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.
While currently the fourth-leading cause of death, chronic obstructive pulmonary disease (COPD) mortality rates are rising each year in the United States. Unfortunately, the greatest increase in COPD is found in the VA population. COPD exacerbations are the most problematic element of the disease's morbidity and mortality and are the greatest healthcare expense associated with treatment. Viral infections followed by secondary bacterial infection are the primary cause of COPD exacerbations. COPD patients demonstrate impaired airway epithelial repair after RSV infection, but the mechanisms of this alteration are unknown.
|Sapkota, Muna; DeVasure, Jane M; Kharbanda, Kusum K et al. (2017) Malondialdehyde-acetaldehyde (MAA) adducted surfactant protein induced lung inflammation is mediated through scavenger receptor a (SR-A1). Respir Res 18:36|
|Sapkota, Muna; Kharbanda, Kusum K; Wyatt, Todd A (2016) Malondialdehyde-Acetaldehyde-Adducted Surfactant Protein Alters Macrophage Functions Through Scavenger Receptor A. Alcohol Clin Exp Res 40:2563-2572|
|Warren, Kristi J; Simet, Samantha M; Pavlik, Jacqueline A et al. (2016) RSV-specific anti-viral immunity is disrupted by chronic ethanol consumption. Alcohol 55:35-42|
|Cannon, Abigail R; Morris, Niya L; Hammer, Adam M et al. (2016) Alcohol and inflammatory responses: Highlights of the 2015 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 54:73-7|
|Gerald, Carresse L; Romberger, Debra J; DeVasure, Jane M et al. (2016) Alcohol Decreases Organic Dust-Stimulated Airway Epithelial TNF-Alpha Through a Nitric Oxide and Protein Kinase-Mediated Inhibition of TACE. Alcohol Clin Exp Res 40:273-83|
|McCaskill, Michael L; Romberger, Debra J; DeVasure, Jane et al. (2012) Alcohol exposure alters mouse lung inflammation in response to inhaled dust. Nutrients 4:695-710|