BM alterations in exacerbation of pulmonary fibrosis

肺纤维化恶化中的 BM 改变

基本信息

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
项目类别：
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

项目摘要

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.

抽象的远端器官侮辱会导致骨髓（BM）的改变，可能会影响对远端器官对随后的侮辱。从博来霉素处理的小鼠的BM转移CD11C+细胞加剧与从盐水处理的对照中接收细胞的人相比，受体小鼠的肺纤维化。相似地 BM衍生的肺髓样细胞的亚群的转移导致受体小鼠的纤维化加剧。但是，这些改变的性质和增强机制的理解很少。急性特发性肺纤维化（IPF）的恶化在致病机制方面的理解很少但是它与急性呼吸窘迫综合征的相似之处表明，先天免疫的参与系统。基于动物模型研究以及先天免疫系统参与急性的影响 IPF加剧的证据表明，肺损伤/纤维化会导致BM的改变，然后影响先天免疫反应，从而导致肺部对随后的侮辱的反应加剧。以前的和初步研究表明，共同调节分子的表达升高，IPF中B7-H3的表达升高 IPF患者的支气管肺泡灌洗液中可溶性B7-H3检测急性加重。 B7H3+细胞增加，BM细胞的Th2反应增强和表观遗传变化与博来霉素模型中加重。因此，该项目的假设是对肺导致的最初侮辱 BM细胞的稳定改变，导致肺纤维化加剧，以应对第二次侮辱同一只动物，或接受这种变化的BM移植时的接受者。该效果由BM介导单核细胞以B7-H3的依赖性方式，部分是由于肺先天免疫细胞的增强招募和TH2免疫反应。为了检验该假设，提出了以下特定目标，1）分析肺损伤/纤维化对BM细胞加重肺的影响纤维化，2）确定来自受伤/纤维性肺的信号，导致BM改变，3）阐明 B7-H3和Th2反应在改变BM的肺纤维化加剧中的作用，4） IPF患者的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嵌合和转基因小鼠评估BM的改变和通过检查人类肺和血液来评估它们与肺纤维化加剧的临床相关性来自有或没有急性加重的IPF患者的样本。