Understanding the role of myeloid cells in ozone-induced airway disease

了解骨髓细胞在臭氧引起的气道疾病中的作用

• 批准号: 10337211
• 负责人: Yogesh Saini
• 金额: $ 49.86万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337211
• 关键词: Ablation; Adoptive Transfer; Adult; Age; Airway Disease; Allergens; Area; Asthma; Binding; Bronchoalveolar Lavage; Cells; Child; Clinical Trials; Complex; Data; Dendritic Cells; Development; Disease; Effector Cell; Elderly; Exposure to; Extrinsic asthma; Female; Functional disorder; Gender; IL-13Ralpha1; IL4 gene; IL4R gene; Inflammation; Inflammation Mediators; Inflammatory Response; Interleukin 4 Receptor; Interleukin-13; Knowledge; Liquid substance; LoxP-flanked allele; Lung; Macrophage; Mediating; Mediator; Metaplasia; Modeling; Molecular; Mouse Strains; Mucous body substance; Muramidase; Mus; Myelogenous; Myeloid Cells; Outcome; Ozone; Pathogenicity; Pathologic; Pathway interactions; Patients; Population; Production; Pulmonary Heart Disease; Role; Signal Transduction; Testing; Therapeutic; United States; Vesicle; aged; cell type; eosinophil; eosinophilic inflammation; granulocyte; inhibitor; innovation; lung injury; male; mouse model; neonate; neutrophil; novel; ozone exposure; receptor; recruit; respiratory; response; therapeutically effective

Project Summary Nearly one-third of the United States population lives in areas with unhealthy levels of ambient ozone. Since increased ozone levels are associated with respiratory problems in children, elderly, and patients with pre- existing cardiopulmonary diseases, elucidating the cellular and molecular mechanisms of ozone-induced lung injury is highly significant in terms of formulating therapeutic strategies. Ozone results in predominantly Type 2 (Th2) inflammatory responses including eosinophilic inflammation and mucous cell metaplasia that are also the hallmarks of allergic asthma. While it is understood that interleukin 4 receptor α (IL4Rα, a common receptor for IL4 and IL13) is essential for Th2 inflammatory responses, what is not clear is which IL4Rα-bearing cell-type is indispensable for various outcomes in Th2-associated diseases. Lack of such knowledge is a major obstacle in the development of effective therapeutic strategies, because, without it, the IL4Rα inhibitors will remain non- specific and not fully effective, as is the case with ongoing clinical trials with IL4Rα inhibitors. Our central hypothesis is that myeloid cell-specific Type II IL4R is essential for ozone-induced granulocyte recruitment and the pathological manifestation of Th2-associated responses, and that the IL4Rα-bearing myeloid cells release IL4 that regulates downstream IL4Rα signaling through Type I IL4Rα on non-myeloid cells. The overall objective of this proposal is to delineate the myeloid cell-specific role of IL4Rα signaling in ozone- induced airway disease and to identify myeloid-IL4Rα-mediated soluble and vesicle-bound mediators of ozone-induced inflammation in airspaces. In aim 1 we will employ myeloid-, macrophage-, and cDC-specific IL4Rα deficient mice or myeloid-only-, macrophage-only-, and cDC-only-IL4Rα sufficient mice, to investigate the role of myeloid-, macrophage-, and cDC-specific IL4Rα in ozone-induced granulocyte recruitment. In aim 2, we will test our hypothesis that mye-specific IL4Rα is required for IL4 production that, in turn, mediates the downstream responses through Type I IL4Rα-receptor on non-myeloid cells. Furthermore, a comprehensive analysis of bronchoalveolar lavage, both fluid and the vesicular fraction, will be performed to reveal the identity of additional mediators released from IL4Rα-bearing myeloid and non-myeloid cells. In aim 3, The myeloid- specific IL4Rα deficient mice (males vs females; neonates vs adults vs aged) will be exposed to ozone as well as ozone superimposed with mixed allergens. This aim will reveal gender- and age-specific role of myeloid IL4Rα in asthma outcomes. The findings from our studies will have a transformative impact on the mechanistic understanding of the pathophysiology of ozone-induced airway disease. Eventually, these findings may be applied towards the development of cell-specific therapeutics against ozone-induced as well as other Th2- associated diseases.

项目摘要 美国将近三分之一的人口生活在不健康的环境臭氧的地区。自从 臭氧水平升高与儿童的呼吸道问题有关 现有的心肺疾病，阐明了臭氧诱导的肺的细胞和分子机制 在制定治疗策略方面，伤害非常重要。臭氧主要导致2型 （TH2）包括嗜酸性粒细胞注射和粘液细胞化生的炎症反应也是 过敏性哮喘的标志。虽然可以理解，白介素4受体α（IL4Rα，一种常见的受体 IL4和IL13）对于Th2炎症反应至关重要，尚不清楚哪种含有IL4Rα的细胞类型是 对于Th2相关疾病的各种结果，必不可少的。缺乏这种知识是一个主要障碍 开发有效的治疗策略，因为没有它，IL4Rα抑制剂将仍然是非 特异性且不完全有效，就像IL4Rα抑制剂正在进行的临床试验一样。我们的中心 假设是髓样细胞特异性II型IL4R对于臭氧诱导的粒细胞募集至关重要 以及与Th2相关反应的病理表现，以及带有IL4Rα的髓样细胞 释放IL4，该IL4通过非乳突细胞上的I型IL4Rα信号调节下游IL4Rα信号传导。这 该建议的总体目的是描述IL4Rα信号在臭氧中的髓样细胞特异性作用 诱导气道疾病并鉴定髓样-IL4Rα介导的固体和囊泡结合的介体 臭氧引起的空域炎症。在AIM 1中，我们将采用髓样，巨噬细胞和CDC特异性 IL4Rα缺陷小鼠或仅骨髓，仅巨噬细胞和仅CDC-IL4Rα足够的小鼠，以研究 髓样，巨噬细胞和CDC特异性IL4Rα在臭氧诱导的粒细胞募集中的作用。目标 2，我们将测试我们的假设，即IL4生产需要Mye特异性IL4Rα，从而介导 通过IL4Rα受体受体在非乳突细胞上的下游响应。此外，这是一个全面的 将进行支气管肺泡灌洗的分析，包括流体和囊泡分数，以揭示身份 从含有IL4Rα的髓样和非肌动物细胞中释放出来的其他介体的介质。在AIM 3中，髓样 - 特定的IL4Rα缺陷小鼠（男性与女性；新生儿与成年人与老年人）也将暴露于臭氧 如臭氧与混合过敏原叠加在一起。这个目标将揭示髓样的性别和年龄特定的作用 IL4Rα在哮喘结局中。我们研究的发现将对机制产生变革性的影响 了解臭氧引起的气道疾病的病理生理学。最终，这些发现可能是 用于开发针对臭氧诱导的以及其他TH2-的细胞特异性治疗 相关疾病。