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

流感是一种主要的世界性人类病原体，可导致严重疾病和死亡。流感的传播 随着原发性病毒性肺炎的发展，终末呼吸道/肺泡是一种危及生命的并发症 流行性感冒。限制流感对肺泡上皮细胞的感染有望阻止病情的发展 病毒性肺炎。在啮齿动物模型中，我们发现肺泡巨噬细胞作用于抑制易感性 肺泡上皮细胞通过抑制上皮细胞中5-脂氧合酶白三烯途径抑制流感病毒感染 细胞。肺泡巨噬细胞缺乏或功能障碍导致肺泡上皮细胞易感性增强 细胞受到感染和致命性伤害。我们还发现，白三烯修饰剂(LMA)在 感染时间模拟肺泡巨噬细胞的活动并抑制肺泡上皮细胞的感染 被感染动物体内的细胞可防止发生致命的流感肺炎。LMA是一类 抑制白三烯形成或作用的口服药物，通常使用安全且价格低廉 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发现可以外推到 对于患有哮喘或过敏性鼻炎的儿童和成人，我们假设使用LMA治疗 将减少流感肺炎的发病率，并降低发病率和死亡率。如果这些 这项拟议的研究验证了概念，这将为减少 使用一种可获得的、廉价的、口服的和安全的药理制剂在所有年龄段的流感发病率。 要将这些发现推进到临床试验或观察中，需要两个关键的证据 大流行性流感期间人类经验性使用的研究：(1)LMA减少流感概念的证据 人类发病率，以及估计的效应大小，以及(2)补充啮齿动物模型中的发现， 人肺泡巨噬细胞和LMA在调节人类易感性中作用的建立 肺泡上皮细胞对流感病毒感染的体外研究。为了达到第一个目标，我们计划进行一次大规模的 接受LMA治疗哮喘或过敏性鼻炎的儿童和成人的观察研究 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 含人肺泡上皮细胞的人肺泡巨噬细胞抑制肺泡上皮细胞感染 体外培养的细胞。接下来，我们将演示用LMAS处理人肺泡上皮细胞可以模拟 对肺泡巨噬细胞的影响，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种新的假说，扩大动物研究的证据 现有和安全的口服药物可以降低流感相关的发病率和死亡率，并证实 在人类肺部的作用。如果这些概念在这项研究中得到验证，那么立即可用的治疗方法 可以在试验中测试，或在大流行性流感的经验使用期间进行研究，以确定它们是否会减少 流感发病率和死亡率。这项研究的结果对临床和公共卫生都有巨大的影响。

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.