Comparison of Alveolar Macrophages in Individuals With COPD Versus Smokers With Normal Pulmonary Function
| Status: | Completed |
|---|---|
| Conditions: | Chronic Obstructive Pulmonary Disease, Pulmonary |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 40 - Any |
| Updated: | 2/7/2015 |
| Start Date: | September 2005 |
| End Date: | July 2015 |
| Contact: | Jeffrey L. Curtis, M.D. |
| Email: | jlcurtis@umich.edu |
| Phone: | 734-845-3457 |
Innate and Adaptive Immunity in COPD Exacerbations: Clinically-Indicated Bronchoscopies
The purpose of this study is to determine whether the alveolar macrophages (AMø) of patients
with chronic obstructive pulmonary disease (COPD ) show abnormal responsiveness to bacterial
and viral products, relative to smokers with normal pulmonary function. Participation in
this study will be offered to patients already scheduled to undergo a bronchoscopy for
clinical indications.
with chronic obstructive pulmonary disease (COPD ) show abnormal responsiveness to bacterial
and viral products, relative to smokers with normal pulmonary function. Participation in
this study will be offered to patients already scheduled to undergo a bronchoscopy for
clinical indications.
BACKGROUND:
COPD is one of the most pressing healthcare problems facing our nation. Acute exacerbations
of COPD (AE-COPD) are responsible for the bulk of healthcare costs, and much of the
morbidity and decline in health status among individuals with this common disease. The lack
of accepted animal models of AE-COPD necessitates novel approaches using human samples.
Advances in the understanding of the pathogenesis have been slowed, in part, due to
controversy as to how exacerbations should be defined. The prevailing paradigm has defined
AE-COPD as event-based. Such definitions clearly identify groups of patients with
accelerated loss of pulmonary function and increased mortality. However, limited data show
that symptom-based definitions of AE-COPD also capture episodes inducing significant
morbidity and functional decline, and hence of concern to patients. Fundamental mechanisms
are lacking to explain AE-COPD defined by either means.
Controversy also surrounds triggers of AE-COPD. Bacteria and viruses are involved in some
episodes, but the relative importance of each is intertwined with disputes over the
definition of AE-COPD. Progress at linking specific pathogens to molecular pathogenesis has
been slow, both due to their diversity, and to the high rates of bacterial colonization of
patients with COPD, even in the stable state. Moreover, in many AE-COPD cases, no pathogen
can be identified. Without negating the value of analyzing infections with specific
species of pathogens, it appears that progress in molecular pathogenesis could be
accelerated by focusing on unifying features of the pulmonary immune response during
AE-COPD.
DESIGN NARRATIVE:
The purpose of this experiment is to determine whether the AMø of patients with COPD show
abnormal responsiveness to bacterial and viral products, relative to smokers with normal
pulmonary function. Specifically, the study will determine the dose-response
characteristics of AMø from these two groups of subjects for production of interleukin
(IL)-6, IL-18, and IL-23 (pro-inflammatory cytokines) on stimulation by purified
Lipopolysaccharide, a synthetic lipopeptide (PAM3-Cys), or poly I:C. These stimuli mimic
the response to Gram-negative bacteria, Gram-positive bacteria, and RNA viruses,
respectively.
This research protocol involves adding a research bronchoalveolar lavage (BAL) to clinically
indicated bronchoscopy that is being performed for evaluation of lung nodules suspected to
possibly be malignant. The research BAL will be performed during the same procedure, but on
the opposite lung from the radiographic lesion that motivated the bronchoscopy. Subjects
will be COPD patients or smokers with normal pulmonary function recruited from the Pulmonary
Clinic. Smoking history will be taken to mean at least 20 pack-years exposure, and could
include current or ex-smokers. Bronchoscopy will be performed under conscious sedation using
a fiberoptic bronchoscope, in almost all cases on outpatients (although stable inpatients
could be considered for consent if they otherwise meet eligibility criteria). The setting
is the Endoscopy suite at the Ann Arbor VA Hospital.
