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2 results on '"Mac-1, macrophage-1 antigen"'

1. Cathelicidin promotes liver repair after acetaminophen-induced liver injury in mice.

Author

Zhai T, Zhang J, Zhang J, Liu B, Zhou Z, Liu F, and Wu Y

Abstract

Background & Aims: Acetaminophen (APAP)-induced acute liver injury (AILI) is a leading cause of acute liver failure (ALF). N -acetylcysteine (NAC) is only effective within 24 h after APAP intoxication, raising an urgent need for alternative approaches to treat this disease. This study aimed to test whether cathelicidin ( Camp ), which is a protective factor in chronic liver diseases, protects mice against APAP-induced liver injury and ALF., Methods: A clinically relevant AILI model and an APAP-induced ALF model were generated in mice. Genetic and pharmacological approaches were used to interfere with the levels of cathelicidin in vivo ., Results: An increase in hepatic pro-CRAMP/CRAMP (the precursor and mature forms of mouse cathelicidin) was observed in APAP-intoxicated mice. Upregulated cathelicidin was derived from liver-infiltrating neutrophils. Compared with wild-type littermates, Camp knockout had no effect on hepatic injury but dampened hepatic repair in AILI and reduced survival in APAP-induced ALF. CRAMP administration reversed impaired liver recovery observed in APAP-challenged Camp knockout mice. Delayed CRAMP, CRAMP(1-39) (the extended form of CRAMP), or LL-37 (the mature form of human cathelicidin) treatment exhibited a therapeutic benefit for AILI. Co-treatment of cathelicidin and NAC in AILI displayed a stronger hepatoprotective effect than NAC alone. A similar additive effect of CRAMP(1-39)/LL-37 and NAC was observed in APAP-induced ALF. The pro-reparative role of cathelicidin in the APAP-damaged liver was attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced neutrophil phagocytosis of necrotic cell debris in an autocrine manner., Conclusions: Cathelicidin reduces APAP-induced liver injury and ALF in mice by promoting liver recovery via facilitating inflammation resolution, suggesting a therapeutic potential for late-presenting patients with AILI with or without ALF., Impact and Implications: Acetaminophen-induced acute liver injury is a leading cause of acute liver failure. The efficacy of N -acetylcysteine, the only clinically approved drug against acetaminophen-induced acute liver injury, is significantly reduced for late-presenting patients. We found that cathelicidin exhibits a great therapeutic potential in mice with acetaminophen-induced liver injury or acute liver failure, which makes up for the limitation of N -acetylcysteine therapy by specifically promoting liver repair after acetaminophen intoxication. The pro-reparative role of cathelicidin, as a key effector molecule of neutrophils, in the APAP-injured liver is attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced phagocytic function of neutrophils in an autocrine manner., Competing Interests: The authors declare that they have no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Published
2023
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2. The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach

Author

Lisa Olive, Eugene Athan, André F. Carvalho, Michael Maes, Michael Berk, Ken Walder, Adrienne O'Neil, Wolfgang Marx, Chiara C. Bortolasci, Gerwyn Morris, and Basant K. Puri

Subjects
SIRS, systemic inflammatory response syndrome, NAC, N-acetylcysteine, PSGL-1, P-selectin glycoprotein ligand-1, COX1, cyclooxygenase 1, 0302 clinical medicine, Medicine, CFR, case fatality rates, Thrombophilia, DIC, disseminated intravascular coagulation, General Pharmacology, Toxicology and Pharmaceutics, LPS, Lipopolysaccharide, Pyroptosis, General Medicine, MCP-1, monocyte chemoattractant protein-1, 3. Good health, CXCL10, C-X-C motif chemokine 10, DAMPS, damage-associated molecular patterns, NK, natural killer, NETs, neutrophil extracellular traps, Pneumonia, Viral, MMP-9, Matrix metallopeptidase 9, AP, activated platelets, Article, General Biochemistry, Genetics and Molecular Biology, Proinflammatory cytokine, RAGE, receptor for advanced glycation endproducts, MERS, middle east respiratory syndrome, 03 medical and health sciences, Betacoronavirus, Macrophages, Alveolar, Humans, Platelet activation, PFA, polyenoic fatty acids, T reg, regulatory T cell, AM, alveolar macrophages, ARDS, acute respiratory distress syndrome, BALF, bronchoalveolar lavage fluids, NO, nitric oxide, EC, endothelial cell, SARS-CoV-2, severe acute respiratory syndrome CoronaVirus 2, NOS2, inducible nitric oxide synthase 2, Macrophage Activation, medicine.disease, URT, upper respiratory tract, NLRs, NOD-like receptors, Immunity, Innate, IL, interleukin, 030104 developmental biology, Immunology, PF4, platelet factor 4, TF, tissue factor, VAP, ventilator associated pneumonia, RSV, respiratory syncytial virus, 0301 basic medicine, TMPRSS2, transmembrane protease, serine 2, MPO, myeloperoxidase, PGE2, Prostaglandin E2, 030226 pharmacology & pharmacy, Neutrophil Activation, ACE, angiotensin converting enzyme, AZM, azithromycin, MAC-1, macrophage-1 antigen, Respiratory infection, NF-kB, Nuclear Factor kappa-light-chain-enhancer of activated B cells, MAPKs, mitogen-activated protein kinases, TGF, transforming growth factor, TNF, tumor necrosis factor, Respiratory Distress Syndrome, PNC, platelet neutrophil complexes, Zn, zinc, PICs, proinflammatory cytokines, medicine.symptom, WHO, World Health Organisation, Coronavirus Infections, PI3K, phosphoinositide 3-kinase, HMG-1, high-mobility group protein 1, Inflammation, Mg, magnesium, RdRp, RNA dependent RNA polymerase, ROS, reactive oxygen species, RCT, randomised controlled trial, Animals, Efferocytosis, Pandemics, TLR, Toll-like receptor 9, business.industry, SARS-CoV-2, HMBG1, high mobility group box 1, COVID-19, Neutrophil extracellular traps, HAART, highly active antiretroviral therapy, Platelet Activation, MDSC, CD11b + Gr-1+ myeloid-derived suppressor cells, Treatment, Alveolar Epithelial Cells, Alveolar macrophage, GM-CSF, Granulocyte-macrophage colony-stimulating factor, business, Cytokine storm
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., Graphical abstract Unlabelled Image

Published
2020
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