Atherogenic effects of cyclosporine in an experimental model of arterial autograft.
One of the effects attributed to CsA is a possible acceleration of atherogenic processes, which contributes to the failure of transplanted organs. This study was undertaken to evaluate the effect of CsA and two vehicles, cremophor and ethanol, in an experimental model of arterial autograft in the rat. Female Sprague-Dawley rats were distributed into 3 study groups: Group 1 (control) had an arterial autograft in the common iliac artery without pretreatment; group 2 (CsA-cremophor) animals were pretreated with a daily dose of CsA (5 mg/kg, Sandimmun) for 4 days before the autograft was made; and group 3 (CsA-ethanol + Tween) animals were pretreated for 4 days before implantation of the autograft with CsA in a vehicle of ethanol + Tween at the same dose as used in group 2 (5 mg/kg). The study periods were 7, 14, 21, 30, and 50 postoperative days. Studies were made by optical microscopy, transmission electron microscopy, scanning electron microscopy, and autoradiography. Evaluation of the results showed that in the control group the postoperative repair process lead to formation of an intimal neolayer throughout the entire surgical zone, with scant participation of white cells. Group 2 (CsA-cremophor) had a marked increase in luminal thrombogenicity, important adhesion and infiltration of white cells, loss of smooth muscle cells in the medial layer, and atherogenic degeneration of the medial layer. The generation of the neointimal layer is delayed by 2 weeks with respect to the control group. However, once the neointimal begins to form, its thickness increases rapidly, reaching values similar to those seen in the control group at 50 days. The myointima also shows atherogenic characteristics, such as monocyte-macrophage infiltration and dystrophic calcification. In group 3 (CsA-ethanol+Tween, that is, CsA in a nonoleaginous vehicle), the effects were similar to those seen in group 2 (CsA-cremophor), with a reduction in the presence of lipid-laden cells in the medial layer. Based on these observations, we conclude that CsA per se induced atherogenic changes in the repair process of the arterial lesion that were independent of the vehicle of administration. CsA delayed, but did not inhibit, formation of a myointima and the myointima formed exhibited atherogenic characteristics. The most important effects were noted in the medial layer, which experienced intense degeneration.
Bellón
J M
JM
Department of Morphological Sciences and Surgery, Faculty of Medicine, University of Alcalá de Henares, Madrid, Spain.
Buján
M J
MJ
Jurado
F
F
Hernando
A
A
Ga-Honduvilla
N
N
Dominguez
B
B
Contreras
L
L
D000818:Animals; D001158:Arteries / Q000473:pathology / Q000637:transplantation*; D001161:Arteriosclerosis / Q000139:chemically induced*; D016572:Cyclosporine / Q000633:toxicity*; D005260:Female; D006965:Hyperplasia; D007166:Immunosuppressive Agents / Q000633:toxicity*; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014182:Transplantation, Autologous
D007166:Immunosuppressive Agents; D016572:Cyclosporine