Endotoxin, allergens and pollutants in asthma

描述(由申请人提供)：很明显，在美国和其他发达国家，称为哮喘的疾病过程正在增加。哮喘发病率的增加并不是由于人口基因构成的变化，而是环境因素的综合作用。哮喘的一些触发因素已经被描绘出来，以及驱动炎症反应的实际分子。然而，引发和传播哮喘的炎性介质的全谱尚未完全确定。我们已经建立了一种新的小鼠哮喘样肺部炎症模型，该模型基于哮喘儿童家中的粉尘。在这个应用中，我们将建立在这个新模型的基础上，提供哮喘样反应的启动者和传播者的更紧密的文档。我们将特别关注这些引发剂如何触发哮喘反应的机制。也许更重要的是，我们将定义由环境触发因素上调的炎症分子，特别强调肿瘤坏死因子(TNF)。该应用将集中在内毒素、过敏原和室外污染物的单独和组合的三重反应上。第一个具体目标将着眼于内毒素在触发哮喘反应中的作用。这个特定的目标将结合使用去除房屋灰尘中的内毒素，以及检测内毒素耐受性动物。使用不止一种方法增加了成功的可能性，并增强了观察的严谨性。在第二个具体目标中，我们将从房屋灰尘提取物中去除过敏原。在第三个具体目标中，我们将确定代表室外污染物的浓缩空气颗粒加剧哮喘反应的可能性。此外，我们将确定暴露在浓缩空气颗粒中是否会使动物产生哮喘反应。对于每一个特定的目标，我们不仅要确定是否存在炎症，而且还要确定炎症介质的范围。在我们的最后一个具体目标中，我们将整合来自先前工作的数据，以通过多种方式阻断肿瘤坏死因子来降低哮喘反应。这些研究的结果将确定内毒素、过敏原和室外污染物在哮喘发病机制中的参与，并确定肿瘤坏死因子在引起炎症中的作用。外行语言：这个应用程序将研究房屋灰尘是如何导致哮喘的。它将专门研究在房屋灰尘、蟑螂和细菌中发现的两种不同成分是如何与室外空气污染相互作用导致肺部炎症的。我们还将调查一种被批准用于治疗类风湿性关节炎的新药是否也有助于预防哮喘。

DESCRIPTION (provided by applicant): It is clear that the disease process known as asthma is on the increase in the United States and other developed countries. This increase in the incidence of asthma is not due to changes in the genetic makeup of the population, but rather a combination of environmental factors. Some of the triggers for asthma have been delineated, as well as the actual molecules that drive the inflammatory response. However, the full spectrum of the inflammatory mediators responsible for the initiation and propagation of asthma have yet to be fully defined. We have established a novel model of murine asthma-like pulmonary inflammation based on house dust from the homes of children with asthma. In this application we will build on this novel model to provide closer documentation of the initiators and propagators of the asthma like response. We will pay particular attention to the mechanisms of how these initiators trigger an asthmatic response. Perhaps of greater importance, we will define the inflammatory molecules upregulated by the environmental triggers with particular emphasis on tumor necrosis factor (TNF). The application will focus on the triumvirate of endotoxin, allergens, and outdoor pollutants both singly and in combination. The first specific aim will look at the role of endotoxin in triggering the asthmatic response. This specific aim will use a combination of removing endotoxin from the house dust in addition to examining endotoxin tolerant animals. Using more than one approach increases the probability of success, as well as enhances the rigor of the observations. In the second specific aim, we will remove the allergen from the house dust extract. In the third specific aim we will determine the potential for concentrated air particles, which represent outdoor pollutants, to exacerbate the asthmatic response. Additionally, we will determine whether exposure to the concentrated air particles will prime an animal to develop an asthmatic response. For each of these specific aims we will not only determine if inflammation is present, but also define the range of inflammatory mediators. In our last specific aim we will integrate the data from the previous work to decrease the asthmatic response by blocking TNF by multiple modalities. The results from these studies will define the participation of endotoxin, allergens and outdoor pollutants in the pathogenesis of asthma and determine the role of TNF in causing the inflammation. Lay language: This application will examine how house dust causes asthma. It will specifically examine how 2 different components found in the house dust, cockroaches and bacteria, interact with outdoor air pollution to result in pulmonary inflammation. We will also investigate if a new drug approved for the treatment of rheumatoid arthritis will also help prevent asthma.