Epithelial Progenitor Cell Dysfunction in the Fibroproliferative Process of CLAD

CLAD 纤维增殖过程中的上皮祖细胞功能障碍

• 批准号: 10450043
• 负责人: JOHN A BELPERIO
• 金额: $ 46.8万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450043
• 关键词: Acute; Affect; Allografting; Alveolar; Area; Binding; Biological; Bronchiolitis Obliterans; Cell Lineage; Cells; Cessation of life; Chronic; Clinical Data; Clinical Trials; Data; Deposition; Development; Diagnosis; Down-Regulation; Environment; Epithelial; Epithelial Cells; Extracellular Matrix; Fibroblasts; Fibrosis; Foundations; Functional disorder; Future; Human; IL10RB gene; Infection; Inflammatory; Injury; Label; Lead; Leukocytes; Lung; Lung Transplantation; Lung diseases; Measures; Mediating; Medical; Mesenchymal; Modeling; Mononuclear; Mus; Natural regeneration; Outcome; Pathway interactions; Phase; Phenotype; Population; Prevention therapy; Prevention trial; Process; Procollagen; Proliferating; Proteins; Pulmonary Fibrosis; Reserve Cell; Risk; Role; Sampling; Signal Transduction; Syndrome; TP53 gene; Transplant Recipients; Transplantation; airway epithelium; base; cell regeneration; cell type; design; effective therapy; epithelial stem cell; exhaust; fibrogenesis; inflammatory milieu; interleukin-22; interstitial; loss of function; lung allograft; mouse model; novel; post-transplant; pre-clinical; prevent; progenitor; pulmonary function; receptor; receptor expression; repaired; stem cells; translational study; transplant model

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.

项目摘要/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（即拒绝）都导致慢性同种异体移植功能障碍（clad） 只有治疗而不是治愈方法。外壳的标志是不懈地将正常上皮的位移 细胞外基质的沉积。目前，没有有效的预防或治疗疗法 外壳。该提案将使用新型的鼠标骨矫形器转移，并重新捕获病理学来建模 层和人类翻译研究的评估，以评估导致上皮祖细胞（EPC）的机制 外壳期间的损失和纤维发生。我们以前已经表明1/17型炎症环境 促进急性排斥（AR），而2型纤维增生环境则支持 外壳中的纤维化。我们的初步数据表明，上皮祖细胞储备（EPCR）的损失导致 纤维状和外壳。此外，我们建议IL-22部分通过p53依赖性途径，功能 移植后不同阶段的不同阶段。在同种异体损伤的早期阶段，IL-22是有益的 通过促进EPCR扩展。但是，后来，IL-22会影响成纤维细胞，从而刺激 外壳中纤维化的发展。 IL-22对肺同种异体移植的结果取决于细胞类型 表达其受体。在炎症类型1/17期间，EPCR表示异二聚体 IL-22受体（IL-22R1和IL-10R2），而成纤维细胞没有。因此，在LT之后的早期受伤阶段，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，当继续侮辱肺同种异体移植时会导致 纤维增生2型2环境，IL-22受体表达在成纤维细胞上诱导并降低。 EPCR。因此，在此阶段，IL-22优先与其受体在成纤维细胞上相互作用，使其偏斜 朝着侵入性的纤维化表型，导致外壳。我们在鼠模型中的初步临床前数据 表明操纵IL-22和p53可以影响外壳的结果，要么通过促进EPC来保护 通过促进纤维浮肿的再生或有害。而且，我们将确保这些途径的相关性 在使用肺移植（LT）接受者的人类中，包括BALF蛋白和培养的生物样品 成纤维细胞以及同种异体移植气道上皮细胞的刷牙。