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Crosstalk between neutrophil extracellular traps and immune regulation: insights into pathobiology and therapeutic implications of transfusion-related acute lung injury

Liu et al., Frontiers in Immunology, doi:10.3389/fimmu.2023.1324021
Dec 2023  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
*, now known with p < 0.00000000001 from 100 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
Ivermectin may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation.
Authors review the role of neutrophil extracellular traps (NETs) in transfusion-related acute lung injury (TRALI). Authors discusses the mechanisms of NET formation, including vital NETosis and NETosis involving cell death. They examine the evidence showing that NETs contribute to endothelial and lung epithelial damage in TRALI. Authors explore the interactions of NETs with other immune cells like macrophages, dendritic cells, and T cells, which create inflammatory feedback loops that exacerbate tissue injury. Authors suggest potential therapeutic approaches targeting NET formation, NET clearance, cytokine signaling, and glucose metabolism pathways to dampen detrimental inflammation in TRALI.
Authors note that ivermectin was shown to inhibit GSDMD oligomerization, alleviating the release of NETs, and that increased NET formation was observed in ARDS induced by COVID-19.
This suggests that ivermectin may be beneficial for COVID-19 ARDS by inhibiting NET formation. Specifically: ivermectin can inhibit GSDMD oligomerization, which the authors note plays an important role in NET release. By blocking GSDMD, ivermectin may suppress detrimental NETosis. Authors state that in COVID-19 ARDS, there is downregulation of respiratory bursts but increased NET formation. So while ROS production from neutrophils may be impaired, excessive NETs are still an issue driving lung damage. By alleviating NET release through GSDMD inhibition, ivermectin could therefore target one of the key pathological pathways - NETosis - that is overactivated in COVID-19 ARDS.
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7 Götz, Dengue Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, Yang, West Nile Yang, Yellow Fever Mastrangelo, Varghese, Japanese encephalitis Mastrangelo, Chikungunya Varghese, Semliki Forest virus Varghese, Human papillomavirus Li, Epstein-Barr Li, BK Polyomavirus Bennett, and Sindbis virus Varghese.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins Götz, Kosyna, Wagstaff, Wagstaff (B), inhibits SARS-CoV-2 3CLpro Mody, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing Fauquet, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination Boschi, Scheim, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation Liu (C), shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-19 DiNicolantonio, Zhang, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage Zhao, may minimize SARS-CoV-2 induced cardiac damage Liu, Liu (B), increases Bifidobacterium which plays a key role in the immune system Hazan, has immunomodulatory Munson and anti-inflammatory DiNicolantonio (B), Yan properties, and has an extensive and very positive safety profile Descotes.
Liu et al., 7 Dec 2023, peer-reviewed, 9 authors.
This PaperIvermectinAll
Crosstalk between neutrophil extracellular traps and immune regulation: insights into pathobiology and therapeutic implications of transfusion-related acute lung injury
Yi Liu, Rong Wang, Congkuan Song, Song Ding, Yifan Zuo, Ke Yi, Ning Li, Bo Wang, Qing Geng
Frontiers in Immunology, doi:10.3389/fimmu.2023.1324021
Transfusion-related acute lung injury (TRALI) is the leading cause of transfusionassociated death, occurring during or within 6 hours after transfusion. Reports indicate that TRALI can be categorized as having or lacking acute respiratory distress syndrome (ARDS) risk factors. There are two types of TRALI in terms of its pathogenesis: antibody-mediated and non-antibody-mediated. The key initiation steps involve the priming and activation of neutrophils, with neutrophil extracellular traps (NETs) being established as effector molecules formed by activated neutrophils in response to various stimuli. These NETs contribute to the production and release of reactive oxygen species (ROS) and participate in the destruction of pulmonary vascular endothelial cells. The significant role of NETs in TRALI is well recognized, offering a potential pathway for TRALI treatment. Moreover, platelets, macrophages, endothelial cells, and complements have been identified as promoters of NET formation. Concurrently, studies have demonstrated that the storage of platelets and concentrated red blood cells (RBC) can induce TRALI through bioactive lipids. In this article, recent clinical and pre-clinical studies on the pathophysiology and pathogenesis of TRALI are reviewed to further illuminate the mechanism through which NETs induce TRALI. This review aims to propose new therapeutic strategies for TRALI, with the hope of effectively improving its poor prognosis.
Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Appendix The proteins/genes described in this review.
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