Mark Walter, Schneeberger Stefan, Seiler Rüdiger, Stroka Deborah M, Amberger Albert, Offner Felix, Candinas Daniel, Margreiter Raimund
Department of Transplant Surgery, University Hospital Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
Transplantation. 2003 Apr 15;75(7):940-5. doi: 10.1097/01.TP.0000056610.22062.03.
Chronic rejection (CR) with graft vasculopathy is recognized as a major cause of graft loss over time. Sinomenine (SN) has anti-inflammatory, antirheumatic, and immunomodulatory effects. Previously, we demonstrated antimacrophage and anti-T cell effects of SN in acute rejection. In the current study, we investigated the effect of SN in a rat cardiac allograft model of CR.
After a brief course of cyclosporine A (CsA), Lewis recipients of F344 hearts were treated with SN alone, CsA alone, or a combination of both drugs. Grafts were analyzed morphometrically and by immunohistochemistry. Expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor, and endothelin 1 was assessed by reverse transcription-polymerase chain reaction. Antidonor IgM formation was investigated by FACS.
Cardiac grafts from SN-treated rats showed less pronounced vasculopathy in comparison with untreated rats or CsA-treated recipients. After treatment with a combination of both drugs, rats had significantly less graft vasculopathy than rats receiving either drug alone. Treatment with CsA alone led to a decrease in bFGF expression, whereas SN alone did not affect gene expression. SN in combination with CsA, however, markedly reduced expression of bFGF, vascular endothelial growth factor, and endothelin 1. SN alone did not inhibit antidonor antibody formation.
These studies demonstrate for the first time the therapeutic value of SN in a model of chronic cardiac allograft rejection. SN in combination with low-dose T cell-targeted immunosuppression is effective in controlling tissue remodeling in the context of CR and is associated with inhibition of intragraft expression of mediators involved in angiogenesis, vascular tone, and tissue remodeling.
伴有移植物血管病变的慢性排斥反应（CR）是导致移植物随时间丢失的主要原因。青藤碱（SN）具有抗炎、抗风湿和免疫调节作用。此前，我们已证明SN在急性排斥反应中具有抗巨噬细胞和抗T细胞作用。在本研究中，我们调查了SN在大鼠心脏同种异体移植CR模型中的作用。
在给予环孢素A（CsA）短期治疗后，将F344心脏的Lewis受体分别单独用SN、单独用CsA或两种药物联合治疗。对移植物进行形态计量分析和免疫组织化学分析。通过逆转录-聚合酶链反应评估碱性成纤维细胞生长因子（bFGF）、血管内皮生长因子和内皮素1的表达。通过流式细胞术研究抗供体IgM的形成。
与未治疗的大鼠或接受CsA治疗的受体相比，接受SN治疗的大鼠的心脏移植物血管病变不那么明显。两种药物联合治疗后，大鼠的移植物血管病变明显少于单独接受任何一种药物治疗的大鼠。单独使用CsA治疗导致bFGF表达降低，而单独使用SN不影响基因表达。然而，SN与CsA联合使用显著降低了bFGF、血管内皮生长因子和内皮素1的表达。单独使用SN不抑制抗供体抗体的形成。
这些研究首次证明了SN在慢性心脏同种异体移植排斥反应模型中的治疗价值。SN与低剂量靶向T细胞的免疫抑制联合使用可有效控制CR情况下的组织重塑，并与抑制移植物内参与血管生成、血管张力和组织重塑的介质表达有关。
