Chronic Innate Immune Adaptation to Organic Dust

描述（由申请人提供） 有机粉尘暴露是养猪场工作人员的重要职业危害 谷仓。有机粉尘暴露于幼稚个体导致强烈的全身和肺部 炎症反应随时间减弱，提示免疫适应。然而，尽管有证据表明工人对暴露有所适应，但仍有三分之一的工人患上慢性肺病。这一重要的观察结果表明，重复接触有机粉尘会调节免疫系统的反应。 许多研究已经描述了单一有机粉尘暴露的炎症反应，但很少有研究描述重复暴露的反应。利用新开发的小鼠模型，研究人员已经证明小鼠适应重复的猪设施有机粉尘暴露，但表现出肺组织炎症的证据。这促使他们探索重复与单一有机粉尘暴露的先天免疫炎症反应。 在人类单核细胞中，研究人员发现，与单次暴露相比，重复猪设施有机粉尘暴露会发生独特的炎症反应，这与内毒素无关。重复暴露于猪舍粉尘导致肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-6和IL-1-β减少，但与单次粉尘激发相比，IL-8和IL-10持续升高。 升高的IL-10抑制促炎细胞因子，但也与小鼠中的粘液化生和肺组织炎症相关。 初步数据还表明，有机粉尘的炎症反应可能是通过蛋白激酶C（PKC）活性介导的。基于这些新的观察结果，研究人员假设慢性先天免疫炎症适应反应发生在重复的有机粉尘暴露中。为了验证这一假设，他们将进行三个具体目标的实验。 在目标1中，研究者将描述并确定与人单核细胞重复暴露于单一有机粉尘相比所涉及的炎症介质。 在目标2中，他们将确定重复与单一有机粉尘诱导的炎症机制，重点是PKC激活的关键作用。 在目标3中，研究人员将使用小鼠重复与单一有机粉尘暴露的体内模型来确定特定炎症介质和PKC激活的作用。 最后，候选人是一个成人过敏症和免疫学家与感兴趣的有机粉尘引起的 疾病她是一个得到良好支持的候选人，长期以来一直有兴趣成为一名医生科学家，他将从临床科学家发展奖中受益匪浅。

DESCRIPTION (provided by applicant) Organic dust exposure is an important occupational hazard for persons who work in swine confinement barns. Organic dust exposure to naive individuals results in an intense systemic and pulmonary inflammatory response that attenuates over time, suggestive of immunologic adaptation. However, despite evidence for adaptation to the exposure, one-third of all workers develop chronic lung disease. This important observation suggests that repeat organic dust exposure modulates the immune system response. Numerous studies have characterized the inflammatory response to a single organic dust exposure, but there have been few studies characterizing the response to repeat exposures. Utilizing a newly developed murine model, the investigators have demonstrated that mice adapt to repeat swine facility organic dust exposure, yet manifest evidence of lung tissue inflammation. This led them to explore the innate immune inflammatory response to repeat versus single organic dust exposure. In human monocytes, the investigators found that a unique inflammatory response occurs to repeat swine facility organic dust exposure as compared to a single exposure, which is independent of endotoxin. Repeat exposure to swine facility dust results in diminished tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-1-beta, but persistently elevated IL-8 and IL-10 compared to a single dust challenge in human monocytes. Elevated IL-10 suppresses pro-inflammatory cytokines, but has also been associated with mucus metaplasia and lung tissue inflammation in mice. Preliminary data also suggest that the inflammatory response to organic dust may be mediated through protein kinase C (PKC) activity. Based on these novel observations, the investigators hypothesize that chronic innate immune inflammatory adaptation responses occur with repeat organic dust exposure. To test this hypothesis, they will perform experiments outlined in three specific aims. In aim 1, the investigators will characterize and establish the inflammatory mediators involved with repeat versus single organic dust exposure in human monocytes. In aim 2, they will determine the mechanisms of repeat versus single organic dust-induced inflammation focusing on the key role of PKC activation. In aim 3, the investigators will determine the role of specific inflammatory mediators and PKC activation using an in vivo model of repeat versus single organic dust exposure in mice. Finally, the candidate is an adult allergist and immunologist with an interest in organic dust-induced diseases. She is a well-supported candidate with a long-standing interest in becoming a physician scientist who will benefit highly from a Clinical Scientist Development Award.