Ischemia-reperfusion (IR) injury remains a major source of early mortality after lung transplantation. The objective of this proposal is to better understand the cellular mechanisms that initiate and mediate this inflammatory process. Our laboratory has established that lung IR injury is dependent on alveolar macrophage activation, CD4+ T cell infiltration, and TNF-alpha induction. Recent data also supports an important role for IL-17 and IL-17-producing CD4+ T cells, such as iNKT, in mediating lung inflammation after IR.
Thus Aim 1 will determine if iNKT cells initiate lung IR injury and neutrophil infiltration via IL-17 production. Oxidative stress and the release of reactive oxygen species via NADPH oxidase is also a component of IR injury as well as phagocytic cell activation.
Thus Aim 2 will determine if NADPH oxidase-generated ROS is a key mechanism for the activation of iNKT cells after IR. Our overall hypothesis is that lung IR injury is initiated through CD4+ iNKT cell activation via production of IL-17 and NADPH oxidase-dependent ROS. Results from this proposal will help design successful strategies to improve outcomes in lung transplant recipients.

Public Health Relevance

Lung reperfusion injury is a major complication after transplantation resulting in dangerous inflammation, higher post-operative mortality, and late complications including chronic rejection. The objective of this proposal is to better understand the cellular mechanisms that initiate and mediate lung reperfusion injury. Results from this proposal will help design successful strategies to improve outcomes in lung transplantations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077301-08
Application #
8490408
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Eu, Jerry Pc
Project Start
2004-07-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$362,855
Indirect Cost
$127,235
Name
University of Virginia
Department
Surgery
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Laubach, Victor E; Sharma, Ashish K (2016) Mechanisms of lung ischemia-reperfusion injury. Curr Opin Organ Transplant 21:246-52
Sharma, Ashish K; LaPar, Damien J; Stone, Matthew L et al. (2016) NOX2 Activation of Natural Killer T Cells Is Blocked by the Adenosine A2A Receptor to Inhibit Lung Ischemia-Reperfusion Injury. Am J Respir Crit Care Med 193:988-99
Stone, Matthew L; Sharma, Ashish K; Zhao, Yunge et al. (2015) Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol 308:L1245-52
Stone, Matthew L; Sharma, Ashish K; Mas, Valeria R et al. (2015) Ex Vivo Perfusion With Adenosine A2A Receptor Agonist Enhances Rehabilitation of Murine Donor Lungs After Circulatory Death. Transplantation 99:2494-503
Sharma, Ashish K; Mulloy, Daniel P; Le, Lamvy T et al. (2014) NADPH oxidase mediates synergistic effects of IL-17 and TNF-* on CXCL1 expression by epithelial cells after lung ischemia-reperfusion. Am J Physiol Lung Cell Mol Physiol 306:L69-79
Sharma, A K; LaPar, D J; Stone, M L et al. (2013) Receptor for advanced glycation end products (RAGE) on iNKT cells mediates lung ischemia-reperfusion injury. Am J Transplant 13:2255-67
Lapar, Damien J; Hajzus, Vanessa A; Zhao, Yunge et al. (2012) Acute hyperglycemic exacerbation of lung ischemia-reperfusion injury is mediated by receptor for advanced glycation end-products signaling. Am J Respir Cell Mol Biol 46:299-305
Laubach, Victor E; French, Brent A; Okusa, Mark D (2011) Targeting of adenosine receptors in ischemia-reperfusion injury. Expert Opin Ther Targets 15:103-18
Sun, Jie; Cardani, Amber; Sharma, Ashish K et al. (2011) Autocrine regulation of pulmonary inflammation by effector T-cell derived IL-10 during infection with respiratory syncytial virus. PLoS Pathog 7:e1002173
Sharma, Ashish K; LaPar, Damien J; Zhao, Yunge et al. (2011) Natural killer T cell-derived IL-17 mediates lung ischemia-reperfusion injury. Am J Respir Crit Care Med 183:1539-49

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