M6229 Protects against Extracellular-Histone-Induced Liver Injury, Kidney Dysfunction, and Mortality in a Rat Model of Acute Hyperinflammation
Extracellular histones have been shown to act as DAMPs in a variety of inflammatory diseases. Moreover, they have the ability to induce cell death. In this study, we show that M6229, a low-anticoagulant fraction of unfractionated heparin (UFH), rescues rats that were challenged by continuous infusion of calf thymus histones at a rate of 25 mg histones/kg/h. Histone infusion by itself induced hepatic and homeostatic dysfunction characterized by elevated activity of hepatic enzymes (ASAT and ALAT) and serum lactate levels as well as by a renal dysfunction, which contributed to the significantly increased mortality rate. M6229 was able to restore normal levels of both hepatic and renal parameters at 3 and 9 mg M6229/kg/h and prevented mortality of the animals. We conclude that M6229 is a promising therapeutic agent to treat histone-mediated disease.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
International journal of molecular sciences - 25(2024), 3 vom: 23. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Reutelingsperger, Chris P M [VerfasserIn] |
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| Links: |
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| Themen: |
9005-49-6 |
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| Anmerkungen: |
Date Completed 14.02.2024 Date Revised 14.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/ijms25031376 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368281442 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Extracellular histones have been shown to act as DAMPs in a variety of inflammatory diseases. Moreover, they have the ability to induce cell death. In this study, we show that M6229, a low-anticoagulant fraction of unfractionated heparin (UFH), rescues rats that were challenged by continuous infusion of calf thymus histones at a rate of 25 mg histones/kg/h. Histone infusion by itself induced hepatic and homeostatic dysfunction characterized by elevated activity of hepatic enzymes (ASAT and ALAT) and serum lactate levels as well as by a renal dysfunction, which contributed to the significantly increased mortality rate. M6229 was able to restore normal levels of both hepatic and renal parameters at 3 and 9 mg M6229/kg/h and prevented mortality of the animals. We conclude that M6229 is a promising therapeutic agent to treat histone-mediated disease | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a DAMPs | |
| 650 | 4 | |a M6229 | |
| 650 | 4 | |a extracellular histones | |
| 650 | 4 | |a hyperinflammation | |
| 650 | 4 | |a organ injury | |
| 650 | 4 | |a rat model | |
| 650 | 4 | |a sepsis | |
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| 650 | 7 | |a Heparin |2 NLM | |
| 650 | 7 | |a 9005-49-6 |2 NLM | |
| 650 | 7 | |a Anticoagulants |2 NLM | |
| 700 | 1 | |a Gijbels, Marion J |e verfasserin |4 aut | |
| 700 | 1 | |a Spronk, Henri |e verfasserin |4 aut | |
| 700 | 1 | |a Van Oerle, Rene |e verfasserin |4 aut | |
| 700 | 1 | |a Schrijver, Roy |e verfasserin |4 aut | |
| 700 | 1 | |a Ekhart, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a de Kimpe, Sjef |e verfasserin |4 aut | |
| 700 | 1 | |a Nicolaes, Gerry A F |e verfasserin |4 aut | |
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