Intrahepatic Delivery of Pegylated Catalase Is Protective in a Rat Ischemia/Reperfusion Injury Model.
Alanine Transaminase
/ blood
Animals
Aspartate Aminotransferases
/ blood
Catalase
/ administration & dosage
Cell Survival
/ drug effects
Disease Models, Animal
Humans
Hydrogen Peroxide
/ pharmacology
Injections, Intralesional
Liver
/ blood supply
Male
Oxidative Stress
/ drug effects
Polyethylene Glycols
/ administration & dosage
Primary Cell Culture
Rats
Reperfusion Injury
/ blood
Treatment Outcome
Warm Ischemia
/ adverse effects
Hepatectomy
Hydrogen peroxide
Ischemia/reperfusion injury
Liver transplantation
Oxidative stress
PEG-CAT
PEGylated catalase
Journal
The Journal of surgical research
ISSN: 1095-8673
Titre abrégé: J Surg Res
Pays: United States
ID NLM: 0376340
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
04
09
2018
revised:
27
11
2018
accepted:
10
01
2019
pubmed:
17
2
2019
medline:
31
1
2020
entrez:
17
2
2019
Statut:
ppublish
Résumé
Ischemia/reperfusion injury (IRI) can occur during liver surgery. Endogenous catalase is important to cellular antioxidant defenses and is critical to IRI prevention. Pegylation of catalase (PEG-CAT) improves its therapeutic potential by extending plasma half-life, but systemic administration of exogenous PEG-CAT has been only mildly therapeutic for hepatic IRI. Here, we investigated the protective effects of direct intrahepatic delivery of PEG-CAT during IRI using a rat hilar clamp model. PEG-CAT was tested in vitro and in vivo. In vitro, enriched rat liver cell populations were subjected to oxidative stress injury (H In vitro, PEG-CAT pretreatment of liver cells showed substantial uptake and protection against oxidative stress injury. In vivo, direct intrahepatic, but not systemic, delivery of PEG-CAT during IRI significantly reduced alanine aminotransferase and aspartate aminotransferase in a time-dependent manner (P < 0.01, P < 0.0001, respectively, for all time points) compared to control. Similarly, tissue malondialdehyde (P = 0.0048), adenosine triphosphate (P = 0.019), and GSH (P = 0.0015), and the degree of centrilobular necrosis, were improved by intrahepatic compared to systemic PEG-CAT delivery. Direct intrahepatic administration of PEG-CAT achieved significant protection against IRI by reducing the volume distribution and taking advantage of the substantial hepatic first-pass uptake of this molecule. The mode of delivery was an important factor for protection against hepatic IRI by PEG-CAT.
Sections du résumé
BACKGROUND
Ischemia/reperfusion injury (IRI) can occur during liver surgery. Endogenous catalase is important to cellular antioxidant defenses and is critical to IRI prevention. Pegylation of catalase (PEG-CAT) improves its therapeutic potential by extending plasma half-life, but systemic administration of exogenous PEG-CAT has been only mildly therapeutic for hepatic IRI. Here, we investigated the protective effects of direct intrahepatic delivery of PEG-CAT during IRI using a rat hilar clamp model.
MATERIALS AND METHODS
PEG-CAT was tested in vitro and in vivo. In vitro, enriched rat liver cell populations were subjected to oxidative stress injury (H
RESULTS
In vitro, PEG-CAT pretreatment of liver cells showed substantial uptake and protection against oxidative stress injury. In vivo, direct intrahepatic, but not systemic, delivery of PEG-CAT during IRI significantly reduced alanine aminotransferase and aspartate aminotransferase in a time-dependent manner (P < 0.01, P < 0.0001, respectively, for all time points) compared to control. Similarly, tissue malondialdehyde (P = 0.0048), adenosine triphosphate (P = 0.019), and GSH (P = 0.0015), and the degree of centrilobular necrosis, were improved by intrahepatic compared to systemic PEG-CAT delivery.
CONCLUSIONS
Direct intrahepatic administration of PEG-CAT achieved significant protection against IRI by reducing the volume distribution and taking advantage of the substantial hepatic first-pass uptake of this molecule. The mode of delivery was an important factor for protection against hepatic IRI by PEG-CAT.
Identifiants
pubmed: 30771685
pii: S0022-4804(19)30035-6
doi: 10.1016/j.jss.2019.01.028
pmc: PMC6752955
mid: NIHMS1519413
pii:
doi:
Substances chimiques
catalase-polyethylene glycol
0
Polyethylene Glycols
3WJQ0SDW1A
Hydrogen Peroxide
BBX060AN9V
Catalase
EC 1.11.1.6
Aspartate Aminotransferases
EC 2.6.1.1
Alanine Transaminase
EC 2.6.1.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
152-163Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL131941
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL135648
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI106704
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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