The procedures in this protocol involve the following upon enrollment: bronchoalveolar
lavage (200 ml maximal instilled volume) and collection of blood for hematocrit, serum
albumin, C-reactive protein, and IL-6.
COPD is one of the most pressing healthcare problems facing our nation. Acute exacerbations
of COPD (AE-COPD) are responsible for the bulk of healthcare costs, and much of the
morbidity and decline in health status among individuals with this common disease. The lack
of accepted animal models of AE-COPD necessitates novel approaches using human samples.
Advances in the understanding of the pathogenesis have been slowed, in part, due to
controversy as to how exacerbations should be defined. The prevailing paradigm has defined
AE-COPD as event-based. Such definitions clearly identify groups of patients with
accelerated loss of pulmonary function and increased mortality. However, limited data show
that symptom-based definitions of AE-COPD also capture episodes inducing significant
morbidity and functional decline, and hence of concern to patients. Fundamental mechanisms
are lacking to explain AE-COPD defined by either means.
Controversy also surrounds triggers of AE-COPD. Bacteria and viruses are involved in some
episodes, but the relative importance of each is intertwined with disputes over the
definition of AE-COPD. Progress at linking specific pathogens to molecular pathogenesis has
been slow, both due to their diversity, and to the high rates of bacterial colonization of
patients with COPD, even in the stable state. Moreover, in many AE-COPD cases, no pathogen
can be identified. Without negating the value of analyzing infections with specific
species of pathogens, it appears that progress in molecular pathogenesis could be
accelerated by focusing on unifying features of the pulmonary immune response during
AE-COPD.
DESIGN NARRATIVE:
The purpose of this experiment is to determine whether the AMø of patients with COPD show
abnormal responsiveness to bacterial and viral products, relative to smokers with normal
pulmonary function. Specifically, the study will determine the dose-response
characteristics of AMø from these two groups of subjects for production of interleukin
(IL)-6, IL-18, and IL-23 (pro-inflammatory cytokines) on stimulation by purified
Lipopolysaccharide, a synthetic lipopeptide (PAM3-Cys), or poly I:C. These stimuli mimic
the response to Gram-negative bacteria, Gram-positive bacteria, and RNA viruses,
respectively.
This research protocol involves adding a research bronchoalveolar lavage (BAL) to clinically
indicated bronchoscopy that is being performed for evaluation of lung nodules suspected to
possibly be malignant. The research BAL will be performed during the same procedure, but on
the opposite lung from the radiographic lesion that motivated the bronchoscopy. Subjects
will be COPD patients or smokers with normal pulmonary function recruited from the Pulmonary
Clinic. Smoking history will be taken to mean at least 20 pack-years exposure, and could
include current or ex-smokers. Bronchoscopy will be performed under conscious sedation using
a fiberoptic bronchoscope, in almost all cases on outpatients (although stable inpatients
could be considered for consent if they otherwise meet eligibility criteria). The setting
is the Endoscopy suite at the Ann Arbor VA Hospital.
The procedures in this protocol involve the following upon enrollment: bronchoalveolar
lavage (200 ml maximal instilled volume) and collection of blood for hematocrit, serum
albumin, C-reactive protein, and IL-6.
Inclusion criteria:
- Diagnosis of COPD and/or chronic bronchitis (study group, following American Thoracic
Society guidelines)
- Willingness to participate in follow-up studies defined in the protocol
- Ability to give informed consent
- Already undergoing clinically indicated bronchoscopy
Exclusion criteria:
- Unstable cardiovascular disease
- Other systemic disease in which survival of more than 2 years is unlikely
- Mental incompetence or active psychiatric illness
- Currently taking more than 20 mg/day of Prednisone
- Participation in another experimental protocol within 6 weeks of study entry
- Asthma
- Cystic fibrosis
- Clinically significant bronchiectasis
- Lung cancer
- Other inflammatory or fibrotic lung disease
We found this trial at
1
site
Click here to add this to my saved trials
