Heparinoid sevuparin inhibits<i>Streptococcus</i>‐induced vascular leak through neutralizing neutrophil‐derived proteins

Rasmuson, Joel; Kenne, Ellinor; Wahlgren, Mats; Soehnlein, Oliver; Lindbom, Lennart

doi:10.1096/fj.201900627r

Cited by 26 publications

(22 citation statements)

References 36 publications

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“…One such heparinoid compound has been successfully tested clinically in phase I/II studies of Plasmodium falciparum malaria disease (Leitgeb et al 2017). This molecule also prevented neutrophil-induced lung plasma leakage in a murine sepsis model (Rasmuson et al 2019). As already mentioned, neutrophil-mediated pathology is of central importance in acute lung injury.…”

Section: Heparin and Heparinoid Compoundsmentioning

confidence: 57%

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

Andersson

Ottestad

Tracey

2020

Mol Med

204

212

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Background: The 2019 novel coronavirus disease (COVID-19) causes for unresolved reasons acute respiratory distress syndrome in vulnerable individuals. There is a need to identify key pathogenic molecules in COVID-19-associated inflammation attainable to target with existing therapeutic compounds. The endogenous damage-associated molecular pattern (DAMP) molecule HMGB1 initiates inflammation via two separate pathways. Disulfide-HMGB1 triggers TLR4 receptors generating pro-inflammatory cytokine release. Extracellular HMGB1, released from dying cells or secreted by activated innate immunity cells, forms complexes with extracellular DNA, RNA and other DAMP or pathogen-associated molecular (DAMP) molecules released after lytic cell death. These complexes are endocytosed via RAGE, constitutively expressed at high levels in the lungs only, and transported to the endolysosomal system, which is disrupted by HMGB1 at high concentrations. Danger molecules thus get access to cytosolic proinflammatory receptors instigating inflammasome activation. It is conceivable that extracellular SARS-CoV-2 RNA may reach the cellular cytosol via HMGB1-assisted transfer combined with lysosome leakage. Extracellular HMGB1 generally exists in vivo bound to other molecules, including PAMPs and DAMPs. It is plausible that these complexes are specifically removed in the lungs revealed by a 40% reduction of HMGB1 plasma levels in arterial versus venous blood. Abundant pulmonary RAGE expression enables endocytosis of danger molecules to be destroyed in the lysosomes at physiological HMGB1 levels, but causing detrimental inflammasome activation at high levels. Stress induces apoptosis in pulmonary endothelial cells from females but necrosis in cells from males.Conclusion: Based on these observations we propose extracellular HMGB1 to be considered as a therapeutic target for COVID-19.

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Section: Heparin and Heparinoid Compoundsmentioning

confidence: 57%

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

Andersson

Ottestad

Tracey

2020

Mol Med

204

212

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“…Rasmuson et al revealed that sevuparin, a heparinoid with low anticoagulant activity, prevented neutrophil-induced lung plasma leakage in a murine model of systemic inflammation evoked by heat-killed group A Streptococcus ( 109 ). Their results demonstrated that sevuparin could interact with neutrophil secretion including serprocidins, S100 proteins and histone H4 and thus attenuate the disruptive effect of histone on endothelial integrity, suggesting a potential therapeutic of sevuparin in acute neutrophilic inflammation like sepsis.…”

Section: Circulating Histones In Sepsis As Potential Therapeutic Targmentioning

confidence: 99%

Circulating Histones in Sepsis: Potential Outcome Predictors and Therapeutic Targets

Wan

Luo

et al. 2021

Front. Immunol.

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Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection and is associated with high morbidity and mortality. Circulating histones (CHs), a group of damage-associated molecular pattern molecules mainly derived from neutrophil extracellular traps, play a crucial role in sepsis by mediating inflammation response, organ injury and death through Toll-like receptors or inflammasome pathways. Herein, we first elucidate the molecular mechanisms of histone-induced inflammation amplification, endothelium injury and cascade coagulation activation, and discuss the close correlation between elevated level of CHs and disease severity as well as mortality in patients with sepsis. Furthermore, current state-of-the-art on anti-histone therapy with antibodies, histone-binding proteins (namely recombinant thrombomodulin and activated protein C), and heparin is summarized to propose promising approaches for sepsis treatment.

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“…These observations stimulated the development of heparinoids that lack anticoagulant properties while keeping their anti-inflammatory effects (Rao et al 2010). Indeed, sevuparin, a low-anticoagulant heparin analog, inhibited NE and histone H4, proteins associated with NETs (Rasmuson et al 2019). In another study, non-anticoagulant heparin prevented histone-mediated cytotoxicity and improved survival in a murine sepsis model (Wildhagen et al 2014).…”

Section: Heparinmentioning

confidence: 99%

Neutrophil Extracellular Traps in Atherosclerosis and Thrombosis

Hofbauer

Ondracek

Lang

2020

Handbook of Experimental Pharmacology

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Despite effective therapeutic and preventive strategies, atherosclerosis and its complications still represent a substantial health burden. Leukocytes and inflammatory mechanisms are increasingly recognized as drivers of atherosclerosis. Neutrophil granulocytes within the circulation were recently shown to undergo neutrophil extracellular trap (NET) formation, linking innate immunity with acute complications of atherosclerosis. In this chapter, we summarize mechanisms of NET formation, evidence for their involvement in atherosclerosis and thrombosis, and potential therapeutic regimens specifically targeting NET components.

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Heparinoid sevuparin inhibitsStreptococcus‐induced vascular leak through neutralizing neutrophil‐derived proteins

Cited by 26 publications

References 36 publications

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

Circulating Histones in Sepsis: Potential Outcome Predictors and Therapeutic Targets

Neutrophil Extracellular Traps in Atherosclerosis and Thrombosis

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