Inhibiting CXCL12 blocks fibrocyte migration and differentiation and attenuates bronchiolitis obliterans in a murine heterotopic tracheal transplant model.
Inhibiting CXCL12 blocks fibrocyte migration and differentiation and attenuates bronchiolitis obliterans in a murine heterotopic tracheal transplant model.
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DOI：
10.1016/j.jtcvs.2012.03.079
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发表时间：
2013-03
影响因子：
6
通讯作者：
Lau, Christine L.
中科院分区：
文献类型：
--
作者：
Harris, David A.;Zhao, Yunge;LaPar, Damien J.;Emaminia, Abbas;Steidle, John F.;Stoler, Mark;Linden, Joel;Kron, Irving L.;Lau, Christine L.
纤维细胞在肺移植后纤维增生性疾病的发展中是不可或缺的。未分化的纤维细胞（CD 45 + Col 1 + CXCR 4+）优先通过CXCR 4/CXCL 12轴运输并分化为平滑肌肌动蛋白产生细胞（CD 45 + CXCR 4 +αSMA+）。我们推测，针对CXCL 12的抗体将减弱异位气管移植同种异体移植物的纤维细胞迁移和纤维闭塞。使用完全同种异体抗原错配小鼠异位气管移植闭塞性细支气管炎模型。用山羊抗人CXCL 12 F（ab′）2或山羊IgG F（ab′）2处理动物。收集血沉棕黄层、骨髓和气管同种异体移植物，并通过流式细胞术进行分析。通过苏木精/伊红和直接红80胶原染色评估气管腔闭塞。与对照相比，抗CXCL 12处理的动物在移植后7天和21天显示气管同种异体移植物纤维细胞群显著减少。第7天骨髓和血沉棕黄层抽吸物显示出相同的趋势。在抗CXCL 12处理的小鼠中，在移植后21天管腔闭塞减少35%（65.00 [四分位距= 38]%对100 [10]%闭塞; p=0.010），并且在移植后21和28天管腔胶原沉积减少（分别为p=0.042和0.012）。了解纤维细胞在肺移植后气道纤维化中的作用可能会导致治疗策略的范式转变。抗CXCL 12抗体提供了对浸润性纤维细胞的保护，并减少了气管同种异体移植物的恶化。因此，CXCR 4/CXCL 12轴是治疗肺移植后纤维闭塞的新靶点，并且纤维细胞群的定量可以为临床医生提供纤维化的生物标志物，从而允许个体化药物治疗。
Fibrocytes are integral in the development of fibroproliferative disease post lung transplantation. Undifferentiated fibrocytes (CD45+Col1+CXCR4+) preferentially traffic via the CXCR4/CXCL12 axis and differentiate into smooth muscle actin producing (CD45+CXCR4+αSMA+) cells. We postulated that an antibody directed against CXCL12 would attenuate fibrocyte migration and fibro-obliteration of heterotopic tracheal transplant allografts. A total alloantigenic mismatch murine heterotopic tracheal transplant model of obliterative bronchiolitis was used. Animals were treated with either goat-anti-human CXCL12 F(ab′)2 or Goat IgG F(ab′)2. Buffy coat, bone marrow, and trachea allografts were collected and analyzed by flow cytometry. Tracheal luminal obliteration was assessed via hematoxylin/eosin and Direct Red 80 collagen stain. Compared to controls, anti-CXCL12 treated animals showed a significant decrease in tracheal allograft fibrocyte populations at 7 and 21 days post-transplantation. Bone marrow and buffy coat aspirates showed the same trend at 7 days. In anti-CXCL12 treated mice, there was a 35% decrease in luminal obliteration at 21 days (65.00 [interquartile range = 38]% vs. 100 [10]% obliterated; p=0.010) and decreased luminal collagen deposition at 21 and 28 days post transplantation (p=0.042 and 0.012, respectively). Understanding the role of fibrocytes in airway fibrosis post lung transplantation may lead to a paradigm shift in treatment strategy. Anti-CXCL12 antibody afforded protection against infiltrating fibrocytes and reduced deterioration of tracheal allografts. Thus the CXCR4/CXCL12 axis is a novel target for the treatment of fibro-obliteration post lung transplantation and quantification of fibrocyte populations may provide clinicians with a biomarker of fibrosis allowing individualized drug therapy.
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DOI：
10.1016/j.healun.2010.07.005
发表时间：
2010-12
期刊：
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
影响因子：
--
作者：
Zhao Y;LaPar DJ;Steidle J;Emaminia A;Kron IL;Ailawadi G;Linden J;Lau CL
通讯作者：
Lau CL
DOI：
10.1038/nri2990
发表时间：
2011-06
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
8.9
作者：
Ahya, Vivek N.;McShane, Pamela J.;Bhorade, Sangeeta
通讯作者：
Bhorade, Sangeeta
影响因子：
12.8
作者：
Song, Jeong Sup;Kang, Chun Mi;Park, Sung Hak
通讯作者：
Park, Sung Hak
影响因子：
9.6
作者：
Strieter, Robert M.;Mehrad, Borna
通讯作者：
Mehrad, Borna