CXCL10/CXCR3 regulation of ozone-induced epithelial permeability

CXCL10/CXCR3 对臭氧诱导的上皮通透性的调节

基本信息

批准号：
10304848
负责人：
Robert Matthew Tighe
金额：
$ 58.45万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304848
关键词：
Acute Address Adult Agonist Air Albumins Alleles Blood Bone Marrow Bronchoalveolar Lavage Bronchoscopy with Bronchoalveolar Lavage Brush Cell CXC chemokine receptor 3 CXCL10 gene CXCL11 gene CXCL9 gene CXCR3 gene Cells Chimera organism Chronic lung disease Coculture Techniques Dose Epithelial Epithelial Cells Flow Cytometry Functional disorder Gene Expression Genetic Polymorphism Genetic Predisposition to Disease Global Warming Harvest Health Human Immune Immune response Immunohistochemistry Individual Inhalation Interferon Type II Interferons Intervention Knockout Mice Link Liquid substance Lung Measures Mediating Minor Modification Mononuclear Mus National Institute of Environmental Health Sciences Oranges Ozone Pathway interactions Permeability Pharmacology Population Predisposition Production Proteins Public Health Registries Regulation Reporter Research Sampling Serum Signal Transduction Source Surface Testing Tight Junctions Translating airway epithelium airway inflammation antagonist base chemokine exposed human population human data human subject in vivo lung injury macrophage mortality mouse model novel novel therapeutics ozone exposure preservation protein expression receptor recruit

项目摘要

ABSTRACT: Ozone (O3), a highly recognized cause of environmental lung injury, contributes to exacerbations of chronic pulmonary diseases and overall mortality. Despite efforts to reduce ambient O3 levels, these are expected to rise with global warming. Addressing this public health concern requires focus on pulmonary mechanism(s) of O3-induced host-responses to identify candidate pathways that can be targeted with precision in susceptible individuals. O3 inhalation is known to compromise barrier integrity of respiratory epithelial surfaces, an initial step in pulmonary injury. Although frequently overlooked, a compromised epithelium compounds susceptibility to subsequent exposures with airborne infectious and/or toxic agents. Epithelial barrier preservation requires coordinated signaling between the epithelium and resident immune cells, principally macrophages. Identifying the specific cellular mechanisms critical to this interaction would identify individuals with heightened susceptibility to O3 inhalation and potential targets for intervention. In controlled exposures of healthy human subjects to O3, the expression of the interferon-γ (IFN-γ) inducible chemokines CXCL9, CXCL10 and CXCL11 in bronchoalveolar lavage (BAL) macrophages are increased and this expression is associated with increased BAL albumin, a marker of epithelial permeability. Consistent with the human data, mice deficient in the receptor for the IFN-γ inducible chemokines (CXCR3-/-) are protected from O3-induced increases in epithelial permeability and demonstrate altered expression of epithelial barrier proteins. To translate the CXCR3-/- finding, a common human polymorphism of CXCR3 exists wherein individuals with the minor allele have reduced CXCR3 gene expression/function. Therefore, this polymorphism may identify individuals with decreased susceptibility to O3-derived health effects. Based on these findings, we hypothesize that O3 induces the production and release of IFN-γ inducible chemokines by airway macrophages, activating CXCR3 on epithelial cells, which leads to O3-induced permeability via modulation of epithelial barrier proteins. Our Specific Aims are: Aim 1: To define the requirements for and mechanisms of CXCR3 signaling in O3-induced epithelial permeability at the cellular level; Aim 2: To define the impact of CXCL10-CXCR3 signaling on O3-induced epithelial barrier dysfunction in vivo; and Aim 3: To define if a human intronic CXCR3 polymorphism that reduces CXCR3 functionality defines genetic susceptibility to O3-derived alterations in airway inflammation, and epithelial permeability. These studies will clearly determine the extent to which the CXCL10/CXCR3 axis mediates increased O3-induced airway epithelial permeability and whether a functional CXCR3 polymorphism is associated with O3 susceptibility. Furthermore, it provides a means to identify O3- susceptible individuals and define novel therapeutics to limit O3-induced epithelial permeability.

抽象的：臭氧（O3）是备受认可的环境肺损伤原因，导致慢性病加剧肺部疾病和总体死亡率。尽管努力降低环境O3水平，但这些预计将随着全球变暖的兴起。解决这种公共卫生问题需要关注 O3诱导的宿主子弹，以识别可以在易感下精确靶向的候选途径个人。 O3吸入已知会损害呼吸上皮表面的屏障完整性，这是一个初始的肺部损伤的一步。尽管经常被忽视，但上皮化合物的易感性随后接触空气传染性和/或有毒药物。上皮屏障准备需要上皮和居民免疫细胞之间的协调信号传导，主要是巨噬细胞。识别这种相互作用至关重要的特定蜂窝机制将确定个人对O3吸入和干预的潜在目标的敏感性。在受控健康人的受控暴露中受到O3的受试者，干扰素-γ（IFN-γ）诱导趋化因子CXCL9，CXCL10和CXCL11的表达在支气管肺泡灌洗（BAL）中，巨噬细胞增加，并且该表达与增加有关 BAL白蛋白，上皮通透性的标志。与人类数据一致，小鼠在接收方缺乏对于IFN-γ诱导趋化因子（CXCR3 - / - ），可以保护上皮诱导的上皮增加渗透性并表明上皮屏障蛋白的表达改变。翻译CXCR3 - / - 发现，存在CXCR3的常见人类多态性，其中未成年人等位基因的个体具有降低CXCR3基因表达/功能。因此，这种多态性可能会确定对O3衍生的健康影响的敏感性降低。基于这些发现，我们假设O3 通过气道巨噬细胞诱导IFN-γ诱导趋化因子的产生和释放，激活上皮细胞上的CXCR3，通过调节上皮屏障导致O3诱导的渗透率蛋白质。我们的具体目的是：目标1：定义CXCR3信号传导的要求和机制在O3诱导的细胞水平上的上皮渗透性中；目标2：定义CXCL10-CXCR3的影响在体内对O3诱导的上皮屏障功能障碍的信号传导；目标3：定义人内含子CXCR3是否降低CXCR3功能的多态性定义了对O3衍生的改变的遗传敏感性气道炎症和上皮通透性。这些研究将明确确定 CXCL10/CXCR3轴介导了O3诱导的气道上皮渗透性增加 CXCR3多态性与O3敏感性有关。此外，它提供了一种识别O3-的手段敏感的个体并定义了新的疗法以限制O3诱导的上皮渗透性。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Air pollution and respiratory infections: the past, present, and future.

空气污染和呼吸道感染：过去、现在和未来。

DOI：
10.1093/toxsci/kfad003
发表时间：
2023
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
0
作者：
Monoson,Alexys;Schott,Evangeline;Ard,Kerry;Kilburg-Basnyat,Brita;Tighe,RobertM;Pannu,Sonal;Gowdy,KymberlyM
通讯作者：
Gowdy,KymberlyM

Wood smoke particle exposure in mice reduces the severity of influenza infection.