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: 7842892
• 负责人: ELIZABETH ANN FITZPATRICK
• 金额: $ 15.86万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842892
• 关键词: Alveolitis; Animal Model; Antigens; Automobile Driving; Breathing; Cells; Detection; Development; Diagnostic; Disease; Educational workshop; Environment; Exposure to; Extrinsic allergic alveolitis; Fibrosis; Goals; Granuloma; Immune; Immune response; Interferons; Interstitial Lung Diseases; Laboratories; Lead; Lung; Mediating; Molecular; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; Neutrophil Infiltration; Pathogenesis; Patients; Pattern recognition receptor; Play; Production; Rare Diseases; 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（HP）或外源性过敏性肺泡炎是一种间质性肺病，在反复暴露于吸入的环境抗原后发生。该疾病的特征是肺泡炎和肉芽肿形成，在一些患者中会进展为纤维化。 HP 纤维化的发展与高发病率相关；不幸的是，缺乏有关疾病发病机制的信息限制了治疗该疾病的疗法的开发。此外，由于疾病症状的变异性、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，该疾病经常被误诊。我们的实验室一直在使用直肠糖多孢菌 (SR) 动物模型研究 IFN( 在 HP 发展中的作用。 IFN( 是一种 Th1 细胞因子，是反复接触 SR 后小鼠肺部肉芽肿发展所必需的。 IFN(的产生对于 T 细胞趋化因子的表达很重要，这些趋化因子在 SR 暴露后将 T 细胞募集到肺部；在缺乏 IFN( 的情况下，T 细胞募集和随后的肉芽肿形成因此，SR 暴露后产生或调节 IFN( 产生) 的细胞在疾病发病机制中发挥着关键作用。我们的研究表明，中性粒细胞是 HP 早期阶段以及 SR 暴露结果之前中性粒细胞耗尽的来源。这些结果表明，中性粒细胞在 HP 的发展中发挥着关键作用，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。拟议研究的目标是： 具体目标 1 - 了解中性粒细胞在 SR 暴露后驱动肺部产生 IFN(的作用)。具体目标 2 - 确定模式识别受体在中性粒细胞募集到肺部中的作用。