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| Deletion of Tissue Plasminogen Activator Prevents Lung Ischemia-Reperfusion Injury via Inhibition of Neutrophil Extravasation |
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Yunge Zhao, Abbas Emaminia, Ashish K. Sharma, John Steidle, Gorav Ailawadi, Irving L. Kron, Christine L. Lau; Surgery, University of Virginia, Charlottesville, VA Objective: Ischemia-reperfusion injury (IRI) continues to be the most common cause for early morbidity following lung transplantation. In acute lung injury processes including IRI, extravascular fibrin has been shown to activate inflammation and promote lung dysfunction. We hypothesized that mice lacking the tissue plasminogen activator gene (tPA KO), which are less efficient at fibrin degradation, would experience increased lung IRI. Methods: tPA KO (n=9) and wild-type (C57BL/6) (n=9) mice underwent in-situ left lung ischemia for 1 hour followed by reperfusion for 2 hours. Sham group (n=9) were used as control. Lung function/injury was assessed by an ex vivo buffer-perfused isolated lung system. The cellular infiltration was evaluated by immunohistochemical staining and densitometric analysis. Lung vascular permeability was determined using Evan’s Blue injection (n=12). The activities of matrix metalloproteinase-2 (MMP-2), MMP-9, urokinase plasminogen activator and tPA were detected by gelatin- and fibrin- zymography, respectively. Results: Compared to wild-type mice, tPA KO mice were significantly protected from IRI with lower pulmonary artery pressures (8.15±1.07 vs 12.53 ± 1.03, P=0.006), increased lung compliance (5.75 ± 0.97 vs 2.55 ± 0.20, P<0.0001), and lower airway resistance (1.01 ± 0.15 vs 2.24 ± 0.28, P=0.005). Compared to sham group, tPA KO mice showed no significant changes in lung compliance (P=0.419), but significant differences in pulmonary artery pressures (P=0.001) and airway resistance (P=0.010). By histology and densitometric analysis, neutrophil (P<0.001) (but not macrophage) extravasation from blood vessels was clearly blocked in tPA KO compared to wild-type mice (Fig1). tPA KO blocked neutrophil infiltration by decreasing lung vascular permeability (tPA KO IR vs C57BL/6 IR, P=0.040) through inhibition of the expression of MMP-9 and platelet endothelial cell adhesion molecule-1 (CD31) expression in the endothelial cells. Conclusion: Deletion of tPA resulted in significantly attenuated lung ischemia-reperfusion injury. The mechanism may be explained via inhibition of MMP-9 and endothelial cell adhesion molecules. These results have clinical implications as targeted therapies directed against tPA, or tPA combined with MMP-9 and/or CD31, and may be novel strategies to protect against IRI. 
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