Does reperfusion injury still cause significant mortality after lung transplantation?

Ailawadi, Gorav; Lau, Christine L.; Smith, Philip W.; Swenson, Brian R.; Hennessy, Sara; Kühn, C.; Fedoruk, Lynn M.; Kozower, Benjamin D.; Krön, Irving L.; Jones, David R.

doi:10.1016/j.jtcvs.2008.11.007

Cited by 39 publications

(41 citation statements)

References 30 publications

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“…In fact, outcomes for lung transplantation are the worst of any solid organ transplant. Lung ischemia-reperfusion (IR) injury, which affects up to 35% of transplant recipients, continues to be a common cause of early morbidity and mortality (1,2). Lung IR injury also has long-term effects on the allograft, predisposing recipients to a greater risk for the development of bronchiolitis obliterans syndrome (3,4).…”

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confidence: 99%

Natural Killer T Cell–derived IL-17 Mediates Lung Ischemia–Reperfusion Injury

Sharma¹,

LaPar²,

Zhao³

et al. 2011

Am J Respir Crit Care Med

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110

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Rationale: We recently implicated a role for CD4 1 T cells and demonstrated elevated IL-17A expression in lung ischemia-reperfusion (IR) injury. However, identification of the specific subset of CD4 1 T cells and their mechanistic role in IR injury remains unknown. Objectives: We tested the hypothesis that invariant natural killer T (iNKT) cells mediate lung IR injury via IL-17A signaling. Methods: Mice underwent lung IR via left hilar ligation. Pulmonary function was measured using an isolated lung system. Lung injury was assessed by measuring edema (wet/dry weight) and vascular permeability (Evans blue dye). Inflammation was assessed by measuring proinflammatory cytokines in lungs, and neutrophil infiltration was measured by immunohistochemistry and myeloperoxidase levels. Measurements and Main Results: Pulmonary dysfunction (increased airway resistance and pulmonary artery pressure and decreased pulmonary compliance), injury (edema, vascular permeability), and inflammation (elevated IL-17A; IL-6; tumor necrosis factor-a; monocyte chemotactic protein-1; keratinocyte-derived chemokine; regulated upon activation, normal T-cell expressed and secreted; and neutrophil infiltration) after IR were attenuated in IL-17A 2/2 and Rag-1 2/2 mice. Anti-IL-17A antibody attenuated lung dysfunction in wildtype mice after IR. Reconstitution of Rag-1 2/2 mice with wild-type, but not IL-17A 2/2 , CD4 1 T cells restored lung dysfunction, injury, and inflammation after IR. Lung dysfunction, injury, IL-17A expression, and neutrophil infiltration were attenuated in Ja18 2/2 mice after IR, all of which were restored by reconstitution with wild-type, but not IL-17A 2/2 , iNKT cells. Flow cytometry and enzyme-linked immunosorbent spot assay confirmed IL-17A production by iNKT cells after IR.Conclusions: These results demonstrate that CD4 1 iNKT cells play a pivotal role in initiating lung injury, inflammation, and neutrophil recruitment after IR via an IL-17A-dependent mechanism.

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mentioning

confidence: 99%

Natural Killer T Cell–derived IL-17 Mediates Lung Ischemia–Reperfusion Injury

Sharma¹,

LaPar²,

Zhao³

et al. 2011

Am J Respir Crit Care Med

Self Cite

110

133

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“…Despite the success of lung transplantation, 20% to 35% of patients experience ischemia-reperfusion injury after lung transplantation [2]. This process results in pulmonary edema and intraalveolar and systemic cytokine release, leading to acute lung injury.…”

Section: Invited Commentarymentioning

confidence: 99%

Invited Commentary

Thistlethwaite

2013

The Annals of Thoracic Surgery

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de Perrot M, Liu M, Waddell TK, Keshavjee S. Ischemiareperfusion-induced lung injury. Am J Respir CritCare Med 2003;167:490 -511. 3. Matthay MA, Robriquet L, Fang X. Alveolar epithelium: role in lung fluid balance and acute lung injury. Proc Am Thorac Soc 2005;2:206 -13. 4. Mehta D, Malik AB. Signaling mechanisms regulating endothelial permeability. Physiol Rev 2006;86:279 -367. 5. Dejana E. Endothelial cell-cell junctions: happy together. Nat Rev Mol Cell Biol 2004;5:261-70. 6. Bach TL, Barsigian C, Yaen CH, Martinez J. Endothelial cell VE-cadherin functions as a receptor for the beta15-42 sequence of fibrin. J Biol Chem 1998;273:30719 -28. 7. Petzelbauer P, Zacharowski PA, Miyazaki Y, et al. The fibrin-derived peptide Bbeta15-42 protects the myocardium against ischemia-reperfusion injury. Nat Med 2005;11:298 -304. 8. Roesner JP, Petzelbauer P, Koch A, et al. The fibrin-derived peptide Bbeta15-42 is cardioprotective in a pig model of myocardial ischemia-reperfusion injury. Crit Care Med 2007; 35:1730 -5. 9. Groger M, Pasteiner W, Ignatyev G, et al. Peptide Bbeta(15-42) preserves endothelial barrier function in shock. PLoS One 2009;4:e5391. 10. Matt U, Warszawska JM, Bauer M, et al. Bbeta(15-42) protects against acid-induced acute lung injury and secondary pseudomonas pneumonia in vivo. Am J Respir Crit Care Med 2009;180:1208 -17. 11. Sorensen I, Rong S, Susnik N, et al. Bbeta(15-42) attenuates the effect of ischemia-reperfusion injury in renal transplantation. J Am Soc Nephrol 2011;22:1887-96. 12. Kiser A, Ciriaco P, Hoffmann S, Egan T. Lung retrieval from non-heart beating cadavers with the use of a rat lung transplant model. J Thorac Cardiovasc Surg 2001;122:18 -23. 13. Inokawa H, Sevala M, Funkhouser WK, Egan TM. Ex-vivo perfusion and ventilation of rat lungs from non-heartAnn Thorac Surg TIAN ET AL 2013;95:1028 -34 EFFECT OF B␤15-42 IN RAT LUNG TRANSPLANT

