Effect of Steroids on Gene Expression in the Healthy Smokers Lungs
| Status: | Withdrawn |
|---|---|
| Conditions: | Chronic Obstructive Pulmonary Disease, Pulmonary |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 5/5/2016 |
| Start Date: | February 2011 |
| End Date: | August 2011 |
Effect of Inhaled Steroids in Combination With a Long Acting Bronchodilator on Gene Expression in the Lungs of Healthy Smokers
Cigarette smoking is the main risk factor for chronic obstructive pulmonary disease (COPD).
The cells lining the lung airways (epithelium) and the cells on the surface of the
epithelium (alveolar macrophages) of healthy smokers develop characteristic gene expression
changes that are different from that of nonsmokers. These gene expression changes include
up- and down-regulation of genes in functional categories known to be relevant to the
development of COPD. Administration of anti-inflammatory medications (inhaled steroids) in
combination with long acting medications that open the airways (bronchodilators), are known
to decrease the rate of acute exacerbations and improve the quality of life of individuals
with COPD; however, the mechanisms underlying these beneficial effects of are poorly
understood. This study will assess the effect of traditional therapy for COPD (inhaled
corticosteroids, an anti-inflammatory medication, plus a bronchodilator, a medication that
helps open the airways) on smoking-induced gene changes in airway epithelium and alveolar
macrophages. Volunteer subjects will be evaluated by bronchoscopy to sample lung cells at 0,
7 and 14 days, with the therapy given at day 1 through day 7. The bronchoscopy aspects of
this study will be covered by approved Weill-Cornell IRB protocol # 0005004439 (see below.)
To participate in this protocol, the research subject will first be enrolled in Weill-IRB
protocol #0005004439 entitled "Evaluation of the Lungs of Normal (Smokers, Ex-smokers,
Non-Smokers) Individuals with Segmental Bronchopulmonary Lung Lavage, Bronchial Brushing,
and Bronchial Wall Biopsy", fulfilling the inclusion/exclusion criteria of that protocol.
They will be invited to participate in this protocol only if they meet the additional
inclusion/exclusion criteria of this protocol.
The cells lining the lung airways (epithelium) and the cells on the surface of the
epithelium (alveolar macrophages) of healthy smokers develop characteristic gene expression
changes that are different from that of nonsmokers. These gene expression changes include
up- and down-regulation of genes in functional categories known to be relevant to the
development of COPD. Administration of anti-inflammatory medications (inhaled steroids) in
combination with long acting medications that open the airways (bronchodilators), are known
to decrease the rate of acute exacerbations and improve the quality of life of individuals
with COPD; however, the mechanisms underlying these beneficial effects of are poorly
understood. This study will assess the effect of traditional therapy for COPD (inhaled
corticosteroids, an anti-inflammatory medication, plus a bronchodilator, a medication that
helps open the airways) on smoking-induced gene changes in airway epithelium and alveolar
macrophages. Volunteer subjects will be evaluated by bronchoscopy to sample lung cells at 0,
7 and 14 days, with the therapy given at day 1 through day 7. The bronchoscopy aspects of
this study will be covered by approved Weill-Cornell IRB protocol # 0005004439 (see below.)
To participate in this protocol, the research subject will first be enrolled in Weill-IRB
protocol #0005004439 entitled "Evaluation of the Lungs of Normal (Smokers, Ex-smokers,
Non-Smokers) Individuals with Segmental Bronchopulmonary Lung Lavage, Bronchial Brushing,
and Bronchial Wall Biopsy", fulfilling the inclusion/exclusion criteria of that protocol.
They will be invited to participate in this protocol only if they meet the additional
inclusion/exclusion criteria of this protocol.
The purpose of this study is to assess the effect of inhaled beclomethasone (an inhaled
corticosteroid) on the pattern of the lung airway epithelium and alveolar macrophages gene
expression of healthy smokers. We hypothesize that the administration of beclomethasone will
result in reversibility of some of the airway epithelium and alveolar macrophage gene
expression changes induced by cigarette smoking.
Background. Chronic obstructive pulmonary disease (COPD), including chronic bronchitis and
emphysema, occurs in 15 to 20% of individuals who smoke, and is a leading cause of disease
and mortality in the US (1, 2). Cigarette smoking is found to be the cause of approximately
90% of the cases of COPD in the US (1, 2). The human lung airway epithelium receives the
initial brunt of cigarette smoking, and the airway epithelium and alveolar macrophages play
a central role in the development of COPD (3-6). Asymptomatic healthy smokers have increased
rate of cell proliferation in the airway epithelium consistent with the concept that the
airway epithelium of smokers undergoes molecular changes that precede the development of
COPD (7). Similarly, smoking increases the number and activates the alveolar macrophages
present in the alveoli of human lung leading to the release of various mediators involved in
the pathogenesis of COPD (4, 6, 8, 9).
