Pharmacologic Protection of Mitochondrial DNA Integrity May Afford a New Strategy for Suppressing Lung Ischemia-Reperfusion Injury.
Ann Am Thorac Soc
; 14(Supplement_3): S210-S215, 2017 Sep.
Article
em En
| MEDLINE
| ID: mdl-28945469
ABSTRACT
Lung ischemia-reperfusion (IR) injury contributes to post-transplant complications, including primary graft dysfunction. Decades of reports show that reactive oxygen species generated during lung IR contribute to pulmonary vascular endothelial barrier disruption and edema formation, but the specific target molecule(s) that "sense" injury-inducing oxidant stress to activate signaling pathways culminating in pathophysiologic changes have not been established. This review discusses evidence that mitochondrial DNA (mtDNA) may serve as a molecular sentinel wherein oxidative mtDNA damage functions as an upstream trigger for lung IR injury. First, the mitochondrial genome is considerably more sensitive than nuclear DNA to oxidant stress. Multiple studies suggest that oxidative mtDNA damage could be transduced to physiologic dysfunction by pathways that are either a direct consequence of mtDNA damage per se or involve formation of proinflammatory mtDNA damage-associated molecular patterns. Second, transgenic animals or cells overexpressing components of the base excision DNA repair pathway in mitochondria are resistant to oxidant stress-mediated pathophysiologic effects. Finally, published and preliminary studies show that pharmacologic enhancement of mtDNA repair or mtDNA damage-associated molecular pattern degradation suppresses reactive oxygen species-induced or IR injury in multiple organs, including preclinical models of lung procurement for transplant. Collectively, these findings point to the interesting prospect that pharmacologic enhancement of DNA repair during procurement or ex vivo lung perfusion may increase the availability of lungs for transplant and reduce the IR injury contributing to primary graft dysfunction.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA Mitocondrial
/
Traumatismo por Reperfusão
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Pulmão
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article