The Role of Neutrophils in Hypersensitivity Pneumonitis

描述（由申请方提供）：过敏性肺泡炎（HP）或外源性过敏性肺泡炎是一种间质性肺病，在反复暴露于吸入性环境抗原后发生。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。我们实验室一直在研究IFN在HP发展中的作用，使用直枝多孢菌（SR）动物模型。IFN α是反复暴露于SR后小鼠肺中肉芽肿发展所需的Th 1细胞因子。IFN α的产生对于在SR暴露后将T细胞募集到肺中的T细胞趋化因子的表达是重要的;在不存在IFN α的情况下，T细胞募集和随后的肉芽肿形成减少。因此，在SR暴露后产生或调节IFN α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，中性粒细胞是IFN（在HP早期阶段）的来源，在SR暴露前中性粒细胞的耗竭导致IFN（表达降低）。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。拟议研究的目标是：具体目标1-了解中性粒细胞在驱动IFN（SR暴露后肺中产生）中的作用。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.