A Critical Role for the Microvasculature in Airway Transplantation

描述（由申请人提供）：微血管丧失可能是所有实体器官移植慢性排斥反应的一个未被认识的根本原因。目前还没有关于移植或同种免疫损伤后气道微血管如何立即修复的知识。在同种异体移植肺中维持健康的微血管系统可能是预防终末期气道纤维化的关键，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）是一个理想的模型，用于检查气道微血管损失和受体来源的祖细胞如何促进血管重建。移植后，人和小鼠气道均出现缺氧。在OTT中，缺氧诱导因子1 α (hif -1 α)随进行性缺氧而升高，这可能是移植后受体和供体循环之间联系的原因。本研究将确定hif -1 α和同种异体T细胞的增加是否会诱导血管生成信号，从而促进携带内皮抗原Tie2的推定修复性内皮细胞的涌入。谱系分析将用于确定迁移内皮细胞的命运在恢复受体来源的微血管。需要验证的整体假设是，气道移植受者对移植物来源的hif -1 α信号作出反应，通过发送Tie2细胞随后融入移植物微血管。特异性Aim 1将使用具有内皮特异性表达的Cre-重组酶（tie - 2cre）与报告基因小鼠Rosa26R （loxP Stop loxP yfp）交叉的小鼠来确定受体Tie2细胞迁移到供体气道的命运。这一目的也将研究缺氧和T细胞亚群对Tie2细胞迁移的影响。特异性目的2将阐明hif -1 α的作用，通过获得和失去的功能实验，气道血运重建，组织pO2，移植物排斥反应和Tie2细胞迁移。这些研究结果可能揭示气道血管修复的基本机制，并可能促进限制纤维生成的新血管生成疗法。

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. PUBLIC HEALTH RELEVANCE: While lung transplantation is a cure for end-stage pulmonary disease, the majority of patients undergoing this procedure will eventually die from scarring of the airways. This may happen, in part, because of a temporary loss of airway blood flow. The proposed studies will investigate how the body's normal reparative processes resupply airways with blood vessels and how this process might be utilized to prevent airway injury.