Abstract

153 Introduction. In this study we describe a new model to investigate the effects of different immunosuppressive drugs on the reduction of vascular changes in syngeneic and allogeneic rat aortic transplants subjected to cold ischaemia. Methods. Segments of abdominal F344 rat aorta preserved in Marshalls solution for 1, 4 or 24 hours at 4°C, were transplanted orthotopically into either F344 or Lewis rats (6/groups = 36 untreated transplants). Further groups(n=36) then received different immunosuppressants by gavage daily at the following doses:- CyA 12mg/kg/day; FK506 0.15mg/kg/day; MMF 20mg/kg/day; SDZ RAD 2.5mg/kg/day. Aortas were retrieved at 2 months and examined by standard histology and computerised morphometry. Results. F344-F344 controls of 1 hour cold ischaemic time (CIT) in all groups showed little histological changes. With increasing ischaemic time in the syngeneic grafts, however, interruptions to the internal elastic lamina were observed, along with reduced medial thickness and cellularity and increased intimal thickness. There was also evidence of smooth muscle cells within the intima. Similar changes occurred in the untreated allogeneic grafts but were more pronounced, changes being most marked in the 24hr CIT allografts. In the treatment groups, the severity of histological changes paralleled their morphometry results. Morphometric analysis showed that CyA resulted in no significant reduction in intimal or medial changes in either the syngeneic or allogeneic groups. Whilst FK506 had a significant effect in reducing damage due to immunological mechanisms (ie. F344-LEW 1hr CIT), it's effect on grafts with longer CIT's was less marked. MMF appeared to reduce immunological damage the greatest and also reduced ischaemic damage. However, SDZ RAD resulted in the most significant reduction in combined damage from immunological and ischaemic mechanisms. Conclusions. This is a reproducible model, and by using orthotopic abdominal aortic transplants, we were able to halve the donor aorta and use each half for two recipients with different CIT, thereby reducing animal numbers. CyA has no effect on the development of CR in this model. FK506 significantly reduces the development of CR only when there is no ischaemic insult. MMF has the greatest effect in reducing CR when immunological insults only are involved, and also reduces CR caused by ischaemic damage. SDZ RAD results in a significant reduction in CR in the presence of ischaemic injury, and also significantly reduces changes caused by combined immunological and ischaemic insults.

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