Artikel
Immunosuppressant-induced microvascular thrombus formation is not further aggravated by ischemia-reperfusion-injury
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Veröffentlicht: | 20. Mai 2011 |
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Gliederung
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Introduction: In the postoperative period following pancreas-kidney transplantation, pancreatic venous thrombosis is one of the major complications leading to allograft dysfunction and -loss. Besides ischemia-reperfusion(I/R)-injury, immunosuppressants have been implicated in the development of microvascular thrombosis.
Materials and methods: Using the skin fold chamber in C57BL/6J-mice, microvascular thrombus formation was induced photochemically and quantitatively analyzed by intravital fluorescence microscopy (IVM). Animals without I/R received NaCl 0,9% (10 ml/kg/d ip, n=7), Tacrolimus (TAC 10 mg/kg/d ip, n=7) and Cyclosporine (CsA 5 mg/kg/d ip, n=6) on 3 consecutive days or ATG (4 mg/kg ip, n=8) as bolus. Additionally, the influence of a 4-h cold ischemia was examined in mice receiving NaCl (NaCl-I/R, n=6), Tacrolimus (TAC-I/R, n=5), Cyclosporine (CsA-I/R, n=5) or ATG (ATG-I/R, n=5). IVM-analysis was performed 24 hrs after reperfusion. Moreover, sVCAM, sP- and sE-Selectin as well as ADMA-plasma levels were measured by ELISA.
Results: In non-ischemic tissue, microvascular thrombus formation was significantly enhanced after application of TAC, CsA and ATG compared to saline-treated mice (arteriolar and venular occlusion: TAC 251±101s and 179±27 s, CsA 346±25 and 177±12, ATG 310±49 and 220±23 vs. NaCl 888±123 s and 708±141 s; p<0,05). I/R-injury significantly accelerated thrombosis in NaCl-treated mice (arteriolar and venular occlusion: NaCl-I/R 520±94 und 380±39 s vs. NaCl 888±123 und 708±141 s, p<0,05). However, the kinetic of thrombus formation induced by TAC, CsA or ATG in non-ischemic tissue was not further accelerated after I/R. Plasma concentrations of sVCAM-1, sP- and sE-selectin were significantly increased after ATG application whereas TAC-treatment significantly elevated ADMA-plasma-levels in non-ischemic animals. In mice undergoing I/R-injury, sP-selectin plasma levels were significantly increased, the ADMA-plasma-concentrations, however, were reduced compared to non-ischemic mice.
Conclusion: The present results show that application of Tacrolimus, Cyclosporine and ATG significantly enhances microvascular thrombus formation in a skinfold chamber model in mice, most likely by influencing the NO-system and platelet activation, respectively. Cold-I/R-injury accelerates thrombus formation but does not further aggravate the thrombogenic effect of the immunosuppressants.