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. Graphical abstract Unlabelled Image
【저자키워드】 COVID-19, Treatment, SARS-CoV-2, SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2, respiratory infection, TMPRSS2, transmembrane protease, serine 2, ARDS, acute respiratory distress syndrome, GM-CSF, granulocyte-macrophage colony-stimulating factor, IL, interleukin, MERS, Middle East respiratory syndrome, ACE, Angiotensin converting enzyme, TNF, Tumor Necrosis Factor, DIC, disseminated intravascular coagulation, NETs, neutrophil extracellular traps, NK, natural killer, NO, Nitric Oxide, TGF, Transforming growth factor, NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells, ROS, reactive oxygen species, AM, alveolar macrophages, WHO, World Health Organisation, MAPKs, mitogen-activated protein kinases, MCP-1, monocyte Chemoattractant Protein-1, PI3K, phosphoinositide 3-kinase, TF, Tissue factor, DAMPs, damage-associated molecular patterns, CXCL10, C-X-C motif chemokine 10, AP, activated platelets, BALF, bronchoalveolar lavage fluids, CFR, case fatality rates, EC, endothelial cell, HMBG1, high mobility group box 1, HMG-1, high-mobility group protein 1, MAC-1, macrophage-1 antigen, MDSC, CD11b + Gr-1+ myeloid-derived suppressor cells, MPO, myeloperoxidase, NLRs, NOD-like receptors, PF4, platelet factor 4, PFA, polyenoic fatty acids, PGE2, Prostaglandin E2, PICs, proinflammatory cytokines, PNC, platelet neutrophil complexes, PSGL-1, P-selectin glycoprotein ligand-1, RAGE, receptor for advanced glycation endproducts, T reg, regulatory T cell, TLR, Toll-like receptor 9, URT, upper respiratory tract, Zn, zinc,