Assessment of human lung airway epithelium and alveolar macrophages gene expression of
healthy smokers compared to healthy non-smoking individuals demonstrate that the epithelium
of the large and the small airways and the alveolar macrophages up- and down-regulate a
variety of genes relevant to the pathogenesis of COPD (10-15). The differential gene
expression in the epithelium of smokers compared to nonsmokers comprises genes in various
functions, including genes involved in inflammation, cell repair, cell differentiation, cell
death, detoxification, and cell signaling. While the airway epithelium is target for the
stress of cigarette smoking, alveolar macrophages (the pulmonary representative of the bone
marrow-derived mononuclear phagocyte system) are activated by smoking, and release a variety
of mediators that can injure the fragile lung structure (4, 6, 16). Thus, while the airway
epithelium is injured by smoking, the alveolar macrophages contribute to the smoking-induced
injury. Many studies in vitro and in vivo in animals and in humans demonstrate the role of
the airway epithelium and alveolar macrophages in the development of COPD with the release
of various pro-inflammatory mediators, and mediators involved in cell apoptosis,
proteolysis, airway remodeling and obstruction contributing to the characteristic findings
of inflammation and obstruction observed in the airways of individuals with COPD (3-9, 17,
18).
Beclomethasone is one of the medications that when administered by inhalation to individuals
with moderate to severe COPD results in reduction of hospitalization by approximately 30%,
increased quality of life, and a decreased in the reduction of lung function (19, 20).
Interestingly, beclomethasone is one of the medications that when administered by inhalation
following hospitalization with acute exacerbation to individuals with COPD, results in a
lower re-hospitalization rate. The mechanisms by which inhaled steroids result in clinical
improvement and increased quality of life in individuals with moderate to severe COPD and
following acute exacerbations are poorly understood (19-24).
corticosteroid) on the pattern of the lung airway epithelium and alveolar macrophages gene
expression of healthy smokers. We hypothesize that the administration of beclomethasone will
result in reversibility of some of the airway epithelium and alveolar macrophage gene
expression changes induced by cigarette smoking.
Background. Chronic obstructive pulmonary disease (COPD), including chronic bronchitis and
emphysema, occurs in 15 to 20% of individuals who smoke, and is a leading cause of disease
and mortality in the US (1, 2). Cigarette smoking is found to be the cause of approximately
90% of the cases of COPD in the US (1, 2). The human lung airway epithelium receives the
initial brunt of cigarette smoking, and the airway epithelium and alveolar macrophages play
a central role in the development of COPD (3-6). Asymptomatic healthy smokers have increased
rate of cell proliferation in the airway epithelium consistent with the concept that the
airway epithelium of smokers undergoes molecular changes that precede the development of
COPD (7). Similarly, smoking increases the number and activates the alveolar macrophages
present in the alveoli of human lung leading to the release of various mediators involved in
the pathogenesis of COPD (4, 6, 8, 9).
Assessment of human lung airway epithelium and alveolar macrophages gene expression of
healthy smokers compared to healthy non-smoking individuals demonstrate that the epithelium
of the large and the small airways and the alveolar macrophages up- and down-regulate a
variety of genes relevant to the pathogenesis of COPD (10-15). The differential gene
expression in the epithelium of smokers compared to nonsmokers comprises genes in various
functions, including genes involved in inflammation, cell repair, cell differentiation, cell
death, detoxification, and cell signaling. While the airway epithelium is target for the
stress of cigarette smoking, alveolar macrophages (the pulmonary representative of the bone
marrow-derived mononuclear phagocyte system) are activated by smoking, and release a variety
of mediators that can injure the fragile lung structure (4, 6, 16). Thus, while the airway
epithelium is injured by smoking, the alveolar macrophages contribute to the smoking-induced
injury. Many studies in vitro and in vivo in animals and in humans demonstrate the role of
the airway epithelium and alveolar macrophages in the development of COPD with the release
of various pro-inflammatory mediators, and mediators involved in cell apoptosis,
proteolysis, airway remodeling and obstruction contributing to the characteristic findings
of inflammation and obstruction observed in the airways of individuals with COPD (3-9, 17,
18).
Beclomethasone is one of the medications that when administered by inhalation to individuals
with moderate to severe COPD results in reduction of hospitalization by approximately 30%,
increased quality of life, and a decreased in the reduction of lung function (19, 20).
Interestingly, beclomethasone is one of the medications that when administered by inhalation
following hospitalization with acute exacerbation to individuals with COPD, results in a
lower re-hospitalization rate. The mechanisms by which inhaled steroids result in clinical
improvement and increased quality of life in individuals with moderate to severe COPD and
following acute exacerbations are poorly understood (19-24).
Inclusion Criteria:
Group A and B
- All study individual should be enrolled in Weill-IRB protocol #0005004439 entitled
"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 able to provide informed consent
- Current smokers with 15-to 40 pack-year history
- All study individuals should be healthy as per protocol #0005004439 entitled
"Evaluation of the Lungs of Normal (Smokers, Ex-smokers, Non-Smokers) Individuals
with Segmental Bronchopulmonary Lung Lavage, Bronchial Brushing, and Bronchial Wall
Biopsy"
Group C
- All study individual should be enrolled in Weill-IRB protocol #0005004439 entitled
"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 able to provide informed consent
- All study individual should be healthy as per protocol #0005004439 entitled
"Evaluation of the Lungs of Normal (Smokers, Ex-smokers, Non-Smokers) Individuals
with Segmental Bronchopulmonary Lung Lavage, Bronchial Brushing, and Bronchial Wall
Biopsy"
Exclusion Criteria:
Group A and B
- Smokers intending to quit smoking in the next 14 days.
- Individuals already receiving any lung related inhalers
- Females who are pregnant or nursing
Group C
Exclusion Criteria:
- Non-smokers who intend to start smoking in the next 14 days
- Individuals already receiving any lung related inhalers
- Females who are pregnant or nursing
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