A Critical Role for the Microvasculature in Airway Transplantation

描述(由申请人提供)：微血管丢失可能是所有实体器官移植慢性排斥反应的未被认识的根本原因。目前还没有关于移植或同种异体免疫损伤后立即修复呼吸道微血管的知识。在移植肺中保持健康的微血管系统可能是预防终末呼吸道纤维化的关键，也被称为闭塞性细支气管炎综合征(BOS)。因此，了解内皮细胞如何促进血管修复可能有助于促进微血管恢复的治疗，从而预防BOS。小鼠原位气管移植(OTT)是研究呼吸道微血管丢失以及受体来源的祖细胞如何促进血管重建的理想模型。移植后人和小鼠的呼吸道都是低氧的。在OTT中，低氧诱导因子-1α(HIF-1α)的升高伴随着进行性低氧，可能与移植后不久受体和供体循环之间的联系有关。这项提议将确定增加的HIF-1α以及同种异体特异性T细胞是否诱导血管生成信号，从而促进携带内皮抗原Tie2的可能修复的内皮细胞的涌入。谱系分析将用于确定移行内皮细胞在受体来源的微血管重建中的命运。有待检验的全球假设是，呼吸道移植受者通过发送Tie2细胞来对移植物衍生的HIF-1α信号做出反应，这些细胞随后整合到移植物微血管中。特定目的1将使用内皮特异性表达Cre重组酶(Tie-2 Cre)的小鼠与报告小鼠Rosa26R(LoxP Stop LoxP YFP)杂交，以确定受体Tie2细胞迁移到供体呼吸道的命运。这一目标还将研究低氧和T细胞亚群对Tie2细胞迁移的影响。具体目标2将通过功能得失实验阐明HIF-1α对气道血管重建、组织氧分压、移植物排斥反应和Tie2细胞迁移的影响。这些研究的结果可能揭示呼吸道血管修复的基本机制，并可能促进限制纤维化形成的新的血管生成疗法。

DESCRIPTION (provided by applicant): Microvascular loss may be an unappreciated root cause of chronic rejection for all solid organ transplants. There is currently no knowledge about how airway microvasculature is repaired immediately following transplantation or alloimmune injury. Maintaining healthy microvasculature in lung allografts could be key for preventing terminal airway fibrosis, also known as the bronchiolitis obliterans syndrome (BOS). Therefore understanding how endothelial cells contribute to vascular repair may facilitate therapies which enhance microvascular recovery and, in so doing, prevent BOS. Mouse orthotopic tracheal transplantation (OTT) is an ideal model for examining microvascular loss in airways and how recipient-derived progenitor cells contribute to revascularization. Both human and mouse airways are hypoxic following transplantation. In OTT, rising hypoxia-inducible factor 1 alpha (HIF-1alpha) is observed with progressive hypoxia and may be responsible for the connection between recipient and donor circulations soon after transplantation. This proposal will determine if increased HIF-1alpha, as well as allospecific T cells, induce angiogenic signals that promote the influx of putatively reparative endothelial cells bearing the endothelial antigen, Tie2. Lineage analysis will be used to determine the fate of migrating endothelial cells in restoration of the recipient-derived microvasculature. The global hypothesis to be tested is that airway transplant recipients respond to graft- derived HIF-1alpha signals by sending Tie2 cells that subsequently incorporate into graft microvasculature. Specific Aim 1 will use mice with endothelial-specific expression of Cre-recombinase (Tie-2 Cre) intercrossed with reporter mice Rosa26R (loxP Stop loxp yfp) to determine the fate of recipient Tie2 cells migrating into donor airways. This aim will also study the effects of hypoxia and T cell subsets on Tie2 cell migration. Specific Aim 2 will elucidate the effects of HIF-1alpha, through gain- and loss- of function experiments, on airway revascularization, tissue pO2, graft rejection, and Tie2 cell migration. The results of these studies are likely to reveal fundamental mechanisms of vascular repair in airways and may promote novel angiogenic therapies that limit fibrogenesis.