Progenitor Cells in Airway Repair

项目概要/摘要： 肺移植通常是终末期肺部疾病唯一可行的治疗选择。 不幸的是，肺移植与许多严重的并发症有关，包括急性 排斥反应和闭塞性细支气管炎综合征（BOS）。研究表明，免疫介导的 气道上皮细胞的损伤和丧失在BOS的发病机制中是关键的。针对这种生物学可以 因此为开发新的预防排斥反应的治疗策略提供了重大突破 在肺移植中。我们已经确定了循环上皮祖细胞（CEPC）， 并帮助修复上皮细胞。这些细胞表达细胞角蛋白5， 气道中的基底上皮祖细胞，以及通过CXCR 4/CXCL 12生物轴的运输。 与CEPC在气道修复中的重要性相一致，阻断CEPC的募集， CXCL 12的中和抗体导致鳞状化生的表型。这意味着 在呼吸道小生境中循环和驻留祖上皮细胞之间的相互作用对于 正常气道修复我们假设增强受体CEPC在供体气道的植入， 肺移植后的上皮将改善上皮修复，导致同种异体识别减少， 供体肺并最终减少BOS。本提案的目标是：1）调查居民的作用 和循环上皮祖细胞群体在BOS的发展，通过选择性消除 这些细胞群，2）检查增强的CEPC动员对 BOS和3）使用患者肺移植血液样本来确定CEPC是否与患者相关 结果。这些研究将使我们进一步了解上皮祖细胞的作用 细胞的呼吸道，并将使利用CEPC的治疗潜力。

Project Summary/Abstract: Lung transplantation is often the only viable therapeutic option for end-stage pulmonary disorders. Unfortunately, lung transplantation is associated with numerous serious complications including acute rejection and bronchiolitis obliterans syndrome (BOS). Studies have indicated that immune-mediated injury and loss of airway epithelial cells is critical in the pathogenesis of BOS. Targeting this biology could therefore provide a major breakthrough for developing new therapeutic strategies for preventing rejection in lung transplantation. We have identified circulating epithelial progenitor cells (CEPC) that are recruited to the injured airway and aid in repair of the epithelium. These cells express cytokeratin 5, a marker of progenitor basal epithelial cells in the airway, and traffic via the CXCR4/CXCL12 biological axis. Consistent with the importance of CEPC in airway repair, blocking the recruitment of CEPC with neutralizing antibodies to CXCL12 resulted in the phenotype of squamous metaplasia. This implies that the interaction between circulating and resident progenitor epithelial cells in the airway niche is critical for normal airway repair. We hypothesize that enhancing engraftment of recipient CEPC into donor airway epithelium after lung transplantation will improve epithelial repair, result in less allo-recognition of the donor lung and ultimately reduce BOS. The goal of this proposal is to: 1) investigate the role of resident and circulating epithelial progenitor cell populations in the development of BOS by selectively eliminating these cell populations, 2) examine the effect of enhanced mobilization of CEPC on the development of BOS and 3) use patient lung transplant blood samples to determine whether CEPC correlate with patient outcome. The proposed studies will allow us to further understanding of the role of epithelial progenitor cells in the airway and will enable the harnessing of the therapeutic potential of CEPC.