Ischemia/reperfusion injury model development
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AbstractA major barrier to the success of renal organ transplantation is the recognition by the recipient's immune system of the graft as foreign. This, ultimately, culminates in rejection. The process of transplantation itself facilitates this outcome by priming the organ for injury and subsequent inflammation through a process known as ischemia/reperfusion (1/R). The Stress Activated Protein Kinases (SAPKs) are a group of intracellular signalling molecules well known to be active under 1/R conditions. However, the mechanism of SAPK activation in response to I/R is, as yet, unknown, as well as its importance. Here, both in vitro and in vivo model systems have been developed for the purpose of understanding the effect of inhibition of the SAPK pathway in response to 1/R injury through the use of recombinant adenoviral vectors carrying dominant/negative transgenes. Two in vitro model systems demonstrate both SAPK activation and leukocyte recruitment to endothelium with the inhibition of SAPK significantly reducing the number of binding leukocytes. In vivo, injury to murine kidneys is produced in response to 1/R, but a renal gene therapy approach requires ex vivo perfusion of the adenoviral vectors to achieve high levels of transfection.
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