CD4+ T Lymphocytes Mediate Acute Pulmonary Ischemia/Reperfusion Injury
Zequan Yang1, Ashish K. Sharma1, Joel Linden2, Victor E. Laubach1, Irving L. Kron1; 1Surgery, University of Virginia Health System, Charlottesville, VA; 2Medicine, University of Virginia Health System, Charlottesville, VA
Comment on this Abstract
Objective: Ischemia/reperfusion (I/R) injury remains a major cause of life-threatening graft dysfunction after lung transplantation. An increasing body of evidence suggests that post-ischemic reperfusion triggers pro-inflammatory responses that eventually activate neutrophils to cause pulmonary injury. However, mechanisms underlying neutrophil activation remain to be defined. We hypothesize that T lymphocytes are activated during reperfusion and mediate neutrophil-induced lung I/R injury.
Methods: A mouse model with in vivo left lung ischemia/reperfusion was employed. 102 C57BL/6 mice were assigned to either sham group (left thoracotomy only) or study groups which underwent 1 hr left hilar occlusion followed by 1, 2, or 24 hr reperfusion. A murine ventilator with pressure control was used. Mice were ventilated only during procedures for hilar ligation or ligature removal (<15 min on ventilator total), so that ventilation-induced injury was minimized. At the end of reperfusion, an isolated buffer-perfused lung system was used to evaluate pulmonary function. Left-lung injury was characterized by wet-to-dry weight ratio and Evan’s blue dye permeability.
Results: A time course study showed that 2 hr reperfusion resulted in more severe lung injury and dysfunction than 1 or 24 hr reperfusion. Thus the model using 1 hr ischemia and 2 hr reperfusion was used throughout the rest of the study. A highly selective adenosine A2A receptor agonist, ATL313, significantly reduced lung injury and dysfunction when applied i.v. at a bolus dose of 3 μg/kg 5 min before reperfusion (*p<0.05 vs. control). Significant protection was also found in antibody-induced neutropenic mice (Anti-NE) or CD4+ T-cell depleted mice (#p<0.05 vs. IgG control group) but not in CD8+ T cell depleted mice. However, no additive effect in lung protection was found when ATL313 was applied to either neutropenic mice or CD4+ T-cell depleted mice (Table).
Conclusion: Both neutrophils and T lymphocytes are activated during pulmonary I/R injury. Neutrophils are end-effectors directly causing pulmonary reperfusion injury; however, CD4+ T cells play a central role in mediating pro-inflammatory responses during acute lung I/R injury. The protective effect of adenosine A2A receptor activation is likely due to its action on CD4+ T cells.
| Groups (n) | Airway Pressure (cmH2O) | Pulmonary Compliance (μl/cmH2O | Pulmonary Artery Pressure (cmH2O) | | Wet to dry ratio (n=3) | Evan’s blue dye (μg/g wet lung) (n=3) |
| Control (5) | 2.20±0.15 | 1.88±0.28 | 14.32±1.42 | 6.19±0.05 | 96.7±11.2 |
| ATL313 (6) | 0.95±0.08* | 3.34±0.22* | 9.03±0.73* | 5.57±0.13* | 40.9±9.4* |
| IgG control (5) | 1.19±0.07 | 2.32±0.15 | 11.40±1.01 | 6.25±0.16 | 91.2±10.5 |
| Anti-NE (8) | 0.76±0.02# | 4.54±0.35# | 8.44±0.39# | 5.13±0.09# | 36.5±3.0# |
| Anti-NE+ATL (5) | 0.89±0.07# | 3.68±0.22# | 7.20±0.30# | 5.16±0.23# | 22.7±9.4# |
| Anti-CD4 (5) | 1.12±0.05φ | 4.23±0.50# φ | 7.50±0.83# φ | 4.93±0.04# φ | 13.1±4.0# φ |
| Anti-CD4 +ATL (4) | 0.88±0.08# | 3.70±0.39# | 7.45±0.80# | 5.13±0.08# | 20.1±6.4# |
| Anti-CD8 (5) | 1.80±0.12 | 2.20±0.33 | 11.4±0.68 | 6.06±0.30 | 73.4±6.4 |
| Data are presented as Mean±SEM. *p<0.05 vs. Control; #p<0.05 vs. IgG control; φp<0.05 vs. anti-CD8 |
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