Therapeutic Myeloperoxidase Inhibition Attenuates Neutrophil Activation, ANCA-Mediated Endothelial Damage, and Crescentic GN

Antonelou, Marilina; Michaëlsson, Erik; Evans, Rhys; Wang, Chun Jing; Henderson, Scott; Walker, Lucy S. K.; Unwin, Robert J.; Salama, Alan D.; Investigators, Rave-Itn

doi:10.1681/asn.2019060618

Cited by 51 publications

(47 citation statements)

References 47 publications

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“…Elastase is produced by neutrophils and can mediate lung injury. Inhibitors of MPO and elastase can directly reduce acute lung injury at inflammatory sites ( 23 , 35 , 36 ). The MAPK-p38 signaling pathway plays an essential role in the production of pro-inflammatory cytokines, inhibition of p38 shows promising in COVID-19 therapy ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Cytokine Signature Induced by SARS-CoV-2 Spike Protein in a Mouse Model

Zhao

Jin

et al. 2021

Front. Immunol.

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Although COVID-19 has become a major challenge to global health, there are currently no efficacious agents for effective treatment. Cytokine storm syndrome (CSS) can lead to acute respiratory distress syndrome (ARDS), which contributes to most COVID-19 mortalities. Research points to interleukin 6 (IL-6) as a crucial signature of the cytokine storm, and the clinical use of the IL-6 inhibitor tocilizumab shows potential for treatment of COVID-19 patient. In this study, we challenged wild-type and adenovirus-5/human angiotensin-converting enzyme 2-expressing BALB/c mice with a combination of polyinosinic-polycytidylic acid and recombinant SARS-CoV-2 spike-extracellular domain protein. High levels of TNF-α and nearly 100 times increased IL-6 were detected at 6 h, but disappeared by 24 h in bronchoalveolar lavage fluid (BALF) following immunostimulant challenge. Lung injury observed by histopathologic changes and magnetic resonance imaging at 24 h indicated that increased TNF-α and IL-6 may initiate CSS in the lung, resulting in the continual production of inflammatory cytokines. We hypothesize that TNF-α and IL-6 may contribute to the occurrence of CSS in COVID-19. We also investigated multiple monoclonal antibodies (mAbs) and inhibitors for neutralizing the pro-inflammatory phenotype of COVID-19: mAbs against IL-1α, IL-6, TNF-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF), and inhibitors of p38 and JAK partially relieved CSS; mAbs against IL-6, TNF-α, and GM-CSF, and inhibitors of p38, extracellular signal-regulated kinase, and myeloperoxidase somewhat reduced neutrophilic alveolitis in the lung. This novel murine model opens a biologically safe, time-saving avenue for clarifying the mechanism of CSS/ARDS in COVID-19 and developing new therapeutic drugs.

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Section: Discussionmentioning

confidence: 99%

Cytokine Signature Induced by SARS-CoV-2 Spike Protein in a Mouse Model

Zhao

Jin

et al. 2021

Front. Immunol.

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“…Thus, the binding of ANCA to endothelial cells has the potential to cause endothelial injury, which might activate the coagulation cascade. In another experiment, in vitro exposure of HUVEC to neutrophils primed by anti-proteinase 3 antibodies and TNF induced endothelial injury and cell death, which was ameliorated by inhibition of myeloperoxidase [ 40 ]. These studies indicate the potential for endothelial injury in patients with AAV, both due to ANCA and other circulating antibodies such as AECA, which might be the first step triggering thrombogenesis in these individuals.…”

Section: Endothelial Cell Injury and Triggering Of Coagulation Cascade In Aavmentioning

confidence: 99%

Mechanisms of thrombosis in ANCA-associated vasculitis

et al. 2021

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Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have a two- to threefold greater risk of developing venous as well as arterial thrombotic events. Although such thrombotic events are more commonly seen during phases of active AAV, they are also recognized to occur during AAV in remission. Endothelial injury is a key pathogenic event in AAV. Endothelial injury can be caused by neutrophil activation and release of thrombogenic tissue factor into the circulation. Neutrophil activation further results in the formation of neutrophil extracellular traps (NETs). NETs contribute to thrombosis by expressing tissue factor. NETs have also been detected in cutaneous thrombi from patients with AAV induced by hydralazine. Activated neutrophils in AAV patients release thrombogenic microparticles loaded with tissue factor which further enhances clotting of blood. Antiphospholipid antibodies (APLs) have been detected in up to a third of AAV and might also be induced by drugs such as cocaine adulterated with levamisole and propylthiouracil, which are known to trigger AAV. Such APLs further drive the thrombosis in AAV. Once thrombogenesis occurs, the homeostatic mechanisms resulting in clot dissolution are further impaired in AAV due to anti-plasminogen antibodies. The ongoing pandemic of coronavirus disease 2019 (COVID-19) is associated with endothelial injury and NETosis, mechanisms which are in common with AAV. Reports of new-onset AAV following COVID-19 have been described in the literature, and there could be shared mechanisms driving these processes that require further evaluation.

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“…This may reflect the known genetic contribution to disease susceptibility and epigenetic factors of disease activity, with reduced DNA methylation of MPO and PRTN3 resulting in increased autoantigen expression and disease activity 50 – 52 . Alternatively, recognising the role of nuclear extracellular traps (NETs) in disease pathogenesis, this this finding may simply reflect increased free cell DNA as a result of NET remnants and apoptotic cells 53 – 56 . Protein groups at the Amide I (1662 cm −1 ) and Amide II (1481 cm −1 ) bands were associated with disease remission.…”

Section: Discussionmentioning

confidence: 99%

Distinguishing active from quiescent disease in ANCA-associated vasculitis using attenuated total reflection Fourier-transform infrared spectroscopy

Morris

Morais

Lima

et al. 2021

Sci Rep

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The current lack of a reliable biomarker of disease activity in anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis poses a significant clinical unmet need when determining relapsing or persisting disease. In this study, we demonstrate for the first time that attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy offers a novel and functional candidate biomarker, distinguishing active from quiescent disease with a high degree of accuracy. Paired blood and urine samples were collected within a single UK centre from patients with active disease, disease remission, disease controls and healthy controls. Three key biofluids were evaluated; plasma, serum and urine, with subsequent chemometric analysis and blind predictive model validation. Spectrochemical interrogation proved plasma to be the most conducive biofluid, with excellent separation between the two categories on PC2 direction (AUC 0.901) and 100% sensitivity (F-score 92.3%) for disease remission and 85.7% specificity (F-score 92.3%) for active disease on blind predictive modelling. This was independent of organ system involvement and current ANCA status, with similar findings observed on comparative analysis following successful remission-induction therapy (AUC > 0.9, 100% sensitivity for disease remission, F-score 75%). This promising technique is clinically translatable and warrants future larger study with longitudinal data, potentially aiding earlier intervention and individualisation of treatment.

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Therapeutic Myeloperoxidase Inhibition Attenuates Neutrophil Activation, ANCA-Mediated Endothelial Damage, and Crescentic GN

Cited by 51 publications

References 47 publications

Cytokine Signature Induced by SARS-CoV-2 Spike Protein in a Mouse Model

Cytokine Signature Induced by SARS-CoV-2 Spike Protein in a Mouse Model

Mechanisms of thrombosis in ANCA-associated vasculitis

Distinguishing active from quiescent disease in ANCA-associated vasculitis using attenuated total reflection Fourier-transform infrared spectroscopy

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