Alcohol consumption and RSV infection in airway injury

描述（由申请人提供）： 呼吸道病毒感染是慢性阻塞性肺疾病（COPD）急性加重的病理生理学基础。COPD急性加重是VA的一个重大问题和成本。已知呼吸道病毒感染在重度饮酒者中更为严重，导致病毒后继发性细菌感染。许多研究已经调查了酒精对免疫细胞应答的影响，但是没有研究在粘膜纤毛运输装置水平上解决酒精加剧宿主对病毒应答的机制。吸入的呼吸道病毒特异性感染肺气道的纤毛气道上皮细胞，其含有粘膜纤毛器并代表肺防御此类吸入病毒的第一道防线。粘膜纤毛清除是通过排列在气道内的纤毛细胞的跳动动作来协调的。呼吸道病毒感染纤毛上皮细胞导致纤毛搏动频率（CBF）减慢和纤毛细胞脱落或丢失。虽然纤毛跳动的刺激机制已被广泛研究，但对减缓纤毛跳动或导致纤毛细胞分离的试剂和机制知之甚少。许多与纤毛搏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，酒精大大增强纤毛减慢和纤毛细胞脱落在体内小鼠模型的呼吸道病毒感染。基于我们的观察，我们假设：酒精通过增强PKC 5依赖的纤毛减慢和纤毛细胞的脱离而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）感染的影响来验证这一假设，确定PKC 5活性是否调节正常和PKC 5（-/-）小鼠气道上皮细胞中的纤毛细胞脱落，并确定酒精介导的增强响应RSV的纤毛减慢和脱落的作用机制。通过利用纤毛调节的体内和体外模型的优势，这些目标中的实验旨在解决关键的未回答的问题，即暴露于酒精中如何使气道内衬的正常保护性粘膜纤毛清除装置失效，从而导致持续和慢性炎症性气道疾病。

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.