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Pharmaceuticals 2014, 7(8), 894-912; doi:10.3390/ph7080894

Mitochondrial Targeted Endonuclease III DNA Repair Enzyme Protects against Ventilator Induced Lung Injury in Mice

1
Department of Physiology, University of South Alabama, Mobile, AL 36688, USA
2
Center for Lung Biology, University of South Alabama, Mobile, AL 36688, USA
3
Department of Pharmacology, University of South Alabama, Mobile, AL 36688, USA
4
Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, AL 36688, USA
*
Author to whom correspondence should be addressed.
Received: 28 April 2014 / Revised: 22 July 2014 / Accepted: 13 August 2014 / Published: 22 August 2014
(This article belongs to the Special Issue Mitochondrial Target-Based Drug Discovery)
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Abstract

The mitochondrial targeted DNA repair enzyme, 8-oxoguanine DNA glycosylase 1, was previously reported to protect against mitochondrial DNA (mtDNA) damage and ventilator induced lung injury (VILI). In the present study we determined whether mitochondrial targeted endonuclease III (EndoIII) which cleaves oxidized pyrimidines rather than purines from damaged DNA would also protect the lung. Minimal injury from 1 h ventilation at 40 cmH2O peak inflation pressure (PIP) was reversed by EndoIII pretreatment. Moderate lung injury due to ventilation for 2 h at 40 cmH2O PIP produced a 25-fold increase in total extravascular albumin space, a 60% increase in W/D weight ratio, and marked increases in MIP-2 and IL-6. Oxidative mtDNA damage and decreases in the total tissue glutathione (GSH) and the GSH/GSSH ratio also occurred. All of these indices of injury were attenuated by mitochondrial targeted EndoIII. Massive lung injury caused by 2 h ventilation at 50 cmH2O PIP was not attenuated by EndoIII pretreatment, but all untreated mice died prior to completing the two hour ventilation protocol, whereas all EndoIII-treated mice lived for the duration of ventilation. Thus, mitochondrial targeted DNA repair enzymes were protective against mild and moderate lung damage and they enhanced survival in the most severely injured group. View Full-Text
Keywords: endonuclease III; albumin spaces; MIP-2; IL-6; glutathione; pulmonary edema; vascular permeability endonuclease III; albumin spaces; MIP-2; IL-6; glutathione; pulmonary edema; vascular permeability
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MDPI and ACS Style

Hashizume, M.; Mouner, M.; Chouteau, J.M.; Gorodnya, O.M.; Ruchko, M.V.; Wilson, G.L.; Gillespie, M.N.; Parker, J.C. Mitochondrial Targeted Endonuclease III DNA Repair Enzyme Protects against Ventilator Induced Lung Injury in Mice. Pharmaceuticals 2014, 7, 894-912.

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