Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the U.S., yet there are no current therapeutic treatments to halt the progression of this disease. COPD is characterized by airflow obstruction, variable degrees of airway remodeling and alveolar destruction, and an influx of lung inflammatory cells, including neutrophils, macrophages, and CD8+ T cells. The inverse correlation between numbers of airway CD8+ T cells and lung function, as determined by FEV1, implicates CD8+ T cells in COPD pathogenesis. CD8+ T cells can release inflammatory cytokines and mediators that could contribute to lung destruction. These effectors functions are augmented when lung CD8+ T cells are co-stimulated with synthetic bacterial ligands recognized by toll-like receptors (TLRs), in particular TLR2/1. TLR2/1 is known to recognize the outer membrane protein of nontypeable Haemophilus influenzae (NTHI), one of the predominant bacterial pathogens associated with airway infection in COPD, both in stable disease and as an important infectious trigger of exacerbations. The goal of this study is to determine whether lung CD8+ T cells will respond to NTHI co-stimulation by up-regulating their effector functions, such as secreting inflammatory cytokines, killing autologous lung cells, and recruiting additional CD8+ T cells. To carry out this objective, lung tissue from consented subjects undergoing clinically-indicated surgical resections will be used. Tissue will be obtained from both subjects with and without COPD. Isolated lung CD8+ T cells will be co-cultured with antigen- presenting cells and NTHI to determine what effect NTHI co-stimulation has on the production of effector molecules, which will be measured by flow cytometry. This will be correlated with measures of lung function. The co-culture assay will also be used to determine whether NTHI co-stimulation induces the lung CD8+ T cells to kill autologous lung cells. By isolating CD8+ T cells directly from human lung tissue and using them in vitro to study CD8 and NTHI interactions, we may gain unique insights into how COPD pathogenesis is initiated and progresses.

Public Health Relevance

COPD is currently the 3rd leading cause of death in the U.S. It ranks as the 5th most prevalent disease in the Veteran population, affecting approximately 15% of VA health care users. Besides incapacitating shortness of breath, COPD patients commonly suffer from anxiety and depression, making this disease a serious medical, financial, and emotional burden on both veterans and their families. No current treatment halts the progressive lung destruction of COPD and understanding of pathogenesis is insufficient for developing new therapies. Due to the lack of animal model systems that adequately reproduce the range of pathological changes in COPD, key questions about pathogenesis must be addressed using human lung specimens. To maximize such precious and limited resources, we have developed innovative techniques allowing us to directly study the cells and mechanisms involved in COPD pathogenesis. Our studies have the potential to define pathological processes in COPD, crucial for drug development, and to result in new paradigms for understanding COPD.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX001389-01A1
Application #
8329810
Study Section
Respiration (PULM)
Project Start
2012-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
096318480
City
Ann Arbor
State
MI
Country
United States
Zip Code
48105