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有助于慢性阻塞性肺疾病（COPD）加剧的病理生理。 COPD加剧代表了VA的重大问题和成本。已知呼吸道病毒感染在繁重的酒精饮用者中更为严重，导致病毒后继发细菌感染。许多研究研究了酒精对免疫细胞反应的影响，但是没有研究涉及粘膜纤毛运输设备水平上宿主对病毒反应加剧宿主反应的机制。吸入的呼吸道病毒特异性感染了肺气道的纤毛气道上皮，其中含有粘膜纤毛仪，代表了针对这种吸入病毒的第一线肺防御。通过衬里的纤毛细胞的跳动作用来精心策划粘膜纤毛清除。纤毛上皮的呼吸道病毒感染会导致睫毛粉频率（CBF）的放缓以及纤毛细胞的脱落或损失。虽然对纤毛跳动的刺激机制进行了广泛的研究，但对缓慢纤毛跳动或导致纤毛细胞脱离的试剂和机制知之甚少。许多与减少睫状激发有关的药物能够在气道上皮细胞中激活蛋白激酶C（PKC）。最近，我们观察到，酒精在呼吸道病毒感染的体内小鼠模型中极大地增强了纤毛的减慢和纤毛细胞脱离。根据我们的观察结果，我们假设：酒精通过增强PKC5依赖性纤毛减慢和脱离纤毛细胞来增强气道病毒感染损伤。我们将通过表征酒精对使用体内小鼠暴露模型对酒精对呼吸道合胞病毒（RSV）感染的影响来检验该假设，从而确定PKC5活性是否调节正常和PKC5（ - - - ）小鼠的气道上皮细胞中的纤毛细胞脱离，并确定对响应速率和cillia的机制，并确定了CILANT和CILIA的良好机制。通过利用体内和纤毛调节的体外模型的优势，这些目标中的实验旨在解决有关如何暴露于酒精功能的关键问题，以禁用正常的保护性粘膜胶质清除设备，导致呼吸道导致持续性和慢性炎症性气道疾病。

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