The Natural History of Gene Expression in the Lung Cells of Non-Smokers, Smokers and Ex-Smokers in Health and Disease

Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD, commonly known as chronic bronchitis and emphysema). Despite this clear link, only 15-20% of smokers develop COPD suggesting that genetic factors affect the lung's susceptibility to the stress of cigarette smoke. The cells lining the airways (epithelium) and cells that help defend the lung (alveolar macrophages) of smokers develop gene expression changes that are different from that of nonsmokers. In the investigators' previous studies they have demonstrated that there are greater than 200 genes that are responsive to cigarette smoke in these cells. But the investigators do not know whether the gene expression is static or changes as a function of time. Genes that show significant changes over time may be relevant to the progression of the disease. Even though quitting smoking reduces the rate at which the lungs decline, many-smokers still go on to develop COPD. This study will provide insights into the natural history of smoking-related gene expression of the lung cells in health and disease.

Cigarette smoke is responsible for the majority of lung cancers and is the major cause of COPD, the fourth leading cause of death in the United States. Despite the well established causal role of cigarette smoking in lung cancer and COPD, only 10-20% of smokers actually develop these diseases. This suggests that there are genetic predisposing factors that place some individuals at greater risk. Our prior work shows that healthy smokers (cigarette smokers with normal history, physical exam, lung function tests and chest x-rays) and smokers with COPD have marked up and down regulation of greater than 200 genes in the small airway epithelium and alveolar macrophages. There is however, a varied response to smoking among individuals, with some individuals abnormally expressing far fewer genes. The focus of this study is to evaluate the hypothesis that the response of the lung cells to the stress of smoking is unique to each individual but is consistent over time. Furthermore, individuals that stop smoking will each have a unique response, but is constant over time for each individual. By defining the patterns of biologic response over time among smoking, ex-smoking and nonsmoking subjects, we will be able to identify common biologic pathways as potential targets for intervention.

Eligibility Criteria:
Inclusion Criteria:

Group A: Healthy nonsmokers

* All study individuals should be enrolled in the "Airway" protocol #1204012331 "Collection of Airway, Blood and/or Urine Specimens from Subjects for Research Studies"
* Willing and able to provide informed consent for the long term follow up study with repeated bronchoscopies
* Male and Female subject ≥18 years of age
* Never smokers is defined as someone who has smoked \< 100 cigarettes per lifetime and whose urine nicotine \<2 ng/mL and/or urine cotinine \<5 ng/mL, at entry into the study

Group B: Healthy current smokers Inclusion:

* All study individuals should be enrolled in the "Airway" protocol
* Willing and able to provide informed consent for the long term follow up study with repeated bronchoscopies
* Male and Female subject ≥18 years of age
* Active smoker as evidenced by self-report and urine nicotine \>30 ng/mL and/or urine cotinine \>50 ng/mL

Group C: Healthy smokers who elect to stop smoking Inclusion:

* All study individuals should be enrolled in the "Airway" protocol
* Willing and able to provide informed consent for the long term follow up study with repeated bronchoscopies
* Male and Female subject ≥18 years of age
* Current smoker as evidenced by self-report and urine nicotine \>30 ng/mL and/or urine cotinine \>50 ng/mL
* Be a current smoker willing to stop smoking

Group D - Current smokers with COPD Inclusion:

* All study subjects will be enrolled in the "Airway" protocol #1204012331 "Collection of Airway, Blood and/or Urine Specimens from Subjects for Research Studies"
* All study subjects should meet the lung disease criteria for having COPD may be of any stage (GOLD I - IV), be ambulatory and have no evidence of respiratory failure
* All study subjects should be able to provide informed consent for the long term follow up study with repeated bronchoscopies
* Male and Female subject ≥18 years of age
* Active smokers as evidenced by urine nicotine \>30 ng/mL and/or urine cotinine \>50 ng/mL

Group E - Current smokers with COPD who elect to stop smoking Inclusion:

* All study subjects will be enrolled in the "Airway" protocol #1204012331 "Collection of Airway, Blood and/or Urine Specimens from Subjects for Research Studies"
* All study subjects should meet the lung disease criteria for having COPD may be of any stage (GOLD I - IV), be ambulatory and have no evidence of respiratory failure
* All study subjects should be able to provide informed consent for the long term follow up study with repeated bronchoscopies
* Male and Female subject ≥18 years of age
* Active smokers as evidenced by urine nicotine \>30 ng/mL and/or urine cotinine \>50 ng/mL
* Be a current smoker willing to stop smoking

Exclusion Criteria:

Groups A - E

* Individuals unable to provide proper informed consent
* Habitual use of drugs and/or alcohol within the past six months (Acceptable: Marijuana one time in three months; average of two alcoholic beverages per day; drug and/or alcohol abuse is defined as per the DSM-IV Substance Abuse Criteria)
* Individuals with asthma and with recurrent or recent (within three months) and/or acute pulmonary infection
* Individuals with allergy to lidocaine
* Significant kidney disease or subjects on dialysis
* Females who are pregnant or lactating or intending to become pregnant in the next 12 months
* Subjects who are HIV positive
* Subjects that have unstable coronary artery disease as evidenced by unstable angina, \>Class II New York Heart Association (NYHA) cardiac status, history of congestive heart failure or MI within the last 12 months
* Subjects who are contraindicated for undergoing bronchoscopy
* Subjects having any medical condition that in the opinion of the investigator would preclude the subject from entering the study

Groups D and E

- Subjects may not have evidence of respiratory failure such as SpO2 \<90% or PaO2 \<60 mmHg

Groups C and E

* Current major depression or other significant psychiatric disorder
* Subjects currently taking anti-depressant medication