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，这可能会影响 远端器官受到随后的侮辱。博莱霉素组小鼠骨髓CD11c+细胞转移加重 受体小鼠的肺纤维化与接受生理盐水对照组细胞的小鼠进行比较。类似 骨髓来源的肺髓系细胞亚群的转移导致了受体小鼠纤维化的加剧。 然而，这些改变的性质和增强的机制尚不清楚。急性 特发性肺纤维化(IPF)的发病机制尚不清楚， 但它与急性呼吸窘迫综合征的相似之处表明，这与先天免疫有关 系统。基于动物模型研究和先天免疫系统参与急性脑梗塞的意义 IPF的恶化，证据表明肺损伤/纤维化导致BM的改变，然后 影响先天免疫反应，导致肺部对后续侮辱的反应加剧。 先前和初步的研究表明，协同调节分子B7-H3在IPF中的表达增加 IPF急性加重期患者肺组织及支气管肺泡灌洗液中可溶性B7-H3的检测 BM细胞中B7H3+细胞增加、Th2反应增强和表观遗传学变化与 博莱霉素模型中的恶化。因此，该项目的假设是，最初对肺的侮辱导致 骨髓细胞的稳定改变导致肺纤维化的加重，以回应第二次损伤 同样的动物，或移植到这种改变的骨髓的受体中。这一效应是由BM介导的 B7-H3依赖的单核细胞，部分原因是肺固有免疫细胞的增强 募集和Th2免疫反应。为了验证这一假设，提出了以下具体目标：1) 分析肺损伤/纤维化对骨髓细胞加重肺损伤能力的影响 纤维化，2)识别导致骨髓改变的损伤/纤维化肺的信号，3)阐明 B7-H3和Th2应答在改变的骨髓加重肺纤维化中的作用；4)评估 特发性肺纤维化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的改变和 通过对人肺和血液的检查来评估它们与肺纤维化加重的临床相关性 样本来自有或没有急性加重的IPF患者。