The role of toll-like receptor 4 in O3-induced lung inflammation and injury.

Toll 样受体 4 在 O3 诱导的肺部炎症和损伤中的作用。

基本信息

批准号：
7516750
负责人：
ALISON K BAUER
金额：
$ 10.7万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-09 至 2010-10-31
项目状态：
已结题

项目摘要

Ozone (O3) exposure associates with exacerbation of asthma and altered lung function in adults and children, and mortality. Over 50% of the U.S. population live in regions where O3 concentrations approach or exceed the National Ambient Air Quality Standard of 0.12parts per million (ppm). We previously identified the innate immunity gene toll-like receptor 4 (Tlr4) as a candidate susceptibility gene for 03-induced lung hyperpermeability and inflammation. C3H/HeOuJ mice (Tlr4 sufficient) are significantly more susceptible to OS-induced hyperpermeability and inflammation compared to coisogenic C3H/HeJ mice (Tlr4 dominant negative mutation). However, the downstream effector mechanisms for TLR4-mediated responses are still unclear. The overall objective of this proposal is to determine the mechanisms by which TLR4 mediates OS- induced lung inflammation and hyperpermeability. The proposed studies will use a multidisciplinary approach using molecular biology, genetics, and pharmacological techniques in an in vivo animal model to address the following specific aims: 1) examine the influence of strain background on the role of TLR4 in OS-induced lung hyperpermeability and inflammation using mice that are TLR4 dominant negative and TLR4 transgenic mice; 2) determine if immediate signaling events downstream of TLR4 are altered in response to O3 exposure in Tlr4 deficient or Tlr4 over-expressed mice and to evaluate the downstream cytokine profiles for these strains to determine if strain background can modulate the types of cytokines produced; 3) investigate the downstream mechanisms by which TLR4-dependent pathways regulate OS- induced responses by verifying the importance of candidate genes identified from Affymetrix global gene arrays in vivo using molecular approaches and utilizing genetic (knockout mice) and pharmacologic methods to investigate specific candidate genes previously identified by the microarray approach. This proposal will enhance our understanding of the mechanisms of OS-induced lung inflammation and injury by the identification of novel pathways regulating OSsusceptibility. These novel pathways may provide preventive strategies for those individuals susceptible to O3.

臭氧 (O3) 暴露与成人哮喘恶化和肺功能改变相关儿童和死亡率。超过 50% 的美国人口居住在 O3 浓度接近的地区或超过国家环境空气质量标准百万分之0.12 (ppm)。我们之前确定的先天免疫基因Toll样受体4（Tlr4）作为03诱导肺的候选易感基因通透性过高和炎症。 C3H/HeOuJ 小鼠（Tlr4 足够）明显更容易受到与同基因 C3H/HeJ 小鼠（Tlr4 显性）相比，OS 诱导的通透性过高和炎症负突变）。然而，TLR4介导的反应的下游效应机制仍不清楚。不清楚。该提案的总体目标是确定 TLR4 介导 OS-的机制诱发肺部炎症和通透性过高。拟议的研究将使用多学科在体内动物模型中使用分子生物学、遗传学和药理学技术的方法解决以下具体目标：1）检查菌株背景对 TLR4 的作用的影响使用 TLR4 显性阴性小鼠和 OS 诱导的肺通透性过高和炎症 TLR4转基因小鼠； 2) 确定 TLR4 下游的直接信号传导事件是否发生改变 Tlr4 缺陷或 Tlr4 过表达小鼠对 O3 暴露的反应并评估下游这些菌株的细胞因子谱以确定菌株背景是否可以调节细胞因子的类型生产； 3）研究TLR4依赖性途径调节OS的下游机制通过验证从 Affymetrix 全局基因中识别出的候选基因的重要性来诱导反应使用分子方法并利用遗传（基因敲除小鼠）和药理学的体内阵列研究先前通过微阵列方法鉴定的特定候选基因的方法。这该提案将增强我们对操作系统引起的肺部炎症和损伤机制的理解识别调节操作系统易感性的新途径。这些新途径可能提供针对 O3 易感人群的预防策略。