The pathogenesis of lung ischemia reperfusion injury (IRI) has historically been characterized by the recruitment and extravasation of neutrophils. However, more recent studies have suggested a role for natural killer T-cells (NKT) in the pathogenesis of this injury. Agonists of the anti-inflammatory Gs-coupled adenosine A2A receptor (A2AR) have been shown to inhibit the activity of most inflammatory cells, and extensive preclinical evidence exists for their use in prevention of acute ischemia reperfusion. Importantly, IRI is a significant risk factor for the development of chronic allograft rejection, bronchiolitis obliterans (BO). Evidence supports alloimmune-dependent and alloimmune-independent factors in the etiology BO. More recently activation of A2ARs on lymphocytes and antigen presenting cells have been shown to attenuate the alloimmune response. Additionally A2AR stimulation and upregulation on lymphocytes promotes peripheral tolerance by inducing T-cell anergy. Currently little is known about the role of A2AR agonists in lung transplant rejection. Our overall hypothesis is that A2AR signaling is critical in modulating the innate and adaptive immune responses relevant to the pathogenesis of BO.
Aim 1 : Will determine, using an in-vivo lung IRI model, if A2AR signaling specifically on NKT cells confers protection from lung IRI.
Aim 2 : Will determine, using a non-revascularized heterotopic tracheal model and genetically modified mice strains, the importance and cellular mechanisms of A2AR signaling in the pathogenesis of BO.
Aim 3 : Will determine if A2AR signaling can be used to promote the development of a tolerant state. Also addressed will be ways to effectively introduce A2AR agonists with standard immunosuppression regimens. This grant encompasses a training program for the PI which includes coursework plus frequent interactions with mentors and advisors. With the guidance of the candidate's advisory committee and the institutional support provided by the University of Virginia's Department of Surgery, the candidate will development the skills required to evolve into an independent investigator.

Public Health Relevance

BO remains the major hurdle to long-term survival in lung transplant recipients. There currently are no uniformly consistent strategies to prevent/treat BO. IRI is a significant risk factor for BO. Given the anti- inflammatory and immunomodulating effects of A2ARs, strategies utilizing A2AR agonists may be uniquely suited to prevent both the alloimmune-independent and alloimmune-dependent factors involved in BO.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL094704-04
Application #
8207878
Study Section
Special Emphasis Panel (ZHL1-CSR-O (O1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2009-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$128,817
Indirect Cost
$9,542
Name
University of Virginia
Department
Surgery
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Gillen, Jacob R; Zhao, Yunge; Harris, David A et al. (2013) Rapamycin blocks fibrocyte migration and attenuates bronchiolitis obliterans in a murine model. Ann Thorac Surg 95:1768-75
Gillen, Jacob R; Zhao, Yunge; Harris, David A et al. (2013) Short-course rapamycin treatment preserves airway epithelium and protects against bronchiolitis obliterans. Ann Thorac Surg 96:464-72
Zhao, Yunge; Steidle, John F; Upchurch, Gilbert R et al. (2013) Prevention of the second stage of epithelial loss is a potential novel treatment for bronchiolitis obliterans. J Thorac Cardiovasc Surg 145:940-7
Rosenberger, Laura H; Hranjec, Tjasa; McLeod, Matthew D et al. (2013) Improvements in pulmonary and general critical care reduces mortality following ventilator-associated pneumonia. J Trauma Acute Care Surg 74:568-74
LaPar, Damien J; Laubach, Victor E; Emaminia, Abbas et al. (2011) Pretreatment strategy with adenosine A2A receptor agonist attenuates reperfusion injury in a preclinical porcine lung transplantation model. J Thorac Cardiovasc Surg 142:887-94
LaPar, Damien J; Burdick, Marie D; Emaminia, Abbas et al. (2011) Circulating fibrocytes correlate with bronchiolitis obliterans syndrome development after lung transplantation: a novel clinical biomarker. Ann Thorac Surg 92:470-7; discussion 477
Zhao, Yunge; Turlington, Mark; LaPar, Damien J et al. (2011) Characterization of novel synthesized small molecular compounds against non-small cell lung cancer. Ann Thorac Surg 92:1031-7
Zhao, Yunge; Sharma, Ashish K; LaPar, Damien J et al. (2011) Depletion of tissue plasminogen activator attenuates lung ischemia-reperfusion injury via inhibition of neutrophil extravasation. Am J Physiol Lung Cell Mol Physiol 300:L718-29
Emaminia, Abbas; Lapar, Damien J; Zhao, Yunge et al. (2011) Adenosine AýýýA agonist improves lung function during ex vivo lung perfusion. Ann Thorac Surg 92:1840-6

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