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

基本信息

批准号：
9978695
负责人：
Thomas J Braciale
金额：
$ 63.66万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-07 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978695
关键词：
Address Adult Age Allergic rhinitis 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 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 alveolar epithelium asthmatic cysteinyl leukotriene receptor cysteinyl-leukotriene enzyme pathway epidemiology study experience human pathogen influenza pneumonia montelukast mortality novel novel therapeutic intervention pandemic influenza prevent programs prophylactic protective effect study population

项目摘要

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.

流感是世界范围内主要的人类病原体，可导致严重疾病和死亡。流感传播随着原发性病毒性肺炎的发展，对终末气道/肺泡的影响是一种危及生命的并发症流感。限制肺泡上皮细胞的流感感染有望预防疾病的发展病毒性肺炎。在啮齿动物模型中，我们发现肺泡巨噬细胞可以抑制对肺泡上皮细胞通过抑制上皮细胞5脂氧合酶白三烯途径对抗流感感染细胞。肺泡巨噬细胞的缺乏或功能障碍导致肺泡上皮细胞的敏感性增强细胞感染和致命伤害。我们还发现，在感染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体内的细胞可预防致命性流感肺炎的发展。 LMA 是一类抑制白三烯形成或作用的口服药物，通常使用安全且便宜用于治疗哮喘和过敏性鼻炎的处方药。如果啮齿动物模型的研究结果可以推断对于人类，我们假设患有哮喘或过敏性鼻炎的儿童和成人接受 LMA 治疗会降低流感肺炎的发病率，并降低发病率和死亡率。如果这些拟议的研究验证了概念，它将提出一种新的治疗方法来减少使用可用的、廉价的、口服的、安全的药物来降低所有年龄段的流感发病率。需要两个关键证据才能将这些发现推进临床试验或观察大流行性流感期间人类经验性使用的研究：(1) LMA 减少流感的概念证明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 在调节人类易感性中的作用肺泡上皮细胞对流感感染的体外影响。为了实现第一个目标，我们计划进行一次大规模的对接受 LMA 治疗哮喘或过敏性鼻炎的儿童和成人进行的观察性研究，以确定对严重流感事件的影响。为了实现第二个目标，我们首先要确定人肺泡巨噬细胞与人肺泡上皮细胞抑制肺泡上皮感染体外细胞。接下来我们将证明用 LMA 模拟人肺泡上皮细胞的治疗肺泡巨噬细胞的作用，降低肺泡上皮细胞对流感感染的易感性。潜在影响：这项研究旨在探索一个新的假设，扩展动物研究的证据，可用且安全的口服药物可能会降低流感相关的发病率和死亡率，并证实在人肺中的作用。如果这些概念在本研究中得到验证，那么立即可用的治疗方法可以在试验中进行测试，或在大流行性流感的经验使用过程中进行研究，以确定它们是否减少流感发病率和死亡率。这项研究的结果具有巨大的临床和公共卫生影响。