Evidence for recipient derived fibroblast recruitment and activation during the development of chronic cardiac allograft rejection.
Evidence for recipient derived fibroblast recruitment and activation during the development of chronic cardiac allograft rejection.
复制标题
慢性心脏同种异体移植排斥反应发生过程中受体来源的成纤维细胞募集和激活的证据。
DOI：
10.1097/01.tp.0000066362.37931.6d
复制
发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Barr,MarkL
中科院分区：
文献类型：
--
作者：
Wu,GordonD;Tuan,Tai-Lan;Bowdish,MichaelE;Jin,Yang-Sun;Starnes,VaughnA;Cramer,DonaldV;Barr,MarkL
背景：同种异体移植物纤维化是慢性排斥反应的一个显著特征。虽然移植物内成纤维细胞有助于这一过程，其起源和确切的作用仍然知之甚少。Methods.使用大鼠模型的慢性排斥反应，LEW F344，心脏成纤维细胞被分离在排斥反应点，并在胶原凝胶收缩试验中检查，以测量成纤维细胞活化。采用免疫组织化学法检测同种异体移植物微环境的纤维化标志物（转化生长因子[TGF]-β、血小板源性生长因子[PDGF]、组织型纤溶酶原激活物[TPA]、纤溶酶原激活物抑制剂[派]-1、基质金属蛋白酶[MMP]-2和基质金属蛋白酶组织抑制剂[TIMP]-2）。采用聚合酶链反应（PCR）和原位杂交技术研究了移植物内成纤维细胞的来源。结果：从慢性排斥反应的同种异体心脏移植物中分离的成纤维细胞具有较高的凝胶收缩性与未处理的心脏成纤维细胞（在4和24小时分别为30.7%±3.5%和55.3%±6.6%; P< 0.05和< 0.05）相比，在4和24小时分别为50.9%±6.1%和68.2%±3.8%。免疫组化染色观察TGF-β、PDGF、TPA、派-1、MMP-2和TIMP-2的表达。原位杂交证明，被男性受体排斥的女性同种异体移植物中存在sry阳性细胞。65%的成纤维细胞集落（55的85）从女性心脏同种异体移植物中分离表达的男性sry gene.Conclusion.心脏成纤维细胞被激活，并存在于一个profibrogenic微环境中接受慢性排斥反应的同种异体移植物。在这种慢性心脏移植排斥反应的实验模型中，移植物内成纤维细胞的相当大的比例是从同种异体移植物受体中募集的。
Background.Allograft fibrosis is a prominent feature of chronic rejection. Although intragraft fibroblasts contribute to this process, their origin and exact role remain poorly understood.Methods.Using a rat model of chronic rejection, LEW to F344, cardiac fibroblasts were isolated at the point of rejection and examined in a collagen gel contraction assay to measure fibroblast activation. The allograft microenvironment was examined using immunohistochemistry for fibrogenic markers (transforming growth factor [TGF]-β, platelet-derived growth factor [PDGF], tissue plasminogen activator [TPA], plasminogen activator inhibitor [PAI]-1, matrix metalloproteinase [MMP]-2, and tissue inhibitor of matrix metalloproteinase [TIMP]-2). The origin of intragraft fibroblasts was studied using female to male allografts followed by polymerase chain reaction [PCR] and in situ hybridization for the male sry gene.Results.The cardiac fibroblasts isolated from allografts with chronic rejection exhibited higher gel contractibility (50.9%±6.1% and 68.2%±3.8% at 4 and 24 hr) compared with naive cardiac fibroblasts (30.7%±3.5% and 55.3%±6.6% at 4 and 24 hr; P< 0.05 and< 0.05, respectively). Immunostaining for TGF-β, PDGF, TPA, PAI-1, MMP-2 and TIMP-2 was observed in all allografts at the time of rejection. In situ hybridization demonstrated the presence of sry positive cells in female allografts rejected by male recipients. Sixty-five percent of fibroblast colonies (55 of 85) isolated from female heart allografts expressed the male sry gene.Conclusion.Cardiac fibroblasts are activated and exist in a profibrogenic microenvironment in allografts undergoing chronic rejection. A substantial proportion of intragraft fibroblasts are recruited from allograft recipients in this experimental model of chronic cardiac allograft rejection.