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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：
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
项目类别：
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

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.

流感是一种世界性的主要人类病原体，可导致严重疾病和死亡。流感的传播