M6229 Protects against Extracellular-Histone-Induced Liver Injury, Kidney Dysfunction, and Mortality in a Rat Model of Acute Hyperinflammation.
Chris P M ReutelingspergerMarion J GijbelsHenri M H SpronkRene Van OerleRoy SchrijverPeter EkhartSjef de KimpeGerry A F NicolaesPublished in: International journal of molecular sciences (2024)
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.
Keyphrases
- oxidative stress
- cell death
- cardiovascular events
- dna methylation
- venous thromboembolism
- risk factors
- low dose
- diabetic rats
- liver failure
- drug induced
- gene expression
- mouse model
- coronary artery disease
- type diabetes
- respiratory failure
- high glucose
- intensive care unit
- growth factor
- extracorporeal membrane oxygenation
- aortic dissection