Epithelial Progenitor Cell Dysfunction in the Fibroproliferative Process of CLAD

项目总结/摘要 肺移植（LT）是晚期肺部疾病的一种选择;不幸的是，由于移植后并发症， 感染和非感染（即，排斥反应），导致慢性肺移植物功能障碍（CLAD）， 只是治疗而不是治愈CLAD的标志是正常上皮细胞被无情的 细胞外基质沉积。目前，还没有有效的治疗方法来预防或治疗 CLAD。这项提议将使用一种新的小鼠原位移植与再移植来模拟病理生物学 CLAD和人类翻译研究，以评估导致上皮祖细胞（EPC） 在CLAD期间的损失和纤维形成。我们之前已经证明，1/17型炎症环境 促进急性排斥反应（AR），而2型纤维增生环境支持AR的发展。 CLAD中的纤维化。我们的初步数据表明，上皮祖细胞储备（EPCR）的损失导致 纤维增生和CLAD。此外，我们认为IL-22部分通过p53依赖性途径发挥作用， 在移植后的不同阶段有所不同。在同种异体移植物损伤的早期阶段，IL-22是有益的 通过促进EPCR扩展。然而，后来，IL-22影响成纤维细胞，从而刺激细胞增殖。 CLAD中纤维化的发展。IL-22对肺同种异体移植物的影响取决于细胞类型， 它的受体是如何表达的。在炎性1/17型阶段，EPCR表达异二聚体 IL-22受体（IL-22R1和IL-10R2），而成纤维细胞没有。因此，在LT后的早期损伤阶段，IL-22 仅在上皮细胞中介导p53信号的下调，从而允许祖细胞增殖 并再生肺上皮。相反，当同种异体肺移植物持续受到损伤时， 在纤维增生2型环境中，IL-22受体表达在成纤维细胞上被诱导，在成纤维细胞上被降低。 EPCR。因此，在这个后期阶段，IL-22优先与成纤维细胞上的其受体相互作用，使它们偏斜， 导致CLAD的侵袭性纤维化表型。我们在小鼠模型中的初步临床前数据 提示调控IL-22和p53可以影响CLAD的结局，或者通过促进EPC而起到保护作用， 再生或通过促进纤维增生而有害。此外，我们将确保这些途径的相关性， 在使用肺移植（LT）接受者生物样品的人中，所述生物样品包括BALF蛋白和培养的 成纤维细胞以及同种异体移植物气道上皮细胞的刷洗。

Project Summary/Abstract Lung transplant (LT) is an option for advanced lung diseases; unfortunately, due to post-transplant complications, both infections and non-infections (i.e., rejections), which leads to chronic lung allograft dysfunction (CLAD) it is only a treatment and not a cure. The hallmark of CLAD is the displacement of normal epithelium by a relentless deposition of extracellular matrix. Currently, there are no effective therapies for the prevention or treatment of CLAD. This proposal will use both a novel mouse orthotopic-transplant-with-regrafting to model the pathobiology of CLAD and human translational studies to evaluate mechanisms that lead to epithelial progenitor cell (EPC) loss and fibrogenesis during CLAD. We have previously shown that a type 1/17 inflammatory environment promotes acute rejection (AR), while the type 2 fibroproliferative environment supports the development of fibrosis in CLAD. Our preliminary data suggests that loss of epithelial progenitor cell reserves (EPCR) leads to fibroplasia and CLAD. Additionally, we propose that IL-22, in part through a p53-dependent pathway, functions differently at different stages post-transplantation. During the early stages of allograft injury, IL-22 is beneficial by promoting EPCR expansion. However, later on, IL-22 influences fibroblasts thereby stimulating the development of fibrosis in CLAD. The consequence of IL-22 upon the lung allograft depends on the cell type on which its receptor is expressed. During the inflammatory type 1/17 phase, the EPCR expresses the heterodimeric IL-22 receptor (IL-22R1 and IL-10R2), while fibroblasts do not. Thus, during early injury stages post-LT, IL-22 mediates downregulation of p53 signaling just in epithelial cells, thereby allowing progenitor cells to proliferate and regenerate the lung epithelium. Conversely, when continued insults to the lung allograft leads to a fibroproliferative type 2 environment, the IL-22 receptor expression is induced on fibroblasts and reduced on EPCR. Thus, at this later stage, IL-22 interacts preferentially with its receptor on fibroblasts, skewing them towards an invasive, fibrotic phenotype resulting in CLAD. Our preliminary pre-clinical data in murine models suggest that manipulating IL-22 and p53 can affect the outcome of CLAD, either protective via promotion of EPC regeneration or harmful via promotion of fibroplasia. Moreover, we will insure the relevance of these pathways in humans using lung transplant (LT) recipients biological samples that include BALF protein and cultured fibroblasts as well as brushing of the allograft airway epithelial cells.