Lung ischemia-reperfusion (IR) injury is a major complication after transplantation leading to higher post-operative mortality and late complications including chronic rejection. Our laboratory has established that early, acute lung IR injury is dependent on alveolar macrophage activation and TNF-alpha induction. One major anti-inflammatory mechanism in IR is mediated through the release of adenosine, and we have showed that activation of the A2A adenosine receptor (AR) reduces lung IR injury. Little is known about the role of other ARs in lung IR injury.
Thus Aim 1 will determine the role of each AR in a mouse model of acute lung IR.
Aim 2 will establish that A2AARs specifically on alveolar macrophages confer protection from acute lung IR injury.
Aim 3 will determine if mechanisms of A2AAR attenuation of IR injury involve MAPK, NF-kB, and apoptosis pathways in macrophages. Our overall hypothesis is that specific activation of A2AARs on alveolar macrophages provides protection from post-transplant acute lung IR injury.
Lung reperfusion injury is a major complication of lung transplantation leading to higher post-operative mortality and late complications including chronic rejection. The objective of this proposal is to better understand the mechanisms of reperfusion injury and potentially prevent this complication. If successful, this will lead to more successful outcomes in lung transplantations and potentially increase the number of organs available to patients with end-stage lung disease.
| Laubach, Victor E; Sharma, Ashish K (2016) Mechanisms of lung ischemia-reperfusion injury. Curr Opin Organ Transplant 21:246-52 |
| Zhao, Yunge; Gillen, Jacob R; Harris, David A et al. (2014) Treatment with placenta-derived mesenchymal stem cells mitigates development of bronchiolitis obliterans in a murine model. J Thorac Cardiovasc Surg 147:1668-1677.e5 |
| Fernandez, Lucas G; Sharma, Ashish K; LaPar, Damien J et al. (2013) Adenosine A1 receptor activation attenuates lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg 145:1654-9 |
| 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 |
| Mulloy, Daniel P; Sharma, Ashish K; Fernandez, Lucas G et al. (2013) Adenosine A3 receptor activation attenuates lung ischemia-reperfusion injury. Ann Thorac Surg 95:1762-7 |
| 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 |
| 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 145:940-947.e1 |
| 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 |
| Anvari, Farshad; Sharma, Ashish K; Fernandez, Lucas G et al. (2010) Tissue-derived proinflammatory effect of adenosine A2B receptor in lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg 140:871-7 |
| Gazoni, Leo M; Walters, Dustin M; Unger, Eric B et al. (2010) Activation of A1, A2A, or A3 adenosine receptors attenuates lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg 140:440-6 |
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