Chronic Innate Immune Adaptation to Organic Dust

描述(由申请人提供) 有机粉尘暴露对在猪舍工作的人来说是一种重要的职业危害。 谷仓。暴露于幼稚个体的有机粉尘会导致强烈的全身和肺脏 炎症反应随着时间的推移而减弱，提示免疫适应。然而，尽管有证据表明工人适应了接触，但三分之一的工人患上了慢性肺部疾病。这一重要的观察结果表明，反复接触有机粉尘会调节免疫系统的反应。许多研究已经表征了单一有机粉尘暴露的炎症反应，但很少有研究表征对重复暴露的反应。利用一种新开发的小鼠模型，研究人员证明，小鼠适应了重复的猪设施有机粉尘暴露，但仍有肺组织炎症的证据。这导致他们探索了重复接触有机粉尘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，与单一暴露相比，重复暴露猪设施有机粉尘会产生一种独特的炎症反应，这与内毒素无关。与单次粉尘暴露相比，重复暴露于猪设施粉尘可导致人单核细胞肿瘤坏死因子-α(TNF-α)、白细胞介素6(IL)-6和IL-1-β降低，但IL-8和IL-10持续升高。升高的IL-10抑制了促炎细胞因子，但也与小鼠的粘液化生和肺组织炎症有关。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)的活性来介导的。基于这些新的观察结果，研究人员假设，反复接触有机粉尘会产生慢性先天免疫炎症适应反应。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，研究人员将确定与人类单核细胞反复接触有机粉尘相比涉及的炎性介质的特征和建立。在目标2中，他们将确定重复与单一有机粉尘引起的炎症的机制，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，候选人是一名成年过敏症专家和免疫学家，对有机粉尘引起的过敏感兴趣。 疾病。她是一位备受支持的候选人，长期以来一直有兴趣成为一名内科科学家，并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.