Sinomenine blocks tissue remodeling in a rat model of chronic cardiac allograft rejection.
Sinomenine blocks tissue remodeling in a rat model of chronic cardiac allograft rejection.
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DOI：
10.1097/01.tp.0000056610.22062.03
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发表时间：
2003-04-15
期刊：
影响因子：
6.2
通讯作者：
Margreiter, R
中科院分区：
文献类型：
--
作者：
Mark, W;Schneeberger, S;Margreiter, R
背景资料。随着时间的推移，慢性排斥反应(CR)合并移植物血管病变是移植物丢失的主要原因。青藤碱(SN)具有抗炎、抗风湿和免疫调节作用。在此之前，我们证实了SN在急性排斥反应中的抗巨噬细胞和抗T细胞作用。在目前的研究中，我们研究了SN在大鼠同种异体心脏移植模型中的作用。在给予环孢素A(CsA)短暂疗程后，接受F344心脏移植的Lewis患者接受单独的SN、单独的CsA或两种药物的联合治疗。对移植物进行形态计量学和免疫组织化学分析。逆转录-聚合酶链式反应检测碱性成纤维细胞生长因子、血管内皮生长因子和内皮素-1的表达。FACS检测抗供体IgM的形成。与未经治疗的大鼠或接受CsA治疗的大鼠相比，接受SN治疗的大鼠的心脏移植物显示出较少的明显血管病变。在两种药物联合治疗后，与单独接受任何一种药物治疗的大鼠相比，大鼠的移植物血管病变明显减少。单独使用CsA治疗导致bFGF表达减少，而单独使用SN不影响基因表达。然而，SN联合CsA可显著降低bFGF、血管内皮细胞生长因子和ET-1的表达。SN单独应用不能抑制抗供体抗体的形成。这些研究首次证明了SN在慢性心脏移植排斥反应模型中的治疗价值。SN联合低剂量T细胞靶向免疫抑制可有效控制CR患者的组织重塑，并与抑制参与血管生成、血管张力和组织重塑的移植物内介质的表达有关。
Background. 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.Materials and Methods. 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. Anti-donor IgM formation was investigated by FACS.Results. 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.Conclusion. 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.