Combination of sivelestat and N-acetylcysteine alleviates the inflammatory response and exceeds standard treatment for acetaminophen-induced liver injury.
Acetaminophen
/ toxicity
Acetylcysteine
/ pharmacology
Analgesics, Non-Narcotic
/ toxicity
Animals
Chemical and Drug Induced Liver Injury
/ drug therapy
Drug Therapy, Combination
Free Radical Scavengers
/ pharmacology
Glycine
/ analogs & derivatives
Inflammation
/ etiology
Male
Mice
Mice, Inbred C57BL
Serine Proteinase Inhibitors
/ pharmacology
Sulfonamides
/ pharmacology
acute liver failure
acute liver injury
hepatotoxicity
paracetamol
Journal
Journal of leukocyte biology
ISSN: 1938-3673
Titre abrégé: J Leukoc Biol
Pays: England
ID NLM: 8405628
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
04
08
2019
revised:
12
11
2019
accepted:
01
12
2019
pubmed:
17
12
2019
medline:
2
7
2020
entrez:
17
12
2019
Statut:
ppublish
Résumé
Hepatocyte death during acetaminophen (APAP) intoxication elicits a reactive inflammatory response, with hepatic recruitment of neutrophils and monocytes, which further aggravates liver injury. Neutrophil elastase (NE), secreted by activated neutrophils, carries degradative and cytotoxic functions and maintains a proinflammatory state. We investigated NE as a therapeutic target in acetaminophen-induced liver injury (AILI). C57BL/6 mice were administered a toxic dose of APAP, 2 h prior to receiving the NE inhibitor sivelestat, N-acetylcysteine (NAC), or a combination therapy, and were euthanized after 24 and 48 h. Upon APAP overdose, neutrophils and monocytes infiltrate the injured liver, accompanied by increased levels of NE. Combination therapy of NAC and sivelestat significantly limits liver damage, as evidenced by lower serum transaminase levels and less hepatic necrosis compared to mice that received APAP only, and this to a greater extent than NAC monotherapy. Lower hepatic expression of proinflammatory markers was observed in the combination treatment group, and flow cytometry revealed significantly less monocyte influx in livers from mice treated with the combination therapy, compared to untreated mice and mice treated with NAC only. The potential of NE to induce leukocyte migration was confirmed in vitro. Importantly, sivelestat did not impair hepatic repair. In conclusion, combination of NE inhibition with sivelestat and NAC dampens the inflammatory response and reduces liver damage following APAP overdose. This strategy exceeds the standard of care and might represent a novel therapeutic option for AILI.
Identifiants
pubmed: 31841237
doi: 10.1002/JLB.5A1119-279R
doi:
Substances chimiques
Analgesics, Non-Narcotic
0
Free Radical Scavengers
0
Serine Proteinase Inhibitors
0
Sulfonamides
0
Acetaminophen
362O9ITL9D
sivelestat
DWI62G0P59
Glycine
TE7660XO1C
Acetylcysteine
WYQ7N0BPYC
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
341-355Informations de copyright
©2019 Society for Leukocyte Biology.
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