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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.

摘要