CXCL10/CXCR3 regulation of ozone-induced epithelial permeability

摘要： 臭氧是一种高度公认的环境肺损伤的原因，它导致慢性肺损伤的恶化。 肺部疾病和总死亡率。尽管努力降低环境中的臭氧水平，但预计这些措施将 随着全球变暖而上升。解决这一公共卫生问题需要关注肺病的发病机制(S) O_3诱导的宿主反应，以识别可精确靶向的敏感基因的候选途径 个人。已知吸入臭氧会损害呼吸道上皮表面屏障的完整性，最初的 导致肺损伤。尽管经常被忽视，但受损的上皮细胞会导致易感性 与随后接触空气传播的传染病和/或有毒物质有关。保护上皮屏障需要 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。识别 对这种相互作用至关重要的特定细胞机制将识别出高度强化的个体。 吸入臭氧的易感性和可能的干预靶点。在健康人的受控暴露中 O_3对干扰素-γ诱导的趋化因子CXCL9、CXCL10和CXCL11表达的影响 在支气管肺泡灌洗(BAL)中，巨噬细胞增加，这种表达与增加有关 白蛋白，上皮通透性的标记物。与人类数据一致的是，受体缺陷的小鼠 对于干扰素-γ诱导的趋化因子(CXCR3-/-)可防止臭氧诱导的上皮细胞增加 通透性，并显示上皮屏障蛋白表达改变。翻译CXCR3-/- 发现，存在一种常见的人类CXCR3基因多态，其中携带少量等位基因的个体具有 CXCR3基因表达/功能降低。因此，这种多态可能会将个体识别为 降低对臭氧产生的健康影响的敏感性。基于这些发现，我们假设臭氧 诱导呼吸道巨噬细胞产生和释放干扰素-γ诱导的趋化因子，激活 CXCR3在上皮细胞上的表达，通过调节上皮屏障导致臭氧诱导的通透性 蛋白质。我们的具体目标是：目标1：定义CXCR3信号的要求和机制 在臭氧诱导的细胞水平上的上皮通透性；目标2：确定CXCL10-CXCR3的影响 体内臭氧诱导的上皮屏障功能障碍的信号转导；以及目标3：确定人内含子CXCR3是否 降低CXCR3功能的多态定义了臭氧衍生的遗传易感性 呼吸道炎症和上皮通透性。这些研究将明确确定在多大程度上 CXCL10/CXCR3轴介导臭氧诱导的呼吸道上皮通透性增加 CXCR3基因多态性与臭氧易感性相关。此外，它还提供了一种识别臭氧- 并定义了限制臭氧诱导的上皮通透性的新疗法。

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.