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Fellstrom, B Akyurek, M L Larsson, F Waltenberger, J Wanders, A Funa, K eng Research Support, Non-U.S. Gov't 1997/09/18 Transplant Proc. 1997 Sep;29(6):2558.

Fellstrom, B C Akyurek, M L Dimeny, E M Kaijser, M Larsson, E Wanders, A Wahlberg, J eng Research Support, Non-U.S. Gov't Review 1996/01/01 Adv Nephrol Necker Hosp. 1996;25:51-62.

Peptide growth factors have been reported to contribute to the atherogenic process, and they are known to mediate signals for vascular remodeling. Using syngeneic and allogeneic rat aorta transplant models, we analyzed the impact of cold ischemia time up to 24 hours and reperfusion injury on development of transplant arteriosclerosis during the first 2 months after transplantation. The expression of the transforming growth factor-beta (TGF-beta) family as well as the platelet-derived growth factor (PDGF) and its receptors was studied by use of immunohistochemistry, followed by semiquantitative evaluation and multivariate analysis. In the syngeneically transplanted aortas, the expression of TGF-beta 1, PDGF, and the two PDGF receptors in the neointima increased significantly with the extent of cold ischemia time. Furthermore, there was a significant induction of the latent TGF-beta binding protein in the neointima as well as TGF-beta 2 in the media, both correlating with the observation time after transplantation. In the allogeneic grafts, all examined proteins were already induced strongly 2 weeks after transplantation, even at the shortest ischemic period studied (1 hour). However, no positive correlation between growth factor expression and cold ischemia or observation time could be found. Double immunohistochemistry revealed that macrophages express PDGF and its receptors as well as TGF-beta 1. Smooth muscle cells express both types of PDGF receptors, and a few T cells express TGF-beta 1 as well as PDGF receptors. In summary, TGF-beta and PDGF are induced by allogeneic as well as ischemic stimuli in transplanted aortas, suggesting a role in the pathogenesis of transplant arteriosclerosis and representing a potential target for therapeutic intervention., Waltenberger, J Akyurek, M L Aurivillius, M Wanders, A Larsson, E Fellstrom, B Funa, K eng Research Support, Non-U.S. Gov't 1996/12/01 Arterioscler Thromb Vasc Biol. 1996 Dec;16(12):1516-23.

Adhesion molecules play a crucial role in transplant rejection in regulating the interaction of inflammatory cells with cells in the vascular wall. In an aortic transplantation model, we have previously analysed the early adhesion process (7.5 min to 24 h) and the impact of cold ischaemia time (1-24 h) upon transplant arteriosclerosis during the first 2 months after transplantation in the rat. The aim of this investigation was to study adhesion molecules in accelerated transplant arteriosclerosis in a rat model by analysing the immunohistochemical expression of CD11b and ICAM-1 up to 2 months and followed by a semiquantitative evaluation and multivariant analysis. Antigen expression of CD11b and ICAM-1 adhesion molecules was stronger in the aortic allografts than in the ischaemia-induced syngeneic aortic grafts in the whole vessel wall. Neither ICAM-1 nor CD11b antigen expression correlated significantly with time periods of ischaemia/reperfusion injury in allogeneic or syngeneic aortic transplants. CD11b and ICAM-1 are induced by allogeneic stimuli in transplanted aortas suggesting a role in the pathogenesis of transplant arteriosclerosis. Our findings have implications for understanding the role of cell adhesion activation in the vascular wall subject to chronic graft rejection., Akyurek, M L Funa, K Wanders, A Larsson, E Fellstrom, B C eng Research Support, Non-U.S. Gov't ENGLAND 1995/06/01 Transpl Immunol. 1995 Jun;3(2):107-13.

