Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and has no cure. While the association between chronic tobacco smoke exposure and COPD has been known for decades, the reasons for ongoing lung damage in COPD after smoking cessation remain undefined. We and others have shown that epithelial remodeling with loss of ciliated cells is widespread in the airways of COPD patients and abnormal epithelial differentiation in individual small airways is strongly associated with loss of the secretory IgA (SIgA) barrier, chronic inflammation, and fibrotic remodeling of the airway wall. Further, we showed that loss of SIgA in the airways is sufficient to induce a COPD-like phenotype in mice, suggesting altered mucosal immunity plays a causal role in COPD pathogenesis. The objective of this proposal is to determine how chronic cigarette smoke exposure causes loss of SIgA in small airways and an impaired mucosal immunobarrier. Our preliminary data demonstrate that the differentiation factor p73, recently shown to be required for the development of multiciliated cells in the airway epithelium, is required for successful delivery of SIgA to the airway lumen. p73 null mice have decreased expression of the polymeric immunoglobulin receptor (pIgR), a transporter protein required for SIgA to be delivered to the airway surface, and spontaneously develop bacterial invasion, chronic inflammation, and lung damage similar to patients with COPD. Further, our preliminary data show that cigarette smoke and NF-?B pathway activation suppress p73 expression. In this proposal, we will test the hypothesis that cigarette smoke-mediated downregulation of p73 results in decreased pIgR expression in multiciliated cells and renders the epithelium more susceptible to bacterial invasion. Bacterial invasion in turn results in NF-?B pathway activation, which further suppresses p73 resulting in a self-sustaining cycle of inflammation and epithelial remodeling.
In Aim 1, we will investigate the impact of targeted deletion of p73 or pIgR in multiciliated cells on airway epithelial differentiation and immune defense.
In Aim 2 we will identify p73-dependent transcription factors that regulate pIgR in murine tracheal epithelial cells and validate our findings in primary human bronchial epithelial cells.
In Aim 3, we will explore the relationships between cigarette smoke exposure, NF-?B activation, and p73 levels in vitro and in vivo, and determine whether pharmacologic blockade of NF-?B can prevent cigarette smoke-mediated p73 suppression. Completion of these studies will advance the field by providing an explanation for how cigarette smoke causes epithelial remodeling, and will further establish loss of the SIgA immunobarrier as the causative factor for chronic inflammation in COPD after smoking cessation.

Public Health Relevance

Chronic obstructive pulmonary disease (COPD) is a common smoking-related lung disease that results in significant morbidity and mortality. Recent studies suggest that cigarette smoke renders the airway epithelium more susceptible to bacterial invasion, resulting in chronic inflammation and ongoing lung damage even after smoking cessation. This proposal will utilize primary airway epithelial cells from mice and patients and a variety of transgenic mouse models to investigate how cigarette smoke destroys the normal immunobarrier that prevents bacteria in airways from invading into the lung.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
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Tigno, Xenia
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Vanderbilt University Medical Center
United States
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Finch, Donna K; Stolberg, Valerie R; Ferguson, John et al. (2018) Lung Dendritic Cells Drive Natural Killer Cytotoxicity in Chronic Obstructive Pulmonary Disease via IL-15R?. Am J Respir Crit Care Med 198:1140-1150
Richmond, Bradley W; Guo, Yan; Yu, Chang et al. (2018) Genome-Wide Association Study of 58 Individuals with Fibrosing Mediastinitis Reveals Possible Underlying Genetic Susceptibility. Am J Respir Crit Care Med 197:1219-1220
Richmond, Bradley W; Du, Rui-Hong; Han, Wei et al. (2018) Bacterial-derived Neutrophilic Inflammation Drives Lung Remodeling in a Mouse Model of Chronic Obstructive Pulmonary Disease. Am J Respir Cell Mol Biol 58:736-744