, Lisa^1,4  Marx, Wolfgang¹  O'Neil, Adrienne^1,5  Athan, Eugene^1,6  Carvalho, Andre F.^1,7,12  Maes, Michael^1,8,9  Walder, Ken^1,2  Berk, Michael^1,10,11 

[1] Deakin Univ, Sch Med, IMPACT Inst Mental & Phys Hlth & Clin Translat, Barwon Hlth, Geelong, Vic, Australia

[2] Deakin Univ, Ctr Mol & Med Res, Sch Med, Geelong, Vic, Australia

[3] CAR, Cambridge, England

[4] Deakin Univ, Sch Psychol, Geelong, Vic, Australia

[5] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia

[6] Barwon Hlth, Geelong, Vic, Australia

[7] Univ Toronto, Dept Psychiat, Toronto, ON, Canada

[8] King Chulalongkorn Univ Hosp, Dept Psychiat, Bangkok, Thailand

[9] Med Univ Plovdiv, Dept Psychiat, Plovdiv, Bulgaria

[10] Univ Melbourne, Natl Ctr Excellence Youth Mental Hlth, Ctr Youth Mental Hlth, Florey Inst Neurosci & Mental Hlth,Orygen, Melbourne, Vic, Australia

[11] Univ Melbourne, Dept Psychiat, Melbourne, Vic, Australia

[12] Ctr Addict & Mental Hlth CAMH, Toronto, ON, Canada

关键词: COVID-19;    SARS-CoV-2;    Respiratory infection;    Treatment;   

DOI  :  10.1016/j.lfs.2020.118166

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free