Leukotriene modifying agents in the prevention of excess morbidity and mortality from influenza

白三烯调节剂预防流感发病率和死亡率过高

• 批准号: 9756319
• 负责人: Thomas J Braciale
• 金额: $ 70.26万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-07 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756319
• 关键词: Address; Adult; Age; Allergic rhinitis; Alveolar; Alveolar Macrophages; Animals; Arachidonate 5-Lipoxygenase; Asthma; Biological; Cells; Cessation of life; Child; Chronic Disease; Clinical; Clinical Trials; Companions; Complement; Complication; Development; Drug Prescriptions; Drug usage; Elderly; Epithelial Cells; Event; Functional disorder; Goals; Health Benefit; Human; In Vitro; Incidence; Individual; Infection; Infection prevention; Influenza; Influenza A virus; Injury; Leukotriene Antagonists; Leukotrienes; Life; Lung; Metabolic Pathway; Morbidity - disease rate; Observational Study; Oral; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pneumonia; Predisposition; Pregnancy; Pregnant Women; Prevention; Production; Property; Public Health; Reducing Agents; Research; Resistance; Retrospective cohort study; Risk; Rodent Model; Role; Seasons; Testing; Therapeutic; Time; Viral Pneumonia; Virus Diseases; Zileuton; asthmatic; cysteinyl leukotriene receptor; cysteinyl-leukotriene; enzyme pathway; epidemiology study; experience; human pathogen; montelukast; mortality; novel; novel therapeutic intervention; pandemic influenza; prevent; programs; prophylactic; protective effect; study population

Influenza is a major worldwide human pathogen that can cause severe illness and death. Spread of influenza to terminal airways/alveoli with the development of primary viral pneumonia is a life-threatening complication of influenza. Limiting influenza infection of alveolar epithelial cells would be expected to prevent the development of viral pneumonia. In a rodent model we found that alveolar macrophages act to suppress the susceptibility of alveolar epithelial cells to influenza infection by inhibiting the 5 lipoxygenase leukotriene pathway in epithelial cells. Deficiency or dysfunction of alveolar macrophages results in enhanced susceptibility of alveolar epithelial cells to infection and lethal injury. We also found that administration of a leukotriene modifying agent (LMA) at the time of infection mimics the action of alveolar macrophages and suppresses infection of alveolar epithelial cells in the infected animals preventing the development of lethal influenza pneumonia. LMAs are a class of oral medication that inhibit leukotriene formation or action, and are commonly used safe and inexpensive prescription drugs used to treat asthma and allergic rhinitis. If the rodent model findings can be extrapolated to the human, we hypothesize that children and adults with asthma or allergic rhinitis that are treated with LMAs would have a reduced incidence of influenza pneumonia and decreased morbidity and mortality. If these concepts are validated by the proposed study, it would suggest a novel therapeutic approach to decreasing influenza morbidity using an available, inexpensive, oral and safe pharmacologic agent across all ages. Two critical pieces of evidence are needed to move these findings forward into a clinical trial or observational study of empiric use in humans during pandemic influenza: (1) proof of concept that LMAs decrease influenza morbidity in humans, and an estimated effect size, and (2) to complement findings in the rodent model, establishment of the role of human alveolar macrophages and LMAs in regulating the susceptibility of human alveolar epithelial cells to influenza infection in vitro. To address the first aim we plan to conduct a large observational study of children and adults who receive LMAs for asthma or allergic rhinitis to determine the impact on severe influenza events. To address the second aim, we will first establish that the interaction of human alveolar macrophages with human alveolar epithelial cells suppresses infection of alveolar epithelial cells in vitro. We will next demonstrate that treatment of human alveolar epithelial cells with LMAs mimics the effect of alveolar macrophages and reduces the susceptibility of alveolar epithelial cells to influenza infection. Potential Impact: This study aims to explore a novel hypothesis, extending evidence from animal studies that available and safe oral drugs may decrease influenza-related morbidity and mortality and to corroborate the action in human lungs. If these concepts are validated in this study, then an immediately available therapy could be tested in trials, or studied during empiric use in pandemic influenza, to determine if they reduce influenza morbidity and mortality. The results of this study have enormous clinical and public health impact.

流感是全球主要的人类病原体，可能导致严重的疾病和死亡。流感传播 随着原发性病毒肺炎的发展，到达末端气道/肺泡是一种威胁生命的并发症 流感。限制肺泡上皮细胞感染的流感感染将预计 病毒性肺炎。在啮齿动物模型中，我们发现肺泡巨噬细胞起作用以抑制 通过抑制上皮细胞5脂氧合酶白细胞途径，肺泡上皮细胞至流感感染。 细胞。肺泡巨噬细胞的缺乏或功能障碍导致肺泡上皮的敏感性增强 细胞感染和致命损伤。我们还发现，在施用白三烯修饰剂（LMA） 感染的时间模仿肺泡巨噬细胞的作用并抑制肺泡上皮的感染 受感染动物的细胞阻止了致死性流感肺炎的发育。 LMA是一类 抑制白三烯形成或作用的口服药物，通常是安全且便宜的 用于治疗哮喘和过敏性鼻炎的处方药。如果可以将啮齿动物模型发现推到 人类，我们假设患有LMA治疗的儿童和成人患有哮喘或过敏性鼻炎 流感肺炎的发病率会降低，发病率和死亡率降低。如果这些 概念通过拟议的研究来验证，这将提出一种新型的治疗方法来减少 在所有年龄段的所有年龄段的可用，廉价，口服和安全的药理剂中，流感发病率。 需要两个关键的证据来将这些发现转发到临床试验或观察性中 研究大流行性流感期间人类经验的研究：（1）概念证明LMA会降低流感 人类的发病率和估计的效应大小，以及（2）补充啮齿动物模型中的发现， 建立人肺泡巨噬细胞和LMA在调节人易感性中的作用 肺泡上皮细胞在体外感染流感。为了解决第一个目标，我们计划进行大型 对接受LMA的儿童和成人的观察性研究，以确定哮喘或过敏性鼻炎 对严重流感事件的影响。为了解决第二个目标，我们将首先确定相互作用 人肺泡巨噬细胞带有人肺泡上皮细胞抑制牙槽上皮的感染 细胞体外。接下来，我们将证明用LMA模拟人类牙槽上皮细胞的治疗 肺泡巨噬细胞的影响并降低肺泡上皮细胞对流感感染的敏感性。 潜在的影响：本研究旨在探索一个新的假设，从动物研究中扩展了证据， 可用的和安全的口服药物可能会降低与流感相关的发病率和死亡率，并证实 人类肺部作用。如果这些概念在本研究中得到了验证，则可以立即可用 可以在试验中进行测试，也可以在大流行性流感中进行经验使用期间进行研究，以确定它们是否减少 流感的发病率和死亡率。这项研究的结果具有巨大的临床和公共卫生影响。