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.

项目摘要 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.以来 臭氧水平升高与儿童、老年人和先天疾病患者的呼吸问题有关 存在的心肺疾病，阐明臭氧致肺的细胞和分子机制 就制定治疗策略而言，损伤具有非常重要的意义。臭氧导致的主要是II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，白介素4受体α(IL4Rα)是一种常见的 白介素4和白介素13)是Th2型炎症反应所必需的，目前尚不清楚携带白介素4Rα的是哪种细胞类型 对于Th2相关疾病的各种结局来说是不可或缺的。缺乏这样的知识是 开发有效的治疗策略，因为如果没有它，IL4Rα抑制剂将保持非 特异性和不完全有效，正在进行的IL4Rα抑制剂临床试验就是这种情况。我们的中央 假说认为髓系细胞特异性II型IL4R对臭氧诱导的粒细胞募集是必不可少的 和Th2型相关反应的病理表现，以及携带IL4Rα的髓系细胞 释放IL4，通过非髓系细胞上的I型IL4Rα调节下游IL4Rα信号。这个 该提案的总体目标是描述IL4Rα信号在臭氧中的髓系细胞特异性作用。 诱导的呼吸道疾病，并鉴定髓系白细胞介素4Rα介导的可溶性和囊泡结合的介质 臭氧在空气中引起的炎症。在目标1中，我们将使用髓系、巨噬细胞和CDC特异性 IL4Rα缺陷小鼠或仅髓系、仅巨噬细胞和仅CDC-IL4Rα充足的小鼠 髓系、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。在AIM 2，我们将检验我们的假设，即Mye特异性的IL4Rα是产生IL4所必需的，而IL4的产生反过来又介导了 非髓系细胞通过I型IL4Rα受体的下游反应。此外，一个全面的 将进行支气管肺泡灌洗，包括液体和囊泡部分的分析，以揭示其身份。 携带IL4Rα的髓系和非髓系细胞释放的额外介质。在《目标3》中，髓系- 特定的IL4Rα缺陷小鼠(雄性和雌性；新生儿和成人与老年人)也将暴露在臭氧中 因为臭氧叠加了混合过敏原。这一目标将揭示髓系细胞在性别和年龄上的特定作用 白介素4受体α在哮喘预后中的作用我们的研究结果将对机械论产生革命性的影响 对臭氧引起的呼吸道疾病的病理生理学的理解。最终，这些发现可能会成为 应用于开发细胞特异性疗法来对抗臭氧诱导的以及其他Th2- 相关疾病。