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“…IR injury entails a rapid inflammatory response upon transplantation resulting in activation of the innate immune system, expression of proinflammatory cytokines, leukocyte infiltration, and edema, all of which contribute to subsequent acute graft failure. With a reported incidence of 25-30%, IR injury results in increased resource utilization, including prolonged mechanical ventilation, intensive care unit duration, and overall hospital lengths of stay (1,2). Moreover, IR injury has also been identified as an important clinical risk factor for the development of chronic graft rejection in the form of bronchiolitis obliterans (3).…”

mentioning

confidence: 99%

“…In light of these findings, the purpose of the present study was twofold: (1) to evaluate the impact of acute perioperative hyperglycemia on lung IR injury; and (2) to evaluate the role of RAGE signaling in hyperglycemia-enhanced IR injury. We hypothesized that acute hyperglycemia worsens lung IR injury through a RAGE signaling mechanism.…”

mentioning

confidence: 99%

Acute Hyperglycemic Exacerbation of Lung Ischemia–Reperfusion Injury Is Mediated by Receptor for Advanced Glycation End-Products Signaling

LaPar

Hajzus

Zhao

et al. 2012

Am J Respir Cell Mol Biol

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The effects of acute hyperglycemia on lung ischemia-reperfusion (IR) injury and the role of receptor for advanced glycation endproducts (RAGE) signaling in this process are unknown. The objective of this study was twofold: (1) evaluate the impact of acute hyperglycemia on lung IR injury; and (2) determine if RAGE signaling is a mechanism of hyperglycemia-enhanced IR injury. We hypothesized that acute hyperglycemia worsens lung IR injury through a RAGE signaling mechanism. C57BL/6 wild-type (WT) and RAGE knockout (RAGE 2/2 ) mice underwent sham thoracotomy or lung IR (1-h left hilar occlusion and 2-h reperfusion). Acute hyperglycemia was established by dextrose injection 30 minutes before ischemia. Lung injury was assessed by measuring lung function, cytokine expression in bronchoalveolar lavage fluid, leukocyte infiltration, and microvascular permeability via Evans blue dye. Mean blood glucose levels doubled in hyperglycemic mice 30 minutes after dextrose injection. Compared with IR in normoglycemic mice, IR in hyperglycemic mice significantly enhanced lung dysfunction, cytokine expression (TNF-a, keratinocyte chemoattractant, IL-6, monocyte chemotactic protein-1, regulated upon activation, normal T cell expressed and secreted), leukocyte infiltration, and microvascular permeability. Lung injury and dysfunction after IR were attenuated in normoglycemic RAGE 2/2 mice, and hyperglycemia failed to exacerbate IR injury in RAGE 2/2 mice. Thus, this study demonstrates that acute hyperglycemia exacerbates lung IR injury, whereas RAGE deficiency attenuates IR injury and also prevents exacerbation of IR injury in an acute hyperglycemic setting. These results suggest that hyperglycemia-enhanced lung IR injury is mediated, at least in part, by RAGE signaling, and identifies RAGE as a potential, novel therapeutic target to prevent post-transplant lung IR injury.Keywords: lung transplant; receptor for advanced glycation end-products; hyperglycemia; inflammation Ischemia-reperfusion (IR) injury remains a leading cause of morbidity and mortality among patients undergoing lung transplantation. IR injury entails a rapid inflammatory response upon transplantation resulting in activation of the innate immune system, expression of proinflammatory cytokines, leukocyte infiltration, and edema, all of which contribute to subsequent acute graft failure. With a reported incidence of 25-30%, IR injury results in increased resource utilization, including prolonged mechanical ventilation, intensive care unit duration, and overall hospital lengths of stay (1, 2). Moreover, IR injury has also been identified as an important clinical risk factor for the development of chronic graft rejection in the form of bronchiolitis obliterans (3). As a result, studies aimed toward the development of therapeutic strategies to combat this complication hold tremendous clinical value.The receptor for advanced glycation end-products (RAGE) is a ubiquitous, multiligand receptor implicated in a variety of pathological conditions, such as diabetes and its compli...

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Does reperfusion injury still cause significant mortality after lung transplantation?

Abstract: Improved early survival after lung transplantation is due to less severe reperfusion injury, as well as improvements in survival with extracorporeal membrane oxygenation.

Cited by 39 publications

References 30 publications

Natural Killer T Cell–derived IL-17 Mediates Lung Ischemia–Reperfusion Injury

Natural Killer T Cell–derived IL-17 Mediates Lung Ischemia–Reperfusion Injury

Invited Commentary

Acute Hyperglycemic Exacerbation of Lung Ischemia–Reperfusion Injury Is Mediated by Receptor for Advanced Glycation End-Products Signaling

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