The Natural History of Gene Expression in the Lung Cells of Non-Smokers, Smokers and Ex-Smokers in Health and Disease
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Purpose
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.
| Condition |
|---|
|
Chronic Obstructive Pulmonary Disease (COPD) Smoking Smoking Cessation Healthy Smoker Smoker Chronic Bronchitis Emphysema |
| Study Type: | Observational |
| Study Design: | Observational Model: Case Control Time Perspective: Prospective |
| Official Title: | The Natural History of Gene Expression in Lung Cells of Non-Smokers, Smokers, and Ex-Smokers in Health and Disease |
- Evaluate gene expression over time [ Time Frame: 12/31/2013 ] [ Designated as safety issue: No ]To prospectively assess changes in lung cell gene expression over time in healthy nonsmokers, healthy smokers and smokers with COPD. To examine what smoking-induced gene expression changes occur in the lung cells of healthy smokers and COPD smokers over time in response to cessation of smoking.
- Quitters who return to smoking and the effects on gene expression [ Time Frame: 12/31/2012 ] [ Designated as safety issue: No ]In individuals who quit but start smoking again despite the standard smoking cessation therapy, what are the effects on gene expression of returning to smoking. To assess whether baseline gene expression determines what genes rapidly change to a more "normal" expression pattern with smoking cessation. Does having established COPD determine the relative reversibility of the gene expression pattern with smoking cessation compared to healthy smokers.
Biospecimen Retention: Samples With DNA
Subjects will not have more than 550 mL of blood drawn over a period of 8 weeks. Airway epithelium from airway brushing samples and alveolar macrophages from bronchoalveolar lavage is processed to yield high quality RNA. Complimentary DNA (cDNA) is transcribed from the RNA in vitro and the product is hybridized onto gene microarray chips.
| Estimated Enrollment: | 210 |
| Study Start Date: | December 2009 |
| Estimated Study Completion Date: | December 2013 |
| Estimated Primary Completion Date: | December 2013 (Final data collection date for primary outcome measure) |
| Groups/Cohorts |
|---|
| Healthy nonsmokers |
| Healthy current smokers |
| Healthy current smokers who quit |
| Current smokers with COPD |
| Current smokers with COPD who quit |
Detailed Description:
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, suggesting 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, but that individuals vary in their response to smoking, with some individuals abnormally expressing far fewer genes1,2. The focus of this present 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. Further, for those individuals that stop smoking, each will have a unique response that differs among individuals, but is constant over time for each individual. By defining these 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.
All of the study populations and assessments to be carried out in this protocol are already covered under two IRB approved protocols; the only purpose of this protocol is to formalize the timing of assessments so that the underlying hypothesis can be assessed.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | Yes |
| Sampling Method: | Non-Probability Sample |
New York Metropolitan area residents
Inclusion Criteria:
Group A - Healthy nonsmokers
- All study individuals should be enrolled in the "Normal" protocol #0005004439 "Evaluation of the Lungs of Normal (Smokers, Ex-smokers, Non-Smokers) Individuals with Segmental Bronchopulmonary Lung Lavage, Bronchial Brushing, and Bronchial Wall Biopsy"
- All study subjects should be healthy according to the "Normal" protocol #0005004439
- 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 urine cotinine <5 ng/mL, at entry into the study
Group B - Healthy current smokers
- All study individuals should be enrolled in the "Normal" protocol #0005004439 "Evaluation of the Lungs of Normal (Smokers, Ex-smokers, Non-Smokers) Individuals with Segmental Bronchopulmonary Lung Lavage, Bronchial Brushing, and Bronchial Wall Biopsy"
- All study subjects should be healthy according to the "Normal" protocol #0005004439
- 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 urine cotinine >50 ng/mL
Group C - Healthy smokers who elect to stop smoking
- All study individuals should be enrolled in the "Normal" protocol #0005004439 "Evaluation of the Lungs of Normal (Smokers, Ex-smokers, Non-Smokers) Individuals with Segmental Bronchopulmonary Lung Lavage, Bronchial Brushing, and Bronchial Wall Biopsy"
- All study subjects should be healthy according to the "Normal" protocol #0005004439
- 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 urine cotinine >50 ng/mL
- Be a current smoker willing to stop smoking
Group D - Current smokers with COPD
- All study subjects will be enrolled in the "Lung Disease" protocol #0005004440 "Evaluation of the Lungs of Individuals with Lung Disease with Segmental Bronchopulmonary Lung Lavage, Bronchial Brushing and Bronchial Wall Biopsy"
- All study subjects should meet the "Lung Disease" protocol 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 urine cotinine >50 ng/mL
Group E - Current smokers with COPD who elect to stop smoking
- All study subjects will be enrolled in the "Lung Disease" protocol #0005004440 "Evaluation of the Lungs of Individuals with Lung Disease with Segmental Bronchopulmonary Lung Lavage, Bronchial Brushing and Bronchial Wall Biopsy"
- All study subjects should meet the "Lung Disease" protocol 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 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
- Drug and/or alcohol abuse within the past six months
- Individuals with asthma and with recurrent or recent (within three months) acute pulmonary infection
- Individuals with allergies 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
- Major depression or other significant psychiatric disorder
- Subjects who are HIV positive
- Subjects that have unstable coronary artery disease as evidenced by unstable angina, >Class II 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 - Current smokers with COPD and smokers with COPD electing to quit
• Subjects may not have evidence of respiratory failure such as SpO2 <90% or PaO2 <60 mmHg
Groups C and E - Current smokers and COPD smokers electing to quit
- Current major depression or other significant psychiatric disorder
- Subjects currently taking anti-depressant medication
Contacts and Locations| United States, New York | |
| Weill Cornell Medical College and Weill Cornell Medical Center, Department of Genetic Medicine | |
| New York, New York, United States, 10065-4870 | |
| Principal Investigator: | Ronald G. Crystal, M.D. | Weill Medical College of Cornell University |
More Information
No publications provided
| Responsible Party: | Weill Medical College of Cornell University |
| ClinicalTrials.gov Identifier: | NCT00974064 History of Changes |
| Other Study ID Numbers: | 0905010391 |
| Study First Received: | September 9, 2009 |
| Last Updated: | December 20, 2012 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by Weill Medical College of Cornell University:
|
COPD Lung disease Chronic bronchitis Emphysema Smoking |
Smoking cessation Quit smoking Healthy smoker Smoker Non-smoker |
Additional relevant MeSH terms:
|
Bronchitis Bronchitis, Chronic Emphysema Pulmonary Emphysema Lung Diseases Respiration Disorders Pulmonary Disease, Chronic Obstructive |
Smoking Lung Diseases, Obstructive Bronchial Diseases Respiratory Tract Diseases Respiratory Tract Infections Pathologic Processes Habits |
ClinicalTrials.gov processed this record on May 23, 2013