PMID- 38338654
OWN - NLM
STAT- MEDLINE
DCOM- 20240214
LR  - 20240214
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 25
IP  - 3
DP  - 2024 Jan 23
TI  - M6229 Protects against Extracellular-Histone-Induced Liver Injury, Kidney 
      Dysfunction, and Mortality in a Rat Model of Acute Hyperinflammation.
LID - 10.3390/ijms25031376 [doi]
LID - 1376
AB  - 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.
FAU - Reutelingsperger, Chris P M
AU  - Reutelingsperger CPM
AUID- ORCID: 0000-0002-2334-9403
AD  - Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University, 6200 MD Maastricht, The Netherlands.
FAU - Gijbels, Marion J
AU  - Gijbels MJ
AD  - Department of Pathology, Maastricht University Medical Center, MUMC+, 6202 AZ 
      Maastricht, The Netherlands.
AD  - Department of Medical Biochemistry, Amsterdam Cardiovascular 
      Sciences-Atherosclerosis & Ischemic Syndrome, Amsterdam Infection and 
      Immunity-Inflammatory Diseases, Amsterdam UMC Location University of Amsterdam, 
      Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
FAU - Spronk, Henri
AU  - Spronk H
AUID- ORCID: 0000-0002-3858-334X
AD  - Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University, 6200 MD Maastricht, The Netherlands.
AD  - Coagulation Profile B.V., 6229 EV Maastricht, The Netherlands.
FAU - Van Oerle, Rene
AU  - Van Oerle R
AD  - Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University, 6200 MD Maastricht, The Netherlands.
FAU - Schrijver, Roy
AU  - Schrijver R
AD  - Matisse Pharmaceuticals B.V., 6163 JT Geleen, The Netherlands.
FAU - Ekhart, Peter
AU  - Ekhart P
AUID- ORCID: 0000-0002-0164-2633
AD  - Matisse Pharmaceuticals B.V., 6163 JT Geleen, The Netherlands.
FAU - de Kimpe, Sjef
AU  - de Kimpe S
AD  - Matisse Pharmaceuticals B.V., 6163 JT Geleen, The Netherlands.
FAU - Nicolaes, Gerry A F
AU  - Nicolaes GAF
AUID- ORCID: 0000-0002-2482-0412
AD  - Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University, 6200 MD Maastricht, The Netherlands.
LA  - eng
PT  - Journal Article
DEP - 20240123
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Histones)
RN  - 9005-49-6 (Heparin)
RN  - 0 (Anticoagulants)
SB  - IM
MH  - Rats
MH  - Animals
MH  - Histones/metabolism
MH  - Heparin/pharmacology
MH  - *Chemical and Drug Induced Liver Injury, Chronic
MH  - Anticoagulants/pharmacology
MH  - Kidney/metabolism
MH  - *Acute Kidney Injury/drug therapy
PMC - PMC10855969
OTO - NOTNLM
OT  - DAMPs
OT  - M6229
OT  - extracellular histones
OT  - hyperinflammation
OT  - organ injury
OT  - rat model
OT  - sepsis
COIS- C.P.M.R. and G.A.F.N. are advisors and shareholders of Matisse Pharmaceuticals 
      B.V. The authors declare no conflict of interest except for H.S., who work at 
      Coagulation Profile B.V.; R.S., P.E. and S.d.K. who work at Matisse 
      Pharmaceuticals B.V. Although these companies provided funding support and 
      experimental products, they had no role in the study design, conduct of the 
      study, data collection, or data interpretation.
EDAT- 2024/02/10 10:49
MHDA- 2024/02/10 14:47
PMCR- 2024/01/23
CRDT- 2024/02/10 01:10
PHST- 2023/11/28 00:00 [received]
PHST- 2024/01/16 00:00 [revised]
PHST- 2024/01/18 00:00 [accepted]
PHST- 2024/02/10 14:47 [medline]
PHST- 2024/02/10 10:49 [pubmed]
PHST- 2024/02/10 01:10 [entrez]
PHST- 2024/01/23 00:00 [pmc-release]
AID - ijms25031376 [pii]
AID - ijms-25-01376 [pii]
AID - 10.3390/ijms25031376 [doi]
PST - epublish
SO  - Int J Mol Sci. 2024 Jan 23;25(3):1376. doi: 10.3390/ijms25031376.