Deletion of cysteine-cysteine receptor 7 promotes fibrotic injury in experimental post-thrombotic vein wall remodeling.
Deletion of cysteine-cysteine receptor 7 promotes fibrotic injury in experimental post-thrombotic vein wall remodeling.
复制标题
DOI：
10.1161/atvbaha.113.302428
复制
发表时间：
2014-02
期刊：
影响因子：
--
通讯作者：
Henke PK
中科院分区：
文献类型：
--
作者：
Laser A;Elfline M;Luke C;Slack D;Shah A;Sood V;Deatrick B;McEvoy B;Ostra C;Comerota A;Kunkel S;Hogaboam C;Henke PK
深静脉血栓形成可导致静脉壁损伤，临床表现为血栓形成后综合征。损伤后纤维化可能部分通过细胞半胱氨酸-半胱氨酸受体7 （CCR7）介导的事件进行调节。我们验证了晚期静脉壁纤维化重构依赖于CCR7的假设。CCR7−/−和C57BL/6野生型（WT）小鼠均存在非瘀或瘀机制诱导的下腔静脉VT。在两种模型中，VT在d1时最大，并在d21时呈下降趋势，而CCR7+细胞在WT小鼠的d8时达到峰值。在两种模型中，CCR7−/−的VT分辨率与WT相比均无显著差异。在非停滞型VT模型中，静脉壁的改变与纤维化损伤一致，在第8天，胶原I、III、MMP2和TGF-b基因表达显著增加，αSMA和FSP-1抗原以及总胶原蛋白增加。相应的，8d时SM22α和FSP-1阳性细胞增加，DDR2阳性细胞未见增加。早期WT血栓暴露抑制体外静脉壁培养中CCR7−/−的促纤维化基因表达。骨髓嵌合体实验进一步显示，循环CCR7+白细胞部分挽救了CCR7−/−小鼠的中期纤维化变化。在慢性血栓形成的股静脉的人类组织学切片中，CCR7+细胞存在于纤维化区域。CCR7 - / -小鼠血栓形成后静脉壁重塑受损，具有纤维化表型，依赖于血栓形成机制，并由循环CCR7+细胞介导。与其他损伤后纤维化反应不同，CCR7+信号可能对VT后阳性静脉壁重塑很重要。
Deep vein thrombosis (VT) can result in vein wall injury, which clinically manifests as post thrombotic syndrome. Post injury fibrosis may be modulated in part through cellular cysteine-cysteine receptor 7 (CCR7) mediated events. We tested the hypothesis that late vein wall fibrotic remodeling is dependent on CCR7. CCR7−/− and C57BL/6 wild type (WT) mice had inferior vena cava VT induced by non-stasis or stasis mechanisms. In both models, VT size was largest at d1, and trended down by d21, while CCR7+ cells peaked at d8 in WT mice. No significant differences in VT resolution were found in CCR7−/− as compared with WT in either model. In the non-stasis VT model, vein wall changes consistent with fibrotic injury was evidenced by significant increases in collagen I, III, MMP2 and TGF-b gene expression, increases in αSMA and FSP-1 antigen, and total collagen at 8d. Correspondingly, SM22α and FSP-1, but not DDR2 positive cells were increased at 8d. Early WT thrombus exposure inhibited profibrotic gene expression in CCR7−/− in ex vivo vein wall culture. Bone marrow chimera experiments further showed circulating CCR7+ leukocytes partially rescued midterm profibrotic changes in CCR7−/− mice. In human histologic sections of chronic thrombosed femoral veins, CCR7+ cells were present in the fibrotic areas. Post thrombotic vein wall remodeling is impaired in CCR7−/− mice, with a profibrotic phenotype, is dependent on the thrombotic mechanism, and is mediated by circulating CCR7+ cells. Unlike other post injury fibrotic responses, CCR7+ signaling may be important for positive vein wall remodeling after VT.