Granulomatous Lung Inflammation

肉芽肿性肺部炎症

基本信息

批准号：
7350226
负责人：
Steven Lynn Kunkel
金额：
$ 41.89万
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：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7350226
关键词：
Adam11 gene Biological Biological Assay CCL17 gene CCL22 gene Cells Chemotactic Factors Chronic Data Development Etiology Event Evolution Fibroblasts Fibrosis Granuloma Granulomatous Impaired wound healing Inflammation Inflammatory Knockout Mice Leukocytes Ligands Lung Lung Inflammation Lung diseases Maintenance Modeling Molecular Profiling Motion Mus Pathology Phenotype Physiology Play Pneumonia Regulation Research Design Reverse Transcriptase Polymerase Chain Reaction Role Source Therapeutic Intervention Thymus Gland Time base chemokine chlorambucil/dactinomycin/methotrexate protocol concept cytokine leukocyte activation leukocyte mediator macrophage-derived chemokine monocyte novel pulmonary granuloma receptor response

Adam11 gene Biological Biological Assay CCL17 gene CCL22 gene Cells Chemotactic Factors Chronic Data Development Etiology Event Evolution Fibroblasts Fibrosis Granuloma Granulomatous Impaired wound healing Inflammation Inflammatory Knockout Mice Leukocytes Ligands Lung Lung Inflammation Lung diseases Maintenance Modeling Molecular Profiling Motion Mus Pathology Phenotype Physiology Play Pneumonia Regulation Research Design Reverse Transcriptase Polymerase Chain Reaction Role Source Therapeutic Intervention Thymus Gland Time base chemokine chlorambucil/dactinomycin/methotrexate protocol concept cytokine leukocyte activation leukocyte mediator macrophage-derived chemokine monocyte novel pulmonary granuloma receptor response

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项目摘要

The initation and maintenance of chronic pulmonary inflammation are dependent upon dynamic interactions between an inciting agent, inflammatory mediators, leukocytes, and structural cells of the lung. Independent of the etiology these interactions set in motion a chronic cascade of events, which contribute to the pathology of granulomatous lung disease, including altered lung physiology, intense inflammation, and an impaired healing response leading to fibrosis. Our over-arching general theme of this section is to determine how the expression and regulation of specific chemokines and their receptors support the initiation and maintenance of experimental lung granulomas characterized by defined cytokine phenotypes. Specifically, we will investigate the mechanisms whereby CCR4 and its IigandsTARC/CCL17 (Thymus and activated chemokine) and MDC/CCL22 (monocyte-derived chemoattractant) contribute to the pathology of chronic lung inflammation. Our data support the concept that CCR4 and it ligands are differentially expressed during the evolution of granulomatous lung inflammation and they possesses novel biological activities associated with granuloma development and fibrosis. Based on these data, we hypothesize that TARC/MDC:CCR4 expression, by both structural cells and leukocytes, are key components of chronic lung inflammation via their ability to modulate cytokine expression, fibroblast activity and leukocyte activation and elicitation. Our studies will focus on the following Specific Aims: To investigate the time-course, magnitude of expression, cellular sources, and mechanisms of expression of CCR4, TARC, and MDC during the evolution of chronic lung inflammation characterized by a type 1 or type 2 cytokine profile. To determine the mechanistic role by which TARC, MDC, and CCR4 expression can regulate the progression of chronic lung inflammation by influencing cytokine expression profiles, fibroblast activation, and leukocyte activation and elicitation. To assess the contribution of resident, structural cell-derived CCR4 and TARC to the maintenance of chronic lung inflammation, via -/- mice and immunoneutralization. To investigate the mechanism of TARC/MDC-CCR4-dependent fibroblast-leukocyte interactions, as an important mechanism for the maintenance of chronic inflammation. We will study well characterized models of chronic lung inflammation in normal and knockout mice using immuno-neutralization, bioassays, ELISAs, Taq-Man RT-PCR, and array analyses. The studies designed in this proposal will show that CCR4 and its ligands play novel roles in the maintenance of chronic lung inflammation and will serve as excellent targets for therapeutic interventions.

慢性肺部炎症的因素和维持取决于动态煽动剂，炎症介质，白细胞和肺的结构细胞之间的相互作用。这些相互作用与病因无关。这些相互作用使一系列慢性事件级联反应，这有助于肉芽肿性肺部疾病的病理学，包括改变肺部生理学，强烈的炎症和导致纤维化的治愈反应受损。我们本节的总体一般主题是确定特定趋化因子及其受体的表达和调节如何支持以定义的细胞因子表型为特征的实验性肺肉芽肿的起始和维持。具体而言，我们将研究CCR4及其IIGANDSTARC/CCL17（胸腺和活化趋化因子）和MDC/CCL22（单核细胞衍生的趋化剂）的机制，有助于慢性肺炎症的病理。我们的数据支持CCR4及其配体在肉芽肿性肺部炎症演化中差异表达的概念，它们具有新颖的与肉芽肿发育和纤维化相关的生物学活性。基于这些数据，我们假设结构细胞和白细胞TARC/MDC：CCR4表达是通过调节细胞因子表达，成纤维细胞活性和白细胞活化和引起的慢性肺炎症的关键组成部分。我们的研究将侧重于以下特定目的：研究以1或2型细胞因子谱的特征的慢性肺部炎症进化期间，CCR4，TARC和MDC表达的时间顺序，细胞来源和CCR4，TARC和MDC的表达机制。为了确定TARC，MDC和CCR4表达可以通过影响细胞因子表达谱，成纤维细胞激活以及白细胞激活和诱导来调节慢性肺炎症的进展。为了评估居民，结构细胞衍生的CCR4和TARC对维持慢性肺部炎症的维持，通过 - / - 小鼠和免疫中性化。为了研究TARC/MDC-CCR4依赖性成纤维细胞 - 白细胞相互作用的机制，这是维持慢性炎症的重要机制。我们将使用正常小鼠和敲除小鼠的慢性肺部炎症模型进行良好的特征模型免疫中和化，生物测定，ELISA，TAQ-MAN RT-PCR和阵列分析。该提案中设计的研究将表明，CCR4及其配体在维持慢性肺部炎症中起着新作用，并将作为治疗干预措施的绝佳靶标。