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: 10545042
• 负责人: Emanuela Marina Bruscia
• 金额: $ 77.17万
• 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/10545042
• 关键词: Affect; Bacteria; Bacterial Infections; Blood Cells; Bone Marrow; CD34 gene; Cell Separation; Cells; Chronic; Cicatrix; 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; Immunologic Memory; Immunology; Impairment; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knockout Mice; Life Expectancy; Lipopolysaccharides; Lung; Lung immune response; Lung infections; Macrophage; Mediating; Methodology; Modeling; Mus; Myelogenous; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; 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 Factor beta; Translating; Umbilical Cord Blood Transplantation; Work; Xenograft Model; chronic inflammatory disease; cystic fibrosis mouse; cystic fibrosis patients; drug efficacy; fighting; hematopoietic stem cell differentiation; immunodeficient mouse model; improved; innovation; lung injury; memory acquisition; migration; monocyte; mouse model; novel; pharmacologic; 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渐进和不可逆的肺结构背后的机制 最终导致囊性纤维化患者（CF）的损伤。我们已经开发了CF 慢性炎症的小鼠模型，该模型概括了进行性和不可逆的肺组织重塑 在晚期CF肺部疾病中。这里的总体目标是了解导致的细胞机制 进行性和不可逆的CF肺确定。目的是研究炎性单核细胞和 单核细胞衍生的MφS（MφS）有助于CF中不可逆的肺组织重塑的发展。我们的 中心假设是，在CF中，慢性肺暴露于脂多糖（LPS）会增加募集 对肺部的炎症单核细胞，这些单核细胞被编程以引起组织损伤，而 无法有效地对抗感染。此外，我们假设这是由CFTR函数丢失引发的 在骨髓中的造血干/祖细胞中。理由是基于观察 在患有 参见当长期暴露于LPS时，我们的CF小鼠模型概括了此功能。而且，六个之后 从慢性LPS暴露中恢复数周，CF肺的单核细胞保持“促炎性” 签名，表明CF单核细胞功能发生了永久变化。此外，我们使用 炎症单核细胞迁移的小鼠模型受损（CCR2 - / - 小鼠）。这些研究表明 炎症单核细胞驱动肺组织重塑，这是由于长期暴露于LPS引起的。我们的 具体目的将检验以下假设：（目标1）降低循环炎症的募集 长期暴露于LPS期间，单核细胞至CF肺足以减少TGFβ信号传导并减轻组织 在CF肺中进行重塑，而没有损害宿主防御细菌的防御； （目标2）先天免疫 由慢性LPS暴露引起的CF髓样祖细胞中的记忆获取将产生 炎性单核细胞无法有效清除感染并造成严重的肺组织损伤； （目的 3）造血茎/祖细胞和单核细胞中的细胞自主CFTR功能障碍有助于 对慢性肺暴露于LPS的致病反应。贡献很重要，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理 持续细菌肺部感染的疾病。我们提出的研究具有创新性，因为我们将使用小说 小鼠模型，我们将桥接肺免疫学和造血干细胞场中的方法， 我们将使用公正的尖端技术。完成这项工作时，我们将确定小说 CF中肺部免疫增强响应的长期煽动破坏单核细胞肺轴的机制 反馈，导致进行性肺部损伤。最终，这些研究可能会确定有效的新途径 减慢CF肺定义的治疗干预措施。