Dewitz Carola, McEachern Elisa, Shin Stephanie, Akong Kathryn, Nagle Dale G, Broide David H, Akuthota Praveen, Crotty Alexander Laura E
Pulmonary & Critical Care Section, Department of Veterans Affairs San Diego Healthcare System (VASDHS), La Jolla, CA, United States; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
Pulmonary & Critical Care Section, Department of Veterans Affairs San Diego Healthcare System (VASDHS), La Jolla, CA, United States; Weill Cornell Medical College, New York, NY, United States.
Clin Immunol. 2017 Mar;176:94-99. doi: 10.1016/j.clim.2017.01.002. Epub 2017 Jan 14.
Hypoxia-inducible factor (HIF)-1α is a master regulator of inflammation and is upregulated in alveolar macrophages and lung parenchyma in asthma. HIF-1α regulates select pathways in allergic inflammation, and thus may drive particular asthma phenotypes. This work examines the role of pharmacologic HIF-1α inhibition in allergic inflammatory airway disease (AIAD) pathogenesis in BALB/c mice, which develop an airway hyperresponsiveness (AHR) asthma phenotype. Systemic treatment with HIF-1α antagonist YC-1 suppressed the increase in HIF-1α expression seen in control AIAD mice. Treatment with YC-1 also decreased AHR, blood eosinophilia, and allergic inflammatory gene expression: IL-5, IL-13, myeloperoxidase and iNOS. AIAD mice had elevated BAL levels of NO, and treatment with YC-1 eliminated this response. However, YC-1 did not decrease BAL, lung or bone marrow eosinophilia. We conclude that HIF-1α inhibition in different genetic backgrounds, and thus different AIAD phenotypes, decreases airway resistance and markers of inflammation in a background specific manner.
Asthma is a common disease that can be difficult to control with current therapeutics. We describe how pharmacologic targeting of a specific transcription factor, HIF-1α, suppresses asthmatic airway reactivity and inflammation.
缺氧诱导因子（HIF）-1α是炎症的主要调节因子，在哮喘患者的肺泡巨噬细胞和肺实质中上调。HIF-1α调节过敏性炎症中的特定途径，因此可能驱动特定的哮喘表型。这项研究探讨了药物抑制HIF-1α在BALB/c小鼠过敏性炎症性气道疾病（AIAD）发病机制中的作用，该小鼠会出现气道高反应性（AHR）哮喘表型。用HIF-1α拮抗剂YC-1进行全身治疗可抑制对照AIAD小鼠中HIF-1α表达的增加。用YC-1治疗还可降低AHR、血液嗜酸性粒细胞增多以及过敏性炎症基因表达：白细胞介素-5、白细胞介素-13、髓过氧化物酶和诱导型一氧化氮合酶。AIAD小鼠的支气管肺泡灌洗（BAL）液中一氧化氮水平升高，用YC-1治疗可消除这种反应。然而，YC-1并没有降低BAL液、肺或骨髓中的嗜酸性粒细胞增多。我们得出结论，在不同遗传背景以及因此不同的AIAD表型中抑制HIF-1α，以背景特异性方式降低气道阻力和炎症标志物。
哮喘是一种常见疾病，目前的治疗方法可能难以控制。我们描述了如何通过药物靶向特定转录因子HIF-1α来抑制哮喘气道反应性和炎症。
