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

流感是一种主要的全球性人类病原体，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，终末气道/肺泡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防止 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 通过抑制肺泡上皮细胞中的5-脂氧合酶-白三烯通路， 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 细胞感染和致命损伤。我们还发现，给予白三烯修饰剂（LMA）， 感染时间模拟肺泡巨噬细胞的作用，并抑制肺泡上皮细胞的感染， 感染动物体内的细胞，防止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发现可以外推到 对于人类，我们假设患有哮喘或过敏性鼻炎的儿童和成人， 将减少流感肺炎的发病率，降低发病率和死亡率。如果这些 这些概念被拟议的研究所验证，它将提出一种新的治疗方法，以减少 流感发病率使用可用的，廉价的，口服和安全的药物在所有年龄。 需要两个关键的证据来将这些发现推进到临床试验或观察性研究中 流感大流行期间人类使用经验性研究：（1）LMAs减少流感的概念证明 人类发病率和估计的效应量，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LMAs在调节人肺癌易感性中的作用 肺泡上皮细胞对流感病毒感染的影响。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，我们将首先确定 人肺泡巨噬细胞与人肺泡上皮细胞抑制肺泡上皮细胞感染 体外细胞我们接下来将证明用LMA处理人肺泡上皮细胞模拟了 流感病毒可以抑制肺泡巨噬细胞的作用，并降低肺泡上皮细胞对流感病毒感染的易感性。 潜在影响：本研究旨在探索一种新的假设，扩展动物研究的证据， 可用和安全的口服药物可降低流感相关的发病率和死亡率，并证实 作用于人体肺部。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 可以在试验中进行测试，或在大流行性流感的经验性使用中进行研究，以确定它们是否能减少 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。

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.