Organic dust epithelial PKC activation & airway disease

有机粉尘上皮PKC激活

• 批准号: 7645606
• 负责人: DEBRA J ROMBERGER
• 金额: $ 34万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645606
• 关键词: Organic; dust; epithelial; PKC; activation

DESCRIPTION (provided by applicant): Exposure to organic dusts is a cause of airway disease, including chronic obstructive pulmonary disease (COPD). As many as 20% of COPD cases are attributed to occupational exposures. In rural areas, an important source of dust exposure occurs in hog confinement barns. Persons exposed to hog barns have airway inflammation and an increased incidence of COPD. Although many substances are present in hog barn dust that induces inflammation including endotoxins, actual mechanisms leading to COPD are not well defined. Understanding mechanisms of hog barn dust-induced airway disease is relevant in developing both targeted treatment and prevention strategies. Epithelial cells respond to inhaled agents with the release of cytokines that recruit and activate inflammatory cells and expression of molecules that serve as receptors and ligands for interactions with other cells. We observed that hog barn dust extract (HDE) augments human airway epithelial protein kinase C (PKC) activation, resulting in IL-8 and IL-6 release and increased ICAM-1 expression, mediating inflammatory cell adhesion to airway epithelium in vitro. Using an intranasal exposure to HDE in mice, we observed an increase in airway epithelial PKC activation and inflammatory responses in vivo. We recently observed that epithelial cell exposure to HDE results in an increase of the lipid mediator lysophosphatidic acid (LPA). Treatment with phospholipase B to inactivate LPA inhibits HDE-stimulated IL-6 and IL-8 release. The role of LPA induced by hog barn dust in directing airway inflammation is not known. The objective of this proposal is to define mechanisms by which hog barn dust activates epithelial cell PKC and the role of PKC in airway inflammation associated with chronic bronchitis occurring in confinement facility workers and to determine the role of hog barn dust-related LPA, an important lipid mediator, in modulating dust effects on PKC and inflammatory responses. We will address our hypothesis with these specific aims: 1) Determine the biochemical nature and specific identity of factor(s) in HDE that activate epithelial cell PKC and identify the specific PKC isoenzymes activated by HDE and these factors. 2) Establish how HDE-associated lysophosphatidic acid (LPA) modulates HDE-induced epithelial cell PKC activity and IL-8/IL-6 release. 3) Identify mechanisms by which HDE augmentation of epithelial cell PKC In vitro mediates recruitment and adhesion of inflammatory cells to airway epithelium in vitro. 4) Determine how HDE modulates airway epithelial PKC activation and inflammatory responses in vivo utilizing an animal model of exposure, including testing the potential role of LPA.

描述（由申请人提供）：暴露于有机粉尘是气道疾病的原因，包括慢性阻塞性肺部疾病（COPD）。多达20％的COPD案件归因于职业暴露。在农村地区，在养猪场谷仓中发生了一个重要的灰尘暴露来源。暴露于养猪谷仓的人患有气道炎症和COPD发病率增加。尽管在猪谷仓粉尘中存在许多物质，这些物质诱导包括内毒素在内的炎症，但导致COPD的实际机制尚未得到很好的定义。了解猪谷仓尘埃引起的气道疾病的机制与制定有针对性的治疗和预防策略有关。上皮细胞通过释放细胞因子的释放对吸入剂反应，这些细胞因子释放并激活炎症细胞以及分子的表达，这些分子用作与其他细胞相互作用的受体和配体。我们观察到，猪谷仓粉尘提取物（HDE）增加了人类气道上皮蛋白激酶C（PKC）激活，从而导致IL-8和IL-6释放，并增加ICAM-1表达，从而介导炎症细胞粘附到体外eachium interium。在小鼠中使用鼻内暴露于HDE，我们观察到气道上皮PKC激活和体内炎症反应的增加。我们最近观察到，上皮细胞暴露于HDE会导致脂质介质溶血磷脂酸（LPA）的增加。用磷脂酶B处理以灭活LPA，抑制了HDE刺激的IL-6和IL-8释放。尚不清楚由猪谷仓粉尘引起的LPA在指导气道炎症中的作用。该提议的目的是定义机制，该机制通过该机制激活上皮细胞PKC以及PKC在与慢性支气管炎相关的气道炎症中的作用在限制设施工人中发生，并确定Hog Barn粉尘相关的LPA的作用，这是一种重要的脂质脂肪，在PKC和PLKC中的重要脂肪效应，对PKC进行了反应效应。我们将以这些特定目的解决我们的假设：1）确定HDE中因子激活上皮细胞PKC的生化性质和特异性身份，并识别由HDE激活的特定PKC同工酶和这些因素。 2）确定与HDE相关的溶血磷脂酸（LPA）如何调节HDE诱导的上皮细胞PKC活性和IL-8/IL-6释放。 3）确定上皮细胞PKC在体外的HDE增强的机制可介导炎症细胞在体外对气道上皮的募集和粘附。 4）确定HDE如何利用暴露动物模型在体内调节气道上皮PKC激活和炎症反应，包括测试LPA的潜在作用。