M6229 Protects against Extracellular-Histone-Induced Liver Injury, Kidney Dysfunction, and Mortality in a Rat Model of Acute Hyperinflammation

Chris P. M. Reutelingsperger, Marion J. Gijbels, Henri Spronk, Rene van Oerle, Roy Schrijver, Peter Ekhart, Sjef de Kimpe, Gerry A. F. Nicolaes

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Abstract

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.
Original languageEnglish
Article number1376
JournalInternational journal of molecular sciences
Volume25
Issue number3
DOIs
Publication statusPublished - 1 Feb 2024

Keywords

  • DAMPs
  • M6229
  • extracellular histones
  • hyperinflammation
  • organ injury
  • rat model
  • sepsis

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