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) 是环境性肺损伤的一个公认原因，会导致慢性肺损伤的恶化。尽管努力降低环境 O3 水平，但预计这些都会降低。随着全球变暖而增加，解决这一公共卫生问题需要关注肺部机制。 O3 诱导的宿主反应，以确定可在易感人群中精确靶向的候选途径众所周知，吸入 O3 会损害呼吸道上皮表面屏障的完整性，这是最初的结果。尽管经常被忽视，但受损的上皮化合物易感性。随后暴露于空气传播的传染性和/或有毒物质，需要保护上皮屏障。上皮细胞和常驻免疫细胞（主要是巨噬细胞）之间的协调信号传导。对这种相互作用至关重要的特定细胞机制将识别患有哮喘的个体健康人对 O3 吸入的易感性和潜在的干预目标。受 O3 影响，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，这种表达与增加 BAL 白蛋白，上皮通透性的标志物，与人类数据一致，小鼠缺乏受体。因为 IFN-γ 诱导趋化因子 (CXCR3-/-) 受到保护，免受 O3 诱导的上皮细胞增加渗透性并证明上皮屏障蛋白的表达改变以翻译 CXCR3-/-。研究发现，CXCR3 存在一种常见的人类多态性，具有次要等位基因的个体具有 CXCR3 基因表达/功能降低，因此，这种多态性可以识别患有以下疾病的个体。降低对 O3 产生的健康影响的敏感性。根据这些发现，我们发现了 O3。诱导气道巨噬细胞产生和释放 IFN-γ 诱导趋化因子，激活上皮细胞上的 CXCR3，通过调节上皮屏障导致 O3 诱导的通透性我们的具体目标是：目标 1：定义 CXCR3 信号传导的要求和机制。目标 2：确定 CXCL10-CXCR3 的影响体内 O3 诱导的上皮屏障功能障碍的信号转导；目标 3：确定人类内含子 CXCR3 是否存在降低CXCR3功能的多态性定义了对O3衍生的改变的遗传易感性这些研究将清楚地确定气道炎症和上皮通透性的程度。 CXCL10/CXCR3 轴介导 O3 诱导的气道上皮通透性增加以及是否具有功能性 CXCR3 多态性与 O3 敏感性相关，此外，它还提供了一种识别 O3- 的方法。易感个体并确定限制 O3 诱导的上皮通透性的新疗法。

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.