The influence of the somatostatin analogue angiopeptin on transplant arteriosclerosis was investigated using two aortic transplantation rat models. One was characterized by ischemia/reperfusion-induced changes in syngeneic transplants while immunologically induced changes dominated in the other allogeneic model. Angiopeptin, 100 micrograms/kg per day, was administered continuously until the sacrifice of the rats after 8 weeks. No additional immunosuppression was used in either model. An image analysis system was used to quantify the intimal and medial thicknesses of the grafts. In the syngeneic grafts, the intimal thickness was less than 50% of that of control grafts (P < 0.05), but no difference was seen in the allogeneic model. The expression of selected cells, TGF-beta s, and PDGF and PDGF alpha-receptors was detected immunohistochemically and displayed a similar picture in control and angiopeptin-treated grafts in both models. We conclude that angiopeptin has no clear immunosuppressive properties but may counteract ischemia-induced transplant arteriosclerosis., Akyurek, M L Wanders, A Aurivillius, M Larsson, E Funa, K Fellstrom, B C eng Research Support, Non-U.S. Gov't GERMANY 1995/01/01 Transpl Int. 1995;8(2):103-10.

Akyurek, M L Larsson, E Funa, K Wanders, A Kaijser, M Fellstrom, B C eng Research Support, Non-U.S. Gov't 1995/12/01 Transplant Proc. 1995 Dec;27(6):3555-6.

The effect of cold graft ischemia time on the development of transplant arteriosclerosis was investigated. Aorta grafts from DA or PVG rats were stored in a cold perfusion solution for 1, 4, or 24 hours before being orthotopically transplanted to PVG recipients. After observation times ranging from 2 to 8 weeks, the grafts were examined for various cell populations. Regional changes in the intima and media layers were measured by using an image analysis system. The arteriosclerosis-like changes seen in syngeneic grafts with the longest ischemia time could be almost as prominent as those seen in the allogeneic transplants. The magnitude of the regional intima changes in the syngeneic group correlated well with the ischemia time and in the allogeneic group with the observation time. The cell composition found in the intima and media of the allogeneic vessels consisted of macrophages, T-lymphocytes, MHC class II-expressing cells, and smooth muscle cells, whereas the syngeneic grafts contained almost exclusively smooth muscle cells and macrophages. We therefore conclude that the damage due to prolonged cold ischemia time is sufficient to cause pronounced graft arteriosclerosis. The pathophysiological mechanism leading to ischemia-induced arteriosclerosis is different from the one seen in the allogeneic situation., Wanders, A Akyurek, M L Waltenberger, J Ren, Z P Stafberg, C Funa, K Larsson, E Fellstrom, B eng Research Support, Non-U.S. Gov't 1995/01/01 Arterioscler Thromb Vasc Biol. 1995 Jan;15(1):145-55.

The presence and function of polymorphonuclear granulocytes has been investigated, in particular, in the microcirculation in many short-term models of ischaemia/reperfusion injury. The aim of this study was to examine the presence of granulocytes in the aorta in a recently established long-term model of transplant arteriosclerosis, based on prolonged cold graft ischaemia time in the rat. Aortic grafts of PVG donors were subjected to two different cold ischaemia times of 1 and 4 h (n = 5 in each group) before an orthotopic transplantation to syngeneic recipients. The grafts were explanted shortly after various times post-reperfusion (7.5 min 24 h) and examined with conventional staining, immunohistochemistry and transmission electron microscopy for the presence of granulocytes. The results showed the presence of these cells adherent to the endothelial layer or in the subendothelial layer in grafts with both ischaemia times and with a maximum seen 2 h after transplantation. The internal elastic lamina was interrupted at sites of granulocyte adherence. We concluded that the polymorphonuclear granulocyte may be involved in the ischaemia/reperfusion injury in this model, thus, contributing to the development of accelerated transplant arteriosclerosis., Wanders, A Akyurek, M L Larsson, E Fellstrom, B C eng Research Support, Non-U.S. Gov't Germany 1994/01/01 00:00 Transpl Int. 1994;7 Suppl 1:S371-5.

Wanders, A Akyurek, M L Waltenberger, J Stafberg, C Larsson, E Zhiping, R Funa, K Fellstrom, B eng Research Support, Non-U.S. Gov't Review 1993/04/01 Transplant Proc. 1993 Apr;25(2):2098-9.