The Role of Neutrophils in Hypersensitivity Pneumonitis

中性粒细胞在过敏性肺炎中的作用

• 批准号: 7342785
• 负责人: ELIZABETH ANN FITZPATRICK
• 金额: $ 29.2万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7342785
• 关键词: Alveolitis; Animal Model; Antigens; Automobile Driving; Blood; Breathing; Cells; Detection; Development; Diagnostic; Disease; Educational workshop; Environment; Exposure to; Extrinsic allergic alveolitis; Fibrosis; Goals; Granuloma; Heart; Hypersensitivity; Immune; Immune response; Institutes; Interferons; Interstitial Lung Diseases; Laboratories; Lead; Lung; Mediating; Molecular; Morbidity - disease rate; Mus; Neutrophil Infiltration; Pathogenesis; Patients; Pattern recognition receptor; Play; Pneumonia; Production; Rare Diseases; Rate; Recruitment Activity; Role; Saccharopolyspora; Shapes; Source; Staging; Symptoms; T-Lymphocyte; Testing; Th1 Cells; Toll-Like Receptor 2; United States National Institutes of Health; chemokine; cytokine; genetic risk factor; improved; insight; neutrophil; response; therapy development

DESCRIPTION (provided by applicant): Hypersensitivity Pneumonitis (HP), or extrinsic allergic alveolitis, is an interstitial lung disease that develops following repeated exposure to inhaled environmental antigens. The disease is characterized by alveolitis and granuloma formation that in some patients progresses to fibrosis. The development of fibrosis in HP is associated with high morbidity rates; unfortunately the lack of information on disease pathogenesis has limited the development of therapies to treat the disease. Additionally, the disease is frequently misdiagnosed due to the variability of disease symptoms, differing diagnostic criteria, and a lack of understanding of the environmental antigens and host/genetic risk factors that lead to disease. Our laboratory has been studying the role of IFN( in the development of HP using the Saccharopolyspora rectivirgula (SR) animal model. IFN( is a Th1 cytokine that is required for the development of granulomas in the lungs of mice following repeated exposure to SR. The production of IFN( is important for the expression of T cell chemokines that recruit T cells into the lung following SR exposure; in the absence of IFN(, T cell recruitment and subsequently granuloma formation are reduced. Therefore the cells that produce or regulate IFN( production following SR exposure play a pivotal role in disease pathogenesis. Our studies have revealed that neutrophils are a source of IFN( during the early stages of HP and depletion of neutrophils prior to SR exposure results in decreased IFN( expression. These results suggest that neutrophils play a critical role in the development of HP and understanding the mechanisms that regulate neutrophil recruitment and production of IFN( may provide important new insights into disease pathogenesis. The goals of the proposed study are: Specific Aim1 - to understand the role of neutrophils in driving IFN( production in the lung following SR exposure. Specific Aim 2 - to determine the role of pattern recognition receptors in neutrophil recruitment into the lung.

描述（由申请人提供）：过敏性肺炎（Hypersensitivity Pneumonitis， HP），或外源性过敏性肺泡炎，是一种间质性肺部疾病，在反复暴露于吸入的环境抗原后发生。该病的特点是肺泡炎和肉芽肿的形成，在一些患者进展为纤维化。HP纤维化的发展与高发病率相关；不幸的是，缺乏疾病发病机制的信息限制了治疗这种疾病的疗法的发展。此外，由于疾病症状的可变性、不同的诊断标准以及对导致疾病的环境抗原和宿主/遗传风险因素缺乏了解，该病经常被误诊。我们的实验室一直在研究干扰素（IFN）在HP发展中的作用，使用了糖多孢子虫（SR）动物模型。IFN(是一种Th1细胞因子，是反复暴露于SR的小鼠肺部肉芽肿形成所必需的。IFN(的产生对于SR暴露后募集T细胞进入肺部的T细胞趋化因子的表达很重要；在缺乏IFN(的情况下，T细胞募集和随后肉芽肿形成减少。因此，SR暴露后产生或调节IFN（）产生的细胞在疾病发病机制中起关键作用。我们的研究表明，在HP的早期阶段，中性粒细胞是IFN(的来源，在SR暴露之前中性粒细胞的消耗导致IFN(表达减少。这些结果表明，中性粒细胞在HP的发展中起着关键作用，了解调节中性粒细胞募集和IFN产生的机制可能为疾病发病机制提供重要的新见解。该研究的目标是：特异性目的1 -了解中性粒细胞在SR暴露后肺中驱动IFN生成中的作用。特异性目的2 -确定模式识别受体在中性粒细胞募集到肺中的作用。