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Pro-inflammatory Role of A2B Adenosine Receptor in Lung Ischemia-Reperfusion Injury
Farshad Anvari1, Ashish K. Sharma1, Lucas G. Fernandez1, Katya Ravid2, Irving L. Kron1, Victor E. Laubach1
1 Surgery, University of Virginia, Charlottesville, VA; 2 Biochemistry, Boston University School of Medicine, Boston, MA
Objective: Reperfusion injury after lung transplantation remains a major source of morbidity and mortality. Adenosine receptors have been implicated in both pro-inflammatory and anti-inflammatory roles in ischemia-reperfusion (IR) organ injury. We have previously demonstrated that the A2A adenosine receptor has an anti-inflammatory role in lung IR injury. We hypothesized that the A2B adenosine receptor has a pro-inflammatory role in lung IR injury.
Methods: An in-vivo mouse left lung hilar clamp model of IR was utilized. Wild-type C57BL6 mice (WT) were used for two groups: WT-Sham (3 hours of perfusion with no ischemia) and WT-IR (1 hour ischemia with 2 hours reperfusion). A third group consisted of A2B receptor knockout (KO) mice (1 hour ischemia with 2 hours reperfusion). At the end of reperfusion, lung function was assessed using an isolated buffer-perfused lung system. Lung inflammation was assessed by measuring pro-inflammatory cytokine levels (IL-6, KC, RANTES, MCP-1) in bronchoalveolar fluid and myeloperoxidase levels in lung tissue.
Results: Compared to wild-type mice, A2B receptor KO mice showed significantly improved lung function after IR as evidenced by lower pulmonary artery pressures and increased lung compliance (Table 1). In addition, the A2B receptor KO mice showed decreased myeloperoxidase levels and reduced pro-inflammatory cytokine levels compared to wild-type mice after IR.
Conclusion: Absence of the A2B adenosine receptor provides significant protection against lung IR injury. A2B adenosine receptor contributes to IR lung injury by increasing pro-inflammatory cytokines and increasing neutrophil infiltration as measured by myeloperoxidase level. These results suggest that specific A2B adenosine receptor antagonists may serve as therapeutic agents to prevent IR injury after lung transplantation.

Pulmonary function and cytokine analysis
WT-Sham (n=5) WT-IR (n=5) A2BKO-IR (n=5)
Pulmonary Function
PAP (cm H2O) 5.5±0.4 12.7±1.1* 6.9±0.6**
Compliance(μl/cm H2O) 5.4±0.3 2.9±0.2* 5.1±0.2**
Myeloperoxidase(ng/ml) 88.6±24.6 150.8±23.9 113.4±28.7
Cytokine Levels(pg/ml)
IL-6 3851±927 6756.1±571.1* 4693.7±410.8
KC 1104.6±160 4749.1±491* 2779.1±505**
MCP-1 59±5.8 272.1±72* 64.3±6.1**
RANTES 58.8±9.3 198.4±30.8* 44.1±3.6**
TNF-α 21.8±1.5 31.5±2.9 22.7±1.5

Data are presented as mean ± SEM. PAP, pulmonary artery pressure. *p<0.05 vs. WT-Sham, **p<0.05 vs. WT-IR.
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