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: 10091437
• 负责人: Yogesh Saini
• 金额: $ 50.11万
• 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/10091437
• 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; 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; Mediating; Mediator of activation protein; Metaplastic Cell; Modeling; Molecular; Mouse Strains; Mucous body substance; Muramidase; Mus; Myelogenous; Myeloid Cells; Outcome; Ozone; Pathogenicity; Pathologic; Pathway interactions; Population; Production; Pulmonary Heart Disease; Role; Signal Transduction; Testing; Therapeutic; United States; Vesicle; aged; cell type; eosinophil; eosinophilic inflammation; granulocyte; inhibitor/antagonist; innovation; lung injury; macrophage; male; mouse model; neonate; neutrophil; novel; older patient; 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.

项目概要 近三分之一的美国人口生活在环境臭氧水平不健康的地区。自从 臭氧水平升高与儿童、老年人和患有先天性心脏病的患者的呼吸系统问题有关。 现有的心肺疾病，阐明臭氧引起的肺病的细胞和分子机制 损伤对于制定治疗策略非常重要。臭氧主要导致 2 型 (Th2) 炎症反应，包括嗜酸性炎症和粘液细胞化生，这也是 过敏性哮喘的特征。据了解，白细胞介素 4 受体 α（IL4Rα，一种常见受体） IL4 和 IL13) 对于 Th2 炎症反应至关重要，目前尚不清楚哪种 IL4Rα 细胞类型是 对于 Th2 相关疾病的各种结果都是不可或缺的。缺乏这方面的知识是一个主要障碍 开发有效的治疗策略，因为如果没有它，IL4Rα抑制剂将仍然是非 特异性且不完全有效，正如正在进行的 IL4Rα 抑制剂临床试验的情况一样。我们的中央 假设骨髓细胞特异性 II 型 IL4R 对于臭氧诱导的粒细胞募集至关重要 以及 Th2 相关反应的病理表现，以及携带 IL4Rα 的骨髓细胞 释放 IL4，通过非骨髓细胞上的 I 型 IL4Rα 调节下游 IL4Rα 信号传导。这 该提案的总体目标是描述 IL4Rα 信号在臭氧中的骨髓细胞特异性作用。 诱导气道疾病并鉴定骨髓-IL4Rα介导的可溶性和囊泡结合介质 臭氧引起的空域炎症。 在目标 1 中，我们将采用髓系、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 充足的小鼠，以研究 骨髓、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。瞄准目标 2，我们将检验我们的假设，即 mye 特异性 IL4Rα 是 IL4 产生所必需的，而 IL4 反过来又介导 通过 I 型 IL4Rα 受体对非骨髓细胞产生下游反应。此外，全面的 将进行支气管肺泡灌洗液（液体和囊泡部分）的分析，以揭示其身份 从携带 IL4Rα 的骨髓细胞和非骨髓细胞释放的额外介质。在目标 3 中，骨髓- 特定 IL4Rα 缺陷小鼠（雄性与雌性；新生儿与成人与老年人）也将暴露于臭氧 臭氧与混合过敏原叠加。这一目标将揭示骨髓的性别和年龄特异性作用 IL4Rα 在哮喘结局中的作用。我们的研究结果将对机制产生变革性影响 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 应用于开发针对臭氧诱导以及其他 Th2- 的细胞特异性疗法 相关疾病。