Lung Macrophage Populations and Functions in Chronic Obstructive Pulmonary Disease (COPD)-Susceptible Smokers

Lung Macrophage Populations and Functions in Chronic Obstructive Pulmonary Disease (COPD)-Susceptible Smokers

Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease that affects only a fraction of those who smoke tobacco. The origin of this variability in susceptibility to develop COPD is unclear, but understanding its underlying biology has important implications for our ability to design suitable preventative and therapeutic strategies for its management. This Department of Defense (DOD) discovery research proposes to develop methodologies and generate preliminary data needed to lay the foundation for a large study that would investigate the underlying biological susceptibility of those who smoke tobacco to develop COPD.

This is a pilot observational study of 20 subjects ≥40 years of age with smoking history of at least 20 pack-years (former or current) who have preserved spirometry, as defined by normal Forced Expiratory Volume (FEV1) / Forced Vital Capacity (FVC). Of the 20 subjects, 10 with and 10 without air trapping as determined by high and abnormal versus low and normal Residual Volume (RV) / Total Lung Capacity (TLC) measured by plethysmography. The cohort will undergo extensive clinical characterization including full Pulmonary Function Testing (PFT) and medical, symptom, activity, and quality of life questionnaires assessment including modified Medical Council Research (mMRC), COPD Assessment Test (CAT), Short Form-12 (SF12), and St. George's Respiratory (SGRQ) questionnaires. Subjects will undergo bronchoscopy with bronchoalveolar lavage (BAL) to obtain luminal macrophages and BAL fluid (BALF). Live BAL cells, BALF, and BAL cell RNA will be collected and stored in our biorepository for proposed studies. Molecular, functional, and transcriptomics analyses of luminal (alveolar) macrophages obtained by BAL (Aim 2) and protease activity measurement in serum and BALF will be performed (Aim 2) and will be examined against the clinical phenotype of the subjects, in particular air trapping-phenotype, to see if an underlying biological signature for susceptibility to develop COPD could be identified.

To perform a more comprehensive molecular and functional phenotype examination of lung macrophages, additional methodologies will be developed including a second mass cytometry (CyTOF) panel for single-cell proteomics and CyTOF-based phagocytosis and efferocytosis assays to allow for performance of truly single-cell functional phenotyping of myeloid cells from BAL and lung tissue (Aim 1).

Inclusion Criteria:

• Ages between 40 to 75 years old.
• History of at least 20 pack-years of smoking.
• No diagnosis of COPD or asthma.
• No spirometric evidence of airflow obstruction as determined by FEV1/FVC ratio ≥0.7.
• FEV1 and FVC >lower limit of normal.
• Less than 1 pack-year history of tobacco smoking and no tobacco use within the past 12 months.
• Subjects will be divided into two groups by their RV/TLC:

Normal RV/TLC Group:

• Plethysmographic RV/TLC equal or less than lower limit of normal.

Abnormal RV/TLC Group:

• Plethysmographic RV/TLC higher than lower limit of normal.

Exclusion Criteria:

• Any history of IV drug use or inhalation of recreational drugs other than marijuana: A- within the past 20 years. B- more than 100 times IV drug usage. C- longer than 1 year usage.
• Marijuana use >400 joints in lifetime or any within past 6 months.
• Inability to walk briskly, run on treadmill, or pedal on ergometer to perform the study-required exercise level.
• Pregnant/breast feeding.
• Serious and active heart conditions- defined by stable or unstable angina, recent myocardial infarction (within the last 2 years), active congestive heart failure, ischemic cardiomyopathy.
• Liver cirrhosis.
• History of chronic active Hepatitis B or C.