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: 10292906
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292906
• 关键词: Adhesions; Adult asthma; Affect; Airway Disease; Allergic; Allergic inflammation; American; Antiinflammatory Effect; Asthma; Back; Biological Products; Blood Circulation; Blood Vessels; Cell Adhesion Molecules; Cell Proliferation; Cell physiology; Cells; Chronic Disease; Data; Development; Disease; Double Effect; Emergency department visit; Endothelial Cells; Gatekeeping; General Population; Goals; Health Care Costs; Healthcare Systems; Heterogeneity; Hospitalization; Human; Hypoxia Inducible Factor; IL5 gene; Immune; Immunologics; Individual; Inflammation; Inflammatory; Inflammatory Response; Inhalation Exposure; Interleukin-17; Knock-out; Knockout Mice; Leukocytes; Lung; Lymphocyte; Metabolism; Modeling; Molecular; Movement; Mus; Myeloid Cells; Pathogenesis; Pathologic; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Play; Population; Productivity; Proteins; Pulmonary Inflammation; Quality of life; Regulation; Role; Schools; Steroid Resistance; Steroid-resistant asthma; Steroids; Structure of parenchyma of lung; Surface; T-Lymphocyte; Testing; Therapeutic; Time; Veterans; Work; anti-IgE; asthma exacerbation; asthma model; asthmatic; body system; 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; macrophage; 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.

哮喘影响12个美国人中的1个。超过50%的哮喘患者（1200万）有哮喘发作， 年哮喘是一种慢性炎症性疾病，严重影响患者的生活质量。不受控制和 未经治疗的哮喘会导致错过工作和学校，以及高昂的医疗费用。有许多不同 哮喘类型，其中一些是目前的治疗方法很好地靶向疾病控制。然而，在这方面， 有一些内源性哮喘，如TH 2-低嗜酸性哮喘，没有靶向治疗， available.这些内型由对类固醇无反应的炎症途径驱动，因此它们 在类固醇抵抗性哮喘中很常见我们建议工作的前提是， 可以在哮喘中识别和靶向的细胞类型和途径。 缺氧诱导因子（HIF）是炎症反应的主要调节因子， 在免疫细胞中。HIF-1α在所有细胞中组成性表达，在代谢调节中起重要作用， 细胞增殖和细胞迁移，以及调节炎症途径。HIF-2α的表达更为有限， 表达，但与HIF-1α一样，它在肺内皮细胞中表达，并调节代谢和 炎症我们研究了哮喘患者中的两种HIF-α亚基，发现每种亚基都调节 通过骨髓细胞以促炎方式抑制炎症。当任何一个被抑制通过全身 给予小分子抑制剂，对过敏性炎症有更深远的影响， 表明非髓系细胞也通过HIF-α亚基促进炎症。 肺内皮细胞是从循环进入肺的门户。我们假设HIF- 1α和HIF-2α在肺部炎症过程中激活肺内皮细胞中起作用，导致肺内炎症反应。 粘附分子在血管表面的表达和循环炎性细胞的迁移 进入肺部我们建议使用肺内皮细胞特异性HIF-1α和HIF-2α基因敲除小鼠， 评估HIFs在哮喘样哮喘中炎症细胞如嗜酸性粒细胞的募集中的作用， 炎症由于哮喘的异质性，以及缺乏非TH 2非TH 3的治疗选择， 哮喘的过敏表型，我们将使用三种免疫学上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。 小鼠模型是强大的，因为它们可以评估生理变化，器官和系统水平 方面的影响.此外，小鼠的基因敲除是了解单个蛋白质作用的有力工具 对疾病的诱发和发展的影响但在免疫功能和炎症方面存在差异 因此，小鼠和人细胞之间的反应，使得小鼠数据并不总是反映人的反应。 因此，我们将使用人内皮细胞和人免疫细胞离体研究抑制的效果 HIF通过小分子抑制剂对哮喘相关细胞类型跨内皮迁移的影响：嗜酸性粒细胞， 尤其是嗜中性粒细胞、巨噬细胞和淋巴细胞。我们希望所提出的研究将阐明新的 哮喘药物开发的目标。