Chronic obstructive pulmonary disease (COPD) is a major source of morbidity and mortality in the Veteran population. Although cigarette smoking is the major risk factor, determinants of COPD development and progression remain incompletely understood. In this application, we propose to test a novel theory of COPD pathogenesis that we developed based on striking correlations between altered mucosal immunity in small airways and key parameters of COPD, including airway wall thickening, inflammatory cell influx, and airflow limitation. Secretory IgA (SIgA), the most abundant immunoglobulin in the airways, is delivered to the surface of small airways by the polymeric immunoglobulin receptor (pIgR), which is expressed on the basolateral surface of airway epithelial cells. In the setting of epithelial remodeling, which is pervasive in COPD, our preliminary data indicate that epithelial cells down-regulate pIgR expression and are no longer able to maintain a normal mucosal immune barrier. Exposure of mice to mainstream cigarette smoke down-regulates pIgR expression and reduces SIgA levels in the airways prior to development of COPD-like pathology. In pIgR deficient (pIgR-/-) mice, which lack SIgA in their airways, lungs are normal at birth and young adulthood but spontaneously develop COPD-like airway and parenchymal remodeling by 6 months of age. These structural changes are worsened by exposure to cigarette smoke and are associated with bacterial invasion of the airway epithelial layer, epithelial NF-kB activation, and influx/activation of leukocytes, similar o findings in humans with COPD. These data suggest that SIgA on the airway surface plays an essential role in defending the airway from environmental challenges and that altered mucosal immunity contributes to development and progression of COPD. Therefore, we hypothesize that in COPD a dysfunctional mucosal immune barrier with reduced SIgA on the surface of small airways allows access of microorganisms and airborne antigens to the airway epithelium. As a result, persistent/recurrent NF-?B activation in the epithelium drives expression of pro- inflammatory mediators that recruit and activate leukocytes. Accumulation of activated leukocytes (particularly macrophages) in the distal airways and lung parenchyma perpetuates the inflammatory state in COPD and leads to small airway remodeling and emphysema. To test this hypothesis, we propose the following specific aims: 1) to identify mechanisms that drive small airway remodeling and emphysema in mice with disrupted mucosal immune barrier function in the lungs, 2) to determine whether altering the bacterial burden in lungs of pIgR deficient mice alters development and progression of COPD-like pathology, and 3) to define the impact of NF-kB activation and macrophage recruitment/activation on development of COPD-like pathology in pIgR deficient mice. By defining the contribution of altered mucosal immunity to COPD, proposed studies will result in improved understanding of COPD pathogenesis and hopefully will lead to new effective therapies.

Public Health Relevance

Many Veterans with Chronic Obstructive Pulmonary Disease (COPD) have persistent airway inflammation and progress to end stage disease even after smoking cessation;therefore, new disease-modifying treatment approaches are needed for this disease. In this proposal, we will test a new hypothesis to explain disease progression in COPD. If successful, our work will result in a better understanding of COPD and could lead to novel interventions to slow progression of this deadly disease.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX002378-01A1
Application #
8733873
Study Section
Respiration (PULM)
Project Start
2014-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
156385783
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
Hewlett, Justin C; Kropski, Jonathan A; Blackwell, Timothy S (2018) Idiopathic pulmonary fibrosis: Epithelial-mesenchymal interactions and emerging therapeutic targets. Matrix Biol 71-72:112-127
Sucre, Jennifer M S; Deutsch, Gail H; Jetter, Christopher S et al. (2018) A Shared Pattern of ?-Catenin Activation in Bronchopulmonary Dysplasia and Idiopathic Pulmonary Fibrosis. Am J Pathol 188:853-862
Polosukhin, Vasiliy V; Richmond, Bradley W; Du, Rui-Hong et al. (2017) Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling. Am J Respir Crit Care Med 195:1010-1021
Richmond, Bradley W; Brucker, Robert M; Han, Wei et al. (2016) Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency. Nat Commun 7:11240
Benjamin, John T; van der Meer, Riet; Im, Amanda M et al. (2016) Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development. Am J Pathol 186:1786-1800
Saxon, Jamie A; Cheng, Dong-Sheng; Han, Wei et al. (2016) p52 Overexpression Increases Epithelial Apoptosis, Enhances Lung Injury, and Reduces Survival after Lipopolysaccharide Treatment. J Immunol 196:1891-9
Zaynagetdinov, Rinat; Sherrill, Taylor P; Gleaves, Linda A et al. (2016) Chronic NF-?B activation links COPD and lung cancer through generation of an immunosuppressive microenvironment in the lungs. Oncotarget 7:5470-82
Du, Rui-Hong; Richmond, Bradley W; Blackwell Jr, Timothy S et al. (2015) Secretory IgA from submucosal glands does not compensate for its airway surface deficiency in chronic obstructive pulmonary disease. Virchows Arch 467:657-665
Lee, Moon-Sun; Yoon, Minyoung; Yang, O-Bong et al. (2011) N,N'-Dimethyl-N,N'-bis-(pyridin-2-yl)methane-diamine. Acta Crystallogr Sect E Struct Rep Online 67:o3226