BM alterations in exacerbation of pulmonary fibrosis

肺纤维化恶化中的 BM 改变

• 批准号: 9898440
• 负责人: SEM H PHAN
• 金额: $ 57.05万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898440
• 关键词: Acute; Adoptive Transfer; Adult Respiratory Distress Syndrome; Amphiregulin; Animal Model; Animals; Bleomycin; Blood; Blood specimen; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Bronchoalveolar Lavage Fluid; CD276 gene; Cells; Chronic; Clinical Trials; Coculture Techniques; Data; Dependence; Detection; Disease; Distal; Epidermal Growth Factor Receptor; Epigenetic Process; Fibroblasts; Fibrosis; Hematopoietic stem cells; Human; Hypertension; ITGAX gene; Immune; Immune response; Inflammatory Response; Innate Immune Response; Innate Immune System; Interleukin-13; Knockout Mice; Ligands; Lung; Lung diseases; Mediating; Mediator of activation protein; Modeling; Mononuclear; Mus; Myeloid Cells; Nature; Organ; Pathogenicity; Patients; Peripheral Blood Mononuclear Cell; Plasma; Play; Population; Progressive Disease; Pulmonary Fibrosis; Pulmonary Hypertension; Research; Role; Saline; Sampling; Signal Transduction; Stable Disease; Stem Cell Factor; Study models; Testing; Transgenic Mice; Transplantation; base; bone cell; chemokine; clinically relevant; effective therapy; endotracheal; epithelium regeneration; human model; idiopathic pulmonary fibrosis; indium-bleomycin; injured; lung injury; monocyte; mutant; novel therapeutic intervention; organ injury; paracrine; protein H(3); pulmonary arterial hypertension; recruit; resistin; response; tool

ABSTRACT Distal organ insult can cause alterations in the bone marrow (BM) that may impact on the response of the distal organ to a subsequent insult. Transfer of CD11c+ cells from BM of bleomycin-treated mice exacerbates pulmonary fibrosis in recipient mice compared to those receiving cells from saline treated controls. Similarly transfer of a subpopulation of BM derived lung myeloid cells caused exacerbation of fibrosis in recipient mice. However, the nature of these alterations and the mechanism of enhancement are poorly understood. Acute exacerbation in idiopathic pulmonary fibrosis (IPF) is poorly understood with respect to pathogenic mechanism, but its resemblance to acute respiratory distress syndrome suggests involvement of the innate immune system. Based on animal model studies and the implication of innate immune system involvement in acute exacerbation in IPF, the evidence suggests that lung injury/fibrosis causes alterations in the BM that then influences the innate immune response to cause exacerbation of the response in the lung to subsequent insult. Previous and preliminary studies revealed elevated expression of the co-regulatory molecule, B7-H3 in IPF lung and detection of soluble B7-H3 in bronchoalveolar lavage fluid of IPF patients with acute exacerbation. Increased B7H3+ cells, an enhanced Th2 response and epigenetic changes in BM cells are associated with exacerbation in the bleomycin model. Thus the project's hypothesis is that initial insult to the lung caused stable alterations in BM cells that result in exacerbation of pulmonary fibrosis in response to a second insult in the same animal, or in recipients when transplanted with this altered BM. This effect is mediated by BM monocytic cells in a B7-H3 dependent manner and in part due to enhancement of lung innate immune cell recruitment and Th2 immune response. To test this hypothesis the following specific aims are proposed, 1) To analyze the effects of lung injury/fibrosis on BM cells with respect to their ability to exacerbate pulmonary fibrosis, 2) To identify the signals from the injured/fibrotic lung causing the BM alterations, 3) To elucidate the role of B7-H3 and the Th2 response in exacerbation of pulmonary fibrosis by the altered BM, and 4) To assess changes in B7-H3 expression in peripheral blood mononuclear cells and plasma from IPF patients with/without acute exacerbation. The studies will use BM chimeric and transgenic mice to evaluate BM alterations and assess their clinical relevance to exacerbation of pulmonary fibrosis by examination of human lung and blood samples from IPF patients with or without acute exacerbation.

摘要 远端器官损伤可引起骨髓（BM）的改变，这可能影响骨髓的反应。 远端器官受到后续损伤。博来霉素处理小鼠BM中的CD 11 c+细胞转移加重 与接受来自盐水处理的对照的细胞的那些小鼠相比，接受者小鼠中的肺纤维化。类似地 转移BM来源的肺髓样细胞亚群导致受体小鼠纤维化恶化。 然而，这些改变的性质和增强的机制知之甚少。急性 特发性肺纤维化（IPF）恶化的致病机制知之甚少， 但它与急性呼吸窘迫综合征的相似之处表明先天免疫系统参与了 系统基于动物模型研究和先天免疫系统参与急性 在IPF恶化时，证据表明肺损伤/纤维化导致BM改变， 影响先天性免疫应答，导致肺中对随后的损伤的应答加重。 既往和初步研究显示，IPF患者中共调节分子B7-H3的表达升高 肺功能及支气管肺泡灌洗液中可溶性B7-H3的检测。 BM细胞中B7 H3+细胞增加、Th 2应答增强和表观遗传变化与 博来霉素模型中的恶化。因此，该项目的假设是，最初的肺损伤导致 BM细胞的稳定改变，其导致肺纤维化响应于第二次损伤的恶化， 相同的动物，或者当移植这种改变的BM时在受体中。这种作用是由BM介导的 单核细胞以B7-H3依赖的方式，部分由于肺先天免疫细胞的增强 募集和Th 2免疫应答。为了检验这一假设，提出了以下具体目标：1） 分析肺损伤/纤维化对BM细胞的影响， 2）为了鉴定来自损伤/纤维化肺的引起BM改变的信号，3）为了阐明BM改变的机制， B7-H3和Th 2应答在由改变的BM引起的肺纤维化恶化中的作用，以及4）评估 有/无IPF患者外周血单核细胞和血浆中B7-H3表达的变化 急性加重这些研究将使用BM嵌合和转基因小鼠来评估BM改变， 通过检查人肺和血液来评估它们与肺纤维化恶化的临床相关性 来自有或无急性加重的IPF患者的样本。