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The Effects of hPTPß Inhibitor on Microcirculatory Hemodynamics of Muscle Flaps Following Ischemia Reperfusion Injury
Andy F Zhu, MD; Kagan Ozer, MD; Geoffrey Burns, MS; Breana Siljander, BS; Jennifer F. Waljee, MD, MPH
University of Michigan, Ann Arbor, MI

Tissue ischemia may negatively influence the outcome of reconstructive procedures performed by microsurgical transfer of skin and muscle flaps and transplantation of organs, which are cut off from blood circulation and remain under ischemic conditions during transplantation. Evidence suggests that activation of receptor tyrosine kinases is negatively regulated by protein tyrosine phosphatases (PTP). Inhibition of PTPs enhances endothelial receptor tyrosine kinases activation and may have beneficial effects on blood vessel growth and improve blood flow to ischemic tissue. Human PTP beta (hPTPµ) is specifically expressed by endothelial cells and may play an important role in dynamic response to injury. The purpose of this study is to determine the influence of hPTPµ inhibitors on ischemia and ischemia-reperfusion injury in the rat cremaster muscle flap model.

Material and Methods
Following the cremaster muscle flap dissection, sixty male Lewis rats divided into 10 experimental groups (control, placebo and treatment groups at different time points). In all groups, following the group-specific treatment, microcirculatory hemodynamics (vessel diameters, functional capillary index, vascular permeability index) and leukocyte-endothelial activation (number of rolling, sticking and transmigrating leukocytes in postcapillary venules) were recorded for 4 hours in 1 hour intervals after a 2h period of reperfusion. The effects of drug and placebo were analyzed with Mann Whitney U and Wilcoxon test.

Results
The results of subcutaneous administration of the hPTPµ inhibitor following different periods of muscle ischemia showed preservation of capillary perfusion in group subjected to 2 hours of ischemia when compared with placebo. hPTPµ treated ischemic groups (1h, 2h and 3h) showed decreased activation of rolling, sticking and transmigrating leukocytes compared to the respective placebo groups at all time points. The differences were significant for transmigrating leukocytes after 2h and 3h of ischemia. There was also a significant reduction in the endothelial edema index in the 2h ischemia group.

Conclusions
This study confirmed that administration of hPTP inhibitors after submission of tissue to sub-critical ischemic conditions (1-2 hours) improved functional capillary perfusion and decreased leukocytes-endothelial activation during 4 hours observation time after muscle reperfusion. These results indicate that hPTPµ has potential as a post-conditioning therapy applied after tissue ischemia, before the reperfusion injury insult will take effect.


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