Pathogenic monocyte response to chronic lung inflammation in cystic fibrosis

致病性单核细胞对囊性纤维化慢性肺部炎症的反应

• 批准号: 10366464
• 负责人: Emanuela Marina Bruscia
• 金额: $ 78.67万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366464
• 关键词: Affect; Bacteria; Bacterial Infections; Blood Cells; Bone Marrow; CD34 gene; Cell Differentiation process; Cells; Chronic; Cicatrix; Complement Factor B; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Delta F508 mutation; Deterioration; Development; Disease; Epigenetic Process; Exposure to; Feedback; Functional disorder; Gene Expression Profile; Genes; Goals; Hematopoietic stem cells; Host Defense; Human; Immune; Immunity; Immunodeficient Mouse; Immunologic Memory; Immunology; Impairment; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knock-out; Lead; Life Expectancy; Lipopolysaccharides; Lung; Lung immune response; Lung infections; Mediating; Methodology; Modeling; Mus; Myelogenous; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Pharmacology; Pseudomonas aeruginosa; Publishing; Pulmonary Cystic Fibrosis; Pulmonary Inflammation; Pulmonary Pathology; Recovery; Research; Research Personnel; Respiratory Failure; Signal Transduction; Structure of parenchyma of lung; Technology; Testing; Therapeutic Intervention; Time; Tissues; Training; Transforming Growth Factors; Translating; Umbilical Cord Blood Transplantation; Work; Xenograft procedure; base; chronic inflammatory disease; cystic fibrosis mouse; cystic fibrosis patients; drug efficacy; fighting; improved; innovation; lung injury; macrophage; memory acquisition; migration; monocyte; mouse model; novel; prevent; progenitor; pulmonary function; recruit; response; stem cells; therapeutic target; therapeutically effective

PROJECT SUMMARY Researchers still do not understand the mechanisms behind the progressive and irreversible lung structural damage that ultimately causes respiratory failure in patients with cystic fibrosis (CF). We have developed a CF mouse model of chronic inflammation that recapitulates the progressive and irreversible lung tissue remodeling in late-stage CF lung disease. The overall goal here is to understand the cellular mechanisms that lead to progressive and irreversible CF lung deterioration. The objective is to study how inflammatory monocytes and monocyte-derived MΦs (MΦs) contribute to the development of irreversible lung tissue remodeling in CF. Our central hypothesis is that, in CF, chronic lung exposure to lipopolysaccharide (LPS) increases recruitment of inflammatory monocytes to the lungs and that these monocytes are programmed to cause tissue damage while failing to effectively fight the infection. Moreover, we hypothesize that this is initiated by the loss of CFTR function in hematopoietic stem/progenitor cells in the bone marrow. The rationale is based on observations that an increased number of inflammatory monocytes and monocyte-derived MΦs are found in the lungs of patients with CF. This feature is recapitulated by our CF mouse model when chronically exposed to LPS. Moreover, after six weeks of recovery from chronic LPS exposure, monocytes from CF lungs maintain a “pro-inflammatory” signature, suggesting a permanent change in CF monocyte functions. Furthermore, we conducted studies using a mouse model in which migration of inflammatory monocytes is impaired (Ccr2-/- mice). These studies suggest that the inflammatory monocytes drive the lung tissue remodeling caused by chronic exposure to LPS. Our specific aims will test the following hypotheses: (aim 1) that lowering the recruitment of circulating inflammatory monocytes to CF lungs during chronic exposure to LPS is sufficient to reduce TGFβ signaling and mitigate tissue remodeling in CF lungs without compromising host defense against bacteria; (aim 2) that the innate immune memory acquisition in CF myeloid progenitor stem cells, caused by chronic LPS exposure, will generate inflammatory monocytes that fail to effectively clear infections and that cause profound lung tissue damage; (aim 3) that cell-autonomous CFTR dysfunction in hematopoietic stem/progenitor cells and monocytes contributes to pathogenic responses to chronic lung exposure to LPS. The contribution is significant because it will result in a better understanding of the pathogenesis of immune-mediated diseases in CF and in other chronic inflammatory diseases with persistent bacterial lung infections. Our proposed research is innovative because we will use novel mouse models, we will bridge together methodologies in lung immunology and hematopoietic stem cell fields, and we will use unbiased cutting-edge technologies. At the completion of this work, we will have identified novel mechanisms by which chronic instigation of the lung immune response in CF disrupts the monocytic-lung axis feedback, leading to progressive lung damage. Ultimately, these studies may identify new pathways for effective therapeutic interventions in slowing down CF lung deterioration.

项目摘要 研究人员仍然不了解进行性和不可逆的肺结构性疾病背后的机制， 最终导致囊性纤维化（CF）患者呼吸衰竭的损伤。我们开发了一种CF 重现进行性和不可逆肺组织重塑的慢性炎症小鼠模型 在晚期CF肺病中。这里的总体目标是了解导致 进行性和不可逆的CF肺恶化。目的是研究炎症单核细胞和 单核细胞来源的MΦ（MΦs）有助于CF中不可逆肺组织重塑的发展。我们 中心假设是，在CF中，长期肺部暴露于脂多糖（LPS）会增加细胞的募集 这些单核细胞被编程为引起组织损伤， 无法有效对抗感染此外，我们假设这是由CFTR功能丧失引起的。 骨髓中的造血干/祖细胞。理由是， 在肺结核患者的肺中发现炎性单核细胞和单核细胞衍生的MΦ数量增加， 参见当长期暴露于LPS时，我们的CF小鼠模型重现了该特征。此外，在6 从慢性LPS暴露中恢复数周后，来自CF肺的单核细胞维持“促炎” 信号，表明CF单核细胞功能的永久性变化。此外，我们进行了研究， 炎性单核细胞迁移受损的小鼠模型（Ccr 2-/-小鼠）。这些研究表明 炎症单核细胞驱动由长期暴露于LPS引起的肺组织重塑。我们 具体目的将检验以下假设：（目的1）降低循环炎性细胞的募集， 在慢性暴露于LPS期间，将单核细胞转移到CF肺足以减少TGFβ信号传导并减轻组织损伤。 在CF肺中重塑而不损害宿主对细菌的防御;（目的2）先天免疫 由慢性LPS暴露引起的CF髓系祖干细胞的记忆获得， 炎性单核细胞不能有效清除感染并导致严重的肺组织损伤;（目的 3)造血干/祖细胞和单核细胞中的细胞自主CFTR功能障碍有助于 慢性肺暴露于LPS的致病反应。这一贡献意义重大，因为它将导致 更好地了解CF和其他慢性炎症中免疫介导疾病的发病机制 持续性细菌性肺部感染的疾病。我们提出的研究是创新的，因为我们将使用新的 小鼠模型，我们将桥梁在肺免疫学和造血干细胞领域的方法， 我们将使用无偏见的尖端技术。在这项工作完成后，我们将确定新的 慢性激发CF中的肺免疫应答破坏单核细胞-肺轴的机制 反馈导致进行性肺损伤最终，这些研究可能会发现新的有效途径， 减缓CF肺恶化的治疗干预。