Hypoxia inducible factors in pulmonary endothelial cells regulate allergic inflammatory airways disease

肺内皮细胞缺氧诱导因子调节过敏性炎症性气道疾病

• 批准号: 10515302
• 负责人: Laura Elise Crotty Alexander
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515302
• 关键词: Absenteeism at work; Adhesions; Adult; Affect; Airway Disease; Allergic; Allergic inflammation; American; Antiinflammatory Effect; Asthma; Biological Products; Blood Vessels; Cell Adhesion Molecules; Cell Proliferation; Cell physiology; Cells; Chronic Disease; Circulation; Data; Development; Disease; Disparate; Double Effect; Emergency department visit; Endothelial Cells; Endothelium; Gatekeeping; General Population; Goals; Health Care Costs; Healthcare Systems; Heterogeneity; Hospitalization; Human; Hypoxia Inducible Factor; IL17 gene; IL5 gene; Immune; Immunologics; Individual; Inflammation; Inflammatory; Inflammatory Response; Inhalation Exposure; Knock-out; Knockout Mice; Leukocytes; Lung; Lymphocyte; Macrophage; Metabolism; Modeling; Molecular; Movement; Mus; Myeloid Cells; Organ; Pathogenesis; Pathologic; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Population; Productivity; Proteins; Pulmonary Inflammation; Quality of life; Regulation; Role; Schools; Steroid Resistance; Steroid-resistant asthma; Steroids; Structure of parenchyma of lung; Surface; System; T-Lymphocyte; Testing; Therapeutic; Time; Veterans; Work; anti-IgE; asthma exacerbation; asthma model; asthmatic; cell motility; cell type; chronic inflammatory disease; conventional therapy; cost; disorder control; drug development; economic cost; eosinophil; health care service utilization; immune function; knockout gene; migration; mouse model; neutrophil; new therapeutic target; novel therapeutics; prevent; promoter; pulmonary function; recruit; response; small molecule inhibitor; targeted treatment; tool

Asthma affects 1 in 12 Americans. More than 50% of asthmatics (12 million) have asthma attacks each year. Asthma is a chronic inflammatory disease which has great impact on quality of life. Uncontrolled and untreated asthma leads to missed work and school, as well as high healthcare costs. There are many different types of asthma, some of which are well targeted by current therapeutics leading to disease control. However, there are some endotypes of asthma, such as TH2-low neutrophilic asthma, that do not have targeted therapies available. These endotypes are driven by inflammatory pathways that do not respond to steroids, and thus they are commonly found in steroid-resistant asthma. The premise of our proposed work is that there are additional cell types and pathways that can be identified and targeted in asthma. Hypoxia inducible factors (HIF) have been found to be master regulators of inflammation when expressed in immune cells. HIF-1α is constitutively expressed in all cells, and is important in the regulation of metabolism, cell proliferation and cell migration, in addition to regulating inflammatory pathways. HIF-2α has more limited expression, but like HIF-1α it is expressed in pulmonary endothelial cells and regulates both metabolism and inflammation. We have studied both HIF-α subunits in the setting of asthma, and have found that each regulates inflammation through myeloid cells in a pro-inflammatory manner. When either was suppressed through systemic administration of small molecule inhibitors, a more profound effect on allergic inflammation was seen, which suggests that non-myeloid cells also promote inflammation via HIF-α subunits. Pulmonary endothelial cells are the gateway to the lungs from the circulation. We hypothesize that HIF- 1α and HIF-2α play a role in activation of pulmonary endothelial cells during pulmonary inflammation, leading to expression of adhesion molecules on the vascular surface and transmigration of circulating inflammatory cells into the lungs. We propose to use pulmonary endothelial cell specific HIF-1α and HIF-2α knock-out mice to evaluate the role of HIFs in the recruitment of inflammatory cells such as eosinophils during asthma-like inflammation. Because of the heterogeneity of asthma, and the lack of therapeutic options for non-TH2 non- allergic phenotypes of asthma, we will use three immunologically disparate mouse models of asthma to evaluate the role of these HIF molecules in asthma pathogenesis. Mouse models are powerful in that they can assess for physiologic changes, and organ and system-level effects. In addition, gene knockouts in mice are a powerful tool for understanding the roles of individual proteins on disease induction and progression. However, there are differences in immune function and inflammatory responses between murine and human cells, such that murine data does not always reflect human responses. Thus, we will use human endothelial cells and human immune cells ex vivo to study the effects of suppression of HIF via small molecule inhibitors on transendothelial migration of cell types relevant to asthma: eosinophils, neutrophils, macrophages and lymphocytes in particular. We hope that the studies proposed will elucidate novel targets for drug development in asthma.

每 12 名美国人中就有 1 人患有哮喘，超过 50% 的哮喘患者（1200 万）患有哮喘。 哮喘是一种慢性炎症性疾病，严重影响生活质量。 未经治疗的哮喘会导致无法上班和上学，以及高昂的医疗费用。原因有很多。 哮喘类型，其中一些是当前治疗方法的良好目标，可实现疾病控制。 有一些哮喘的内型，例如 TH2 低中性粒细胞性哮喘，没有靶向治疗 这些内型是由对类固醇没有反应的炎症途径驱动的，因此它们是可用的。 常见于类固醇抵抗性哮喘。我们提出的工作的前提是还有其他的。 可以识别和靶向治疗哮喘的细胞类型和途径。 缺氧诱导因子 (HIF) 被发现在表达时是炎症的主要调节因子 HIF-1α 在所有细胞中组成型表达，并且在代谢调节中发挥重要作用， HIF-2α除了调节炎症通路外，对细胞增殖和细胞迁移的作用也较为有限。 表达，但与 HIF-1α 一样，它在肺内皮细胞中表达，调节代谢和 我们研究了哮喘中的两个 HIF-α 亚基，发现每个亚基都具有调节作用。 当任一者通过全身受到抑制时，通过骨髓细胞以促炎方式发生炎症。 给予小分子抑制剂，发现对过敏性炎症有更深远的影响， 表明非骨髓细胞也通过 HIF-α 亚基促进炎症。 肺内皮细胞是循环系统通往肺部的门户。 1α和HIF-2α在肺部炎症过程中激活肺内皮细胞，从而导致 血管表面粘附分子的表达和循环炎症细胞的迁移 我们建议使用肺内皮细胞特异性 HIF-1α 和 HIF-2α 敲除小鼠 评估 HIF 在哮喘样炎症细胞（如嗜酸性粒细胞）募集中的作用 由于哮喘的异质性，并且缺乏针对非 TH2 非炎症的治疗选择。 为了了解哮喘的过敏表型，我们将使用三种免疫学不同的哮喘小鼠模型来评估 这些 HIF 分子在哮喘发病机制中的作用。 小鼠模型的强大之处在于它们可以评估生理变化以及器官和系统水平 此外，小鼠基因敲除是了解单个蛋白质作用的有力工具。 然而，在疾病诱导和进展方面存在差异。 小鼠和人类细胞之间的反应，因此小鼠数据并不总是反映人类的反应。 因此，我们将使用人内皮细胞和人免疫细胞离体来研究抑制效果 HIF 通过小分子抑制剂影响与哮喘相关的细胞类型的跨内皮迁移：嗜酸性粒细胞、 我们希望所提出的研究能够阐明新的嗜中性粒细胞、巨噬细胞和淋巴细胞。 哮喘药物开发的目标。