Clifford Akateh1, Eliza W Beal1, Jung-Lye Kim2, Brenda F Reader1, Katelyn Maynard2, Jay L Zweier3, Bryan A Whitson1, Sylvester M Black4. 1. The COPPER Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio; Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio. 2. The COPPER Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio. 3. Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio. 4. The COPPER Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio; Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio. Electronic address: Sylvester.Black@osumc.edu.
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.
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: Y Yabe; N Kobayashi; T Nishihashi; R Takahashi; M Nishikawa; Y Takakura; M Hashida Journal: J Pharmacol Exp Ther Date: 2001-09 Impact factor: 4.030
Authors: Yong Gyu Lee; Jung-Lye Kim; Andre F Palmer; Brenda F Reader; Jianjie Ma; Sylvester M Black; Bryan A Whitson Journal: J Vis Exp Date: 2021-10-28 Impact factor: 1.424
Authors: Mina Mousavi; Saman Hakimian; Mahsa Ale-Ebrahim; Twana Ahmed Mustafa; Falah Mohammad Aziz; Abbas Salihi; Mirsasan Mirpour; Behnam Rasti; Keivan Akhtari; Koorosh Shahpasand; Osama K Abou-Zied; Mojtaba Falahati Journal: Int J Nanomedicine Date: 2019-07-16