The Role of Neutrophils in Hypersensitivity Pneumonitis

描述(申请人提供)：过敏性肺炎(HP)，或外源性过敏性肺泡炎，是一种间质性肺部疾病，在反复暴露于吸入性环境抗原后发展。这种疾病的特点是肺泡炎和肉芽肿形成，在一些患者进展为纤维化。幽门螺杆菌纤维化的发展与高发病率有关；不幸的是，缺乏关于疾病发病机制的信息，限制了治疗该疾病的治疗方法的发展。此外，由于疾病症状的多样性、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。我们实验室一直在利用直立型糖多孢菌(SR)动物模型研究干扰素在幽门螺杆菌发生发展中的作用。干扰素是一种Th1细胞因子，在反复暴露于SR后小鼠肺部肉芽肿的发展过程中是必需的。在SR暴露后，产生的干扰素对T细胞趋化因子的表达很重要；在没有干扰素的情况下，T细胞募集和随后的肉芽肿形成减少。因此，SR暴露后产生或调节干扰素产生的细胞在疾病发病机制中起着关键作用。我们的研究表明，中性粒细胞是干扰素的来源(在幽门螺杆菌的早期阶段)，在SR暴露之前，中性粒细胞的耗尽会导致干扰素的表达减少。这些结果表明，中性粒细胞在幽门螺杆菌的发生发展中起着关键作用，了解中性粒细胞募集和产生干扰素的机制可能为疾病的发病机制提供重要的新见解。拟议研究的目标是：特异性Aim1-了解中性粒细胞在SR暴露后推动肺内产生干扰素的作用。特定目的2-确定模式识别受体在中性粒细胞重新进入肺中的作用。

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.