Microarray meta-analysis identifies acute lung injury biomarkers in donor lungs that predict development of primary graft failure in recipients

Hu, Pingzhao; Wang, Xinchen; Haitsma, Jack J.; Furmli, Suleiman; Masoom, Hussain; Liu, Mingyao; Slutsky, Arthur S.; Beyene, Joseph; Greenwood, Celia; Santos, Claudia C. dos

doi:10.1016/j.jcrc.2012.10.042

Cited by 2 publications

(2 citation statements)

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“…The recognition that GST genes are consistently altered in various animal models of lung injury and are among the top genes that accurately predict development of primary graft failure in lung transplant donors (19) certainly points toward these promising directions. Our pilot genetic data may also highlight a role of specific GST gene polymorphism in the development of perioperative myocardial infarction (20), thus extending the paradigm beyond lung ischemia reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism

Fletcher

Boshier

Wakabayashi

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism. Am J Physiol Lung Cell Mol Physiol 308: L1274 -L1285, 2015. First published April 10, 2015; doi:10.1152/ajplung.00220.2014.-Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione-S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H2O2), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-but not GST-expression reduced cell viability and significantly enhanced stress (H2O2/HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD ϩ /NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications.N-acetylcysteine; ethacrynic acid; caffeic acid; reactive oxygen species; viability ACUTE LUNG INJURY (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening inflammatory disorders, which may result from both medical and surgical situations such as sepsis, heart surgery, and lung transplantation (41). Among these, ischemia and reperfusion injury constitutes a unique entity, wherein metabolic and oxygen starvation and subsequent reoxygenation can lead to the release and accumulation of reactive oxygen species (ROS) (4). ROS can directly oxidize and damage DNA, protein, and lipid membranes, inactivate antioxidant enzymes, and enhance expression of proinflammatory genes, ultimately leading to cell injury and apoptosis (11).The glutathione-S-transferase (GST) antioxidant enzymes form a multifunctional superfamily of intracellular isozymes that catalyze the conjugation of reduc...

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Section: Discussionmentioning

confidence: 99%

Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism

Fletcher

Boshier

Wakabayashi

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

“…Using a more stringent a priori selection of patients with poor vs. good outcomes, Keshavjee's group identified four significantly up-regulated genes in the PGD samples, which were tested in a subsequent validation cohort (61). Hu and colleagues has constructed a "meta-analysis" of genetic injury patterns from single and double hit animal models of ALI and applied these genetic markers to microarray data from donor lungs (63). This enabled accurate prediction of later PGF development following transplantation.…”

Section: E Critical Evaluation and Future Directionsmentioning

confidence: 99%