Recipient-derived EDA fibronectin promotes cardiac allograft fibrosis.
Recipient-derived EDA fibronectin promotes cardiac allograft fibrosis.
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DOI：
10.1002/path.3010
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发表时间：
2012-03
影响因子：
7.3
通讯作者：
Bishop, D. Keith
中科院分区：
文献类型：
--
作者：
Booth, Adam J.;Wood, Sherri C.;Cornett, Ashley M.;Dreffs, Alyssa A.;Lu, Guanyi;Muro, Andres F.;White, Eric S.;Bishop, D. Keith
供体配型和免疫抑制治疗的进展降低了心脏移植物急性排斥反应的发生率;然而，慢性排斥反应仍然是移植物长期存活的重要障碍。虽然抗同种异体移植免疫应答的起始因素已经被确定，但这些因素与心脏纤维化最终发展之间的联系尚未得到很好的理解。组织纤维化类似于夸张的伤口愈合反应，其中细胞外基质（ECM）分子是中心。一种这样的ECM分子是普遍存在的糖蛋白纤连蛋白（FN）的选择性剪接同种型，称为含有额外结构域A的细胞纤连蛋白（EDA cFN）。EDA cFN在纤维形成中起作用，因此，我们假设它也可能调节与慢性排斥反应相关的纤维化重塑。我们比较了EDA cFN缺陷（EDA−/−）和野生型（WT）小鼠的急性和慢性心脏移植排斥反应的发展。虽然EDA−/−小鼠以与WT对照难以区分的方式发生急性心脏排斥反应，但EDA−/−小鼠中的心脏同种异体移植物受到保护，免于与慢性排斥反应相关的纤维化。纤维化减少与心肌细胞肥大或移植物内促纤维化介质表达的差异无关。此外，我们研究了在促进各种T辅助细胞谱系的条件下，整个脾细胞的EDA cFN和总FN的表达。支持调节性T细胞（Treg）发育的条件的特征在于总FN和EDA cFN的最大产量，尽管EDA cFN与总FN的比率在Th 1培养物中最高。这些发现表明，血管内皮细胞衍生的EDA cFN对急性同种异体移植排斥反应是不利的，但它促进了与慢性排斥反应相关的纤维化的发展。此外，有利于调节性T细胞（广泛认为是移植物保护性的）发育的条件可能驱动增强有害重塑反应的ECM分子的产生。因此，EDA cFN可能是改善慢性心脏移植排斥相关纤维化的治疗靶点。
Advances in donor matching and immunosuppressive therapies have decreased the prevalence of acute rejection of cardiac grafts; however, chronic rejection remains a significant obstacle for long-term allograft survival. While initiating elements of anti-allograft immune responses have been identified, the linkage between these factors and the ultimate development of cardiac fibrosis is not well understood. Tissue fibrosis resembles an exaggerated wound healing response, in which extracellular matrix (ECM) molecules are central. One such ECM molecule is an alternatively spliced isoform of the ubiquitous glycoprotein fibronectin (FN), termed extra domain A-containing cellular fibronectin (EDA cFN). EDA cFN is instrumental in fibrogenesis; thus, we hypothesized that it might also regulate fibrotic remodelling associated with chronic rejection. We compared the development of acute and chronic cardiac allograft rejection in EDA cFN-deficient (EDA−/−) and wild-type (WT) mice. While EDA−/− mice developed acute cardiac rejection in a manner indistinguishable from WT controls, cardiac allografts in EDA−/− mice were protected from fibrosis associated with chronic rejection. Decreased fibrosis was not associated with differences in cardiomyocyte hypertrophy or intra-graft expression of pro-fibrotic mediators. Further, we examined expression of EDA cFN and total FN by whole splenocytes under conditions promoting various T-helper lineages. Conditions supporting regulatory T-cell (Treg) development were characterized by greatest production of total FN and EDA cFN, though EDA cFN to total FN ratios were highest in Th1 cultures. These findings indicate that recipient-derived EDA cFN is dispensable for acute allograft rejection responses but that it promotes the development of fibrosis associated with chronic rejection. Further, conditions favouring the development of regulatory T cells, widely considered graft-protective, may drive production of ECM molecules which enhance deleterious remodelling responses. Thus, EDA cFN may be a therapeutic target for ameliorating fibrosis associated with chronic cardiac allograft rejection.
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DOI：
10.1111/j.1600-6143.2009.02826.x
发表时间：
2010-02
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Booth AJ;Csencsits-Smith K;Wood SC;Lu G;Lipson KE;Bishop DK
通讯作者：
Bishop DK
影响因子：
6.2
作者：
Chan, SY;Goodman, RE;Bishop, DK
通讯作者：
Bishop, DK
影响因子：
8.8
作者：
Csencsits, K;Wood, SC;Bishop, DK
通讯作者：
Bishop, DK
影响因子：
3.5
作者：
BORSI, L;CASTELLANI, P;ZARDI, L
通讯作者：
ZARDI, L
DOI：
10.1161/01.atv.15.11.1958
发表时间：
1995-11-01
影响因子：
8.7
作者：
DUBIN, D;PETERS, JH;VANDEWATER, L
通讯作者：
VANDEWATER, L