Alcohol consumption and RSV infection in airway injury

饮酒和 RSV 感染导致气道损伤

• 批准号: 8764671
• 负责人: Todd A Wyatt
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764671
• 关键词: Acute bronchitis; Address; Adult; Alcohol consumption; Alcohols; Asthma; Bacterial Infections; Breathing; Cause of Death; Cell Line; Cell-Cell Adhesion; Cells; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Cilia; Cystic Fibrosis; Disease; Elements; Epithelial; Epithelial Cells; Epithelium; Frequencies; Functional disorder; Healthcare; Heavy Drinking; Immune; Immune response; Inflammatory; Injury; Lead; Lung; Mediating; Modeling; Morbidity - disease rate; Motor; Mucociliary Clearance; Mus; Patients; Phosphorylation; Population; Production; Protein Isoforms; Protein Kinase C; Proteins; Regulation; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Risk Factors; Small Interfering RNA; Smoker; Smoking; Testing; United States; Viral; Virus; Virus Diseases; airway epithelium; alcohol effect; alcohol exposure; alcohol response; antimicrobial; base; cost; cytotoxicity; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; injured airway; link protein; mortality; mouse model; pathogen; repaired; research study; respiratory; respiratory infection virus; respiratory virus; response; surfactant; therapeutic target; virus infection mechanism

DESCRIPTION (provided by applicant): ABSTRACT Respiratory viral infections contribute to the pathophysiology of chronic obstructive pulmonary disease (COPD) exacerbations. COPD exacerbations represent a significant problem and cost to the VA. Respiratory virus infections are known to be more severe in heavy alcohol drinkers leading to post-viral secondary bacterial infections. Many studies have investigated the effect of alcohol on immune cell response, but no studies have addressed the mechanism(s) for alcohol exacerbation of host response to viruses at the level of the mucociliary transport apparatus. Inhaled respiratory viruses specifically infect the ciliated airway epithelia lining the lung airways, which contain the mucociliary apparatus and represents the first line of lung defense against such inhaled viruses. Mucociliary clearance is orchestrated via the beating action of the ciliated cells lining the airways. Respiratory viral infection of the ciliated epithelia results in the slowing of the ciliary beat frequency (CBF) and the detachment or loss of ciliated cells. While the stimulatory mechanisms of ciliary beating have been widely studied, little is known about agents and mechanisms that slow cilia beating or cause ciliated cells to detach. Many agents associated with decreased ciliary beating are capable of activating protein kinase C (PKC) in airway epithelial cells. Recently, we have observed that alcohol greatly potentiates cilia slowing and ciliated cell detachment in an in vivo mouse model of respiratory viral infection. Based on our observations, we hypothesize that: Alcohol potentiates airway viral infection injury by enhancing PKC5-dependent cilia slowing and detachment of ciliated cells. We will test this hypothesis by characterizing the impact of alcohol on respiratory syncytial virus (RSV) infection using an in vivo mouse exposure model, determining if PKC5 activity regulates ciliated cell detachment in airway epithelial cells from normal and PKC5(-/-) mice, and determining the mechanism of action for alcohol-mediated enhancement of cilia slowing and detachment in response to RSV. By exploiting the strengths of in vivo and in vitro models of cilia regulation, the experiments in these aims are intended to address key unanswered questions regarding how exposure to alcohol functions to disable the normal protective mucociliary clearance apparatus lining the airways leading to sustained and chronic inflammatory airway disease.

描述（由申请人提供）： 摘要 呼吸道病毒感染导致慢性阻塞性肺病（COPD）恶化的病理生理学。 COPD 恶化对 VA 来说是一个重大问题和成本。众所周知，酗酒者的呼吸道病毒感染更为严重，导致病毒后继发细菌感染。许多研究调查了酒精对免疫细胞反应的影响，但没有研究探讨酒精在粘液纤毛运输装置水平上加剧宿主对病毒反应的机制。吸入性呼吸道病毒专门感染肺部气道内的纤毛气道上皮，其中含有粘膜纤毛器，是肺部抵御此类吸入病毒的第一道防线。粘膜纤毛清除是通过气道内纤毛细胞的跳动来协调的。纤毛上皮的呼吸道病毒感染导致纤毛跳动频率（CBF）减慢以及纤毛细胞的脱离或损失。虽然纤毛跳动的刺激机制已被广泛研究，但对于减缓纤毛跳动或导致纤毛细胞分离的药物和机制知之甚少。许多与纤毛跳动减少相关的药物能够激活气道上皮细胞中的蛋白激酶 C (PKC)。最近，我们观察到，在呼吸道病毒感染的体内小鼠模型中，酒精极大地增强了纤毛减慢和纤毛细胞脱离。根据我们的观察，我们假设： 酒精通过增强 PKC5 依赖性纤毛减慢和纤毛细胞脱离来增强气道病毒感染损伤。我们将通过使用体内小鼠暴露模型表征酒精对呼吸道合胞病毒（RSV）感染的影响来测试这一假设，确定 PKC5 活性是否调节正常小鼠和 PKC5(-/-) 小鼠气道上皮细胞中的纤毛细胞脱离，并确定酒精介导的增强纤毛减慢和脱离对 RSV 反应的作用机制。通过利用纤毛调节的体内和体外模型的优势，这些目的的实验旨在解决一些尚未解答的关键问题，即暴露于酒精如何使气道内的正常保护性粘液纤毛清除装置失效，从而导致持续和慢性炎症。气道疾病。

项目成果

Neutralization of IL-33 modifies the type 2 and type 3 inflammatory signature of viral induced asthma exacerbation.

• DOI: 10.1186/s12931-021-01799-5
• 发表时间: 2021-07-15
• 期刊: Respiratory research
• 影响因子: 5.8
• 作者: Warren KJ;Poole JA;Sweeter JM;DeVasure JM;Dickinson JD;Peebles RS Jr;Wyatt TA
• 通讯作者: Wyatt TA