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。以来 臭氧含量的增加与儿童、老年人和患有早产儿的患者的呼吸问题有关。 现有的心肺疾病，阐明臭氧诱导肺的细胞和分子机制 就制定治疗策略而言，损伤是非常重要的。臭氧主要导致2型 (Th2)炎症反应，包括嗜酸性粒细胞炎症和粘液细胞化生，也是 过敏性哮喘的症状虽然可以理解白细胞介素4受体α（IL 4 R α，一种常见的 IL 4和IL 13）是Th 2炎症反应所必需的，目前尚不清楚哪种携带IL 4 R α的细胞类型是Th 2炎症反应所必需的。 在Th 2相关疾病的各种结果中不可或缺。缺乏此类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，IL 4 R α抑制剂将保持非 特异性和不完全有效，与正在进行的IL 4 R α抑制剂临床试验一样。我们的中央 一种假设是髓系细胞特异性II型IL 4 R对于臭氧诱导的粒细胞募集是必需的 和Th 2相关反应的病理表现，携带IL 4 R α的髓系细胞 释放IL 4，通过非髓细胞上的I型IL 4 R α调节下游IL 4 R α信号传导。的 该提案的总体目标是描述IL 4 R α信号在臭氧中的髓样细胞特异性作用， 诱导的气道疾病，并确定髓样IL 4 R α介导的可溶性和囊泡结合的介质， 空气中臭氧引起的炎症 在目标1中，我们将采用骨髓，巨噬细胞和cDC特异性 IL 4 R α缺陷小鼠或仅骨髓、仅巨噬细胞和仅cDC-IL 4 R α充足小鼠，以研究 髓系、巨噬细胞和cDC特异性IL 4 R α在臭氧诱导的粒细胞募集中的作用在aim中 2，我们将检验我们的假设，即Mye特异性IL 4 R α是IL 4产生所必需的，而IL 4反过来又介导了IL 4的产生。 通过非髓细胞上的I型IL 4 R α受体的下游反应。此外，全面 将对支气管肺泡灌洗液（液体和囊泡部分）进行分析，以揭示 从携带IL 4 R α的髓样和非髓样细胞释放的额外介质。在目标3中，骨髓- 特定的IL 4 R α缺陷小鼠（雄性与雌性;新生儿与成年人与老年人）也将暴露于臭氧 混合了过敏原的臭氧这一目标将揭示骨髓细胞的性别和年龄特异性作用。 IL 4 R α在哮喘预后中的作用我们的研究结果将对机械学产生变革性的影响。 了解臭氧引起的呼吸道疾病的病理生理学。最终，这些发现可能 应用于开发针对臭氧诱导的以及其他Th 2- 相关疾病。