Intrahepatic Delivery of Pegylated Catalase Is Protective in a Rat Ischemia/Reperfusion Injury Model.

Abstract

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 (H2O2), and measures of cell health and viability were assessed. In vivo, rats underwent segmental (70%) hepatic warm ischemia for 1 h, followed by 6 h of reperfusion, and plasma alanine aminotransferase and aspartate aminotransferase, tissue malondialdehyde, adenosine triphosphate, and GSH, and histology were assessed.

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.

• Authors: Clifford Akateh, Eliza W Beal, Jung-Lye Kim, Brenda F Reader, Katelyn Maynard, Jay L Zweier, Bryan A Whitson, Sylvester M Black
• Journal: The Journal of surgical research (J Surg Res) Vol. 238 Pg. 152-163 (06 2019) ISSN: 1095-8673 [Electronic] United States
• PMID: 30771685 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• catalase-polyethylene glycol
• Polyethylene Glycols
• Hydrogen Peroxide
• Catalase
• Aspartate Aminotransferases
• Alanine Transaminase

Topics

• 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, cytology, surgery)
• Male
• Oxidative Stress (drug effects)
• Polyethylene Glycols (administration & dosage)
• Primary Cell Culture
• Rats
• Reperfusion Injury (blood, drug therapy, etiology)
• Treatment Outcome
• Warm Ischemia (adverse effects)