Clara Cells, Their Secretions in Lung Immuno-regulation

描述(由申请人提供)： 即使免疫系统细胞产生的细胞因子可以 显著影响上皮细胞功能，对相互作用知之甚少 上皮细胞在免疫系统调节中的作用。这是一个 在试图理解复杂的一系列事件时的重要问题 导致慢性阻塞性肺疾病患者肺功能恶化 炎症性和/或免疫性肺部疾病，如慢性阻塞性肺病和哮喘。 人们越来越认识到，传导的呼吸道上皮是 它的功能是动态的，慢性肺部疾病导致可预见的 上皮细胞的变化。在这些变化中，包括 无纤毛的呼吸道上皮细胞功能，为此减少了丰度 Clara细胞分泌蛋白(CCSP)是一种生物标志物。是否更改为 Clara细胞是一种原因或一种非纤毛的呼吸道上皮细胞 肺部疾病加重，肺功能持续下降。我们的 最近对CCSP缺失小鼠(CCSP-/-)的研究表明，Clara 细胞在抵御环境因素方面发挥着重要作用 除了发挥关键的免疫调节功能外。这是关键所在 建议是观察到CCSP-/-小鼠提高了当地的产量 免疫球蛋白A。此外，免疫球蛋白A的表达显著上调 CCSP-/-小鼠体内暴露内毒素，但不是野生型小鼠，证明 CCSP缺乏症与B细胞反应性的根本差异。我们 假设CCSP通过以下两种途径之一抑制免疫系统 直接或间接调节局部B细胞功能，这些 B细胞功能的改变影响固有的粘膜防御。如果正确，则更改 在Clara中，细胞功能可能会导致局部免疫的过度刺激 这一反应，虽然有益于急性清除 定植微生物，可能会加剧呼吸道疾病和功能障碍。 AIMS将讨论肺功能改变的四个具体方面 CCSP缺乏症：1)CCSP缺乏症是否导致先天改变 和/或获得性免疫，2)是肺免疫调节和先天免疫的变化 防御与CCSP的丧失直接相关，3)先天防御的差异 CCSP缺乏与B和/或T细胞功能改变直接相关，以及 4)哪些细胞类型对CCSP依赖的改变最敏感 内毒素信号。通过解决这些目标，我们将通过以下方式定义机制 哪种CCSP缺陷会导致肺内免疫调节改变。这 知识可能有助于制定阻止不适当行为的策略 导致肺功能恶化的免疫反应 患有慢性肺病的个人。

DESCRIPTION (provided by applicant): Even though cytokine production by cells of the immune system can significantly impact epithelial cell function, little is known of reciprocal roles for epithelial cells in regulation of the immune system. This is a significant issue when trying to understand the complex series of events that lead to deteriorating lung function among individuals with chronic inflammatory and/or immunological lung diseases such as COPD and asthma. There is a growing recognition that the conducting airway epithelium is dynamic in its function and that chronic lung disease results in predictable changes to epithelial cells. Among these changes are alterations in nonciliated airway epithelial cell function, for which reduced abundance of Clara cell secretory protein (CCSP) serves as a biomarker. Whether changes to Clara cells are a cause or a nonciliated airway epithelial cells contribute to exacerbation of lung disease and a continuing decline in lung function. Our recent studies in CCSP null mice (CCSP-/-) demonstrate that Clara cells fulfill important roles in defense against environmental agents in addition to serving critical immunoregulatory functions. Central to this proposal is the observation that CCSP-/- mice have elevated local production of IgA. Moreover, expression of IgA is dramatically up regulated following in vivo endotoxin exposure of CCSP-/- but not wild type mice, demonstrating fundamental differences in B-cell responsiveness with CCSP deficiency. We hypothesize that CCSP functions to suppress the immune system through either directly or indirectly regulating local B-cell function, and that these changes in B-cell function impact innate mucosal defense. If correct, changes in Clara cell function may lead to hyperstimulation of the local immune response which, although beneficial with respect to the acute clearance of colonizing microorganisms, could exacerbate airway disease and dysfunction. Aims will address four specific aspects of altered lung function that accompanies CCSP deficiency: 1) does CCSP deficiency result in altered innate and/or adaptive immunity, 2) are changes in lung immunoregulation and innate defense directly related to loss of CCSP, 3) are differences in innate defense with CCSP deficiency directly related to altered B-and/or T-cell function, and 4) which cell types are most sensitive to CCSP-dependent alterations in endotoxin signaling. By addressing these aims we will define mechanisms by which CCSP deficiency leads to altered immunoregulation within the lung. This knowledge may help in the development of strategies to block inappropriate immunological responses that lead to deteriorating lung function among individuals with chronic lung disease.