Attenuation of obliterative bronchiolitis by a CXCR4 antagonist in the murine heterotopic tracheal transplant model.
Attenuation of obliterative bronchiolitis by a CXCR4 antagonist in the murine heterotopic tracheal transplant model.
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DOI：
10.1016/j.healun.2008.08.010
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Rojas M
中科院分区：
文献类型：
--
作者：
Xu J;Torres E;Mora AL;Shim H;Ramirez A;Neujahr D;Brigham KL;Rojas M
闭塞性细支气管炎(OB)限制了肺移植的长期成功，而这种疾病的发病机制尚不清楚。趋化因子SDF-1及其受体CXCR4通过招募炎性和成纤维细胞前体细胞进入损伤组织，参与多种纤维化过程。我们推测SDF-1/CXCR4轴在OB的发病机制中也起一定作用。采用小鼠异位同种异体呼吸道移植模型，将Balb/C供体的小鼠气管移植到C57BL/6受体体内。在移植后第10天，我们发现SDF-1在同种异体移植物上皮下层细胞中高表达。流式细胞仪分析表明，CD45+CXCR4+细胞约占移植物细胞总数的26%。受体用CXCR4拮抗剂TN 14003治疗，在植入后第10天减少了细胞对移植物的侵袭。在第42天，与对照组相比，使用TN14003的动物的管腔闭塞显著减少(57.40%比98.21%，p<；0.01)。为了证明SDF-1/CXCR4轴在OB中的相关性，对OB肺移植患者的肺组织切片进行SDF-1和CXCR4的表达检测。我们发现OB患者肺组织中CXCR4和SDF-1阳性细胞数明显高于正常肺组织。这些发现为肺慢性排斥反应的机制提供了新的见解，并可能导致治疗OB的新的干预工具。
Long-term success in lung transplantation is limited by obliterative bronchiolits (OB), while the mechanism for this disease is not well-understood. Chemokine SDF-1 and its receptor CXCR4 have been reported to be involved in several fibrogenic processes by recruiting inflammatory and fibroblast progenitor cells into injured tissues. We hypothesized that SDF-1/CXCR4 axis also plays a role in the pathogenesis of OB. Using the mouse heterotopic allogeneic airway transplant model, we transplanted mouse tracheas from Balb/C donors into C57BL/6 recipients. At day 10 after transplant, we found high expression of SDF-1 in cells in sub-epithelial layers of the allograft. Approximately 26% of cells infiltrating the allograft were CD45+CXCR4+ as was determined by flow cytometry analysis. Treatment of the recipients with a CXCR4 antagonist, TN 14003, decreased cell infiltration into the grafts at day 10 post implantation. At day 42 a significant reduction of the luminal occlusion was found in the TN14003 treated animals compared to controls (57.40% versus 98.21%, p<0.01). To demonstrate the relevance of SDF-1/CXCR4 axis in OB, sections of lung tissue obtained from lung transplanted patients with OB, were examined for SDF-1 and CXCR4 expression. We found higher number of CXCR4 and SDF-1 positive cells in samples from patients with OB compared with normal lungs. These findings provide new insights into the mechanisms of lung chronic rejection and may lead to new intervention tools for the treatment of OB.
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