Comparison of Alveolar Macrophages in Individuals With COPD Versus Smokers With Normal Pulmonary Function
NCT ID: NCT00281190
Last Updated: 2014-12-16
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
32 participants
OBSERVATIONAL
2005-09-30
2014-10-31
Brief Summary
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Detailed Description
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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.
Conditions
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Keywords
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Study Design
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CASE_CONTROL
PROSPECTIVE
Study Groups
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Healthy smokers
Smokers with normal pulmonary function
Blood drawing
blood will be drawn at the time of starting the intravenous (IV) line for the procedure.
Bronchoalveolar lavage during indicated bronchoscopy
A small amount of liquid will be introduced and immediately sucked back out of portions of the lung, and the cells that are recovered will be analyzed in the laboratory. All test will be solely for research, and there will be no results reported to the subject from that fluid.
COPD patients
COPD patients
Blood drawing
blood will be drawn at the time of starting the intravenous (IV) line for the procedure.
Bronchoalveolar lavage during indicated bronchoscopy
A small amount of liquid will be introduced and immediately sucked back out of portions of the lung, and the cells that are recovered will be analyzed in the laboratory. All test will be solely for research, and there will be no results reported to the subject from that fluid.
Interventions
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Blood drawing
blood will be drawn at the time of starting the intravenous (IV) line for the procedure.
Bronchoalveolar lavage during indicated bronchoscopy
A small amount of liquid will be introduced and immediately sucked back out of portions of the lung, and the cells that are recovered will be analyzed in the laboratory. All test will be solely for research, and there will be no results reported to the subject from that fluid.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Willingness to participate in follow-up studies defined in the protocol
* Ability to give informed consent
* Already undergoing clinically indicated bronchoscopy
Exclusion Criteria
* 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
40 Years
ALL
Yes
Sponsors
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National Heart, Lung, and Blood Institute (NHLBI)
NIH
University of Michigan
OTHER
Responsible Party
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Jeffrey L. Curtis
Professor of Internal Medicine (Pulmonary & Critical Care Medicine)
Principal Investigators
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Jeffrey L. Curtis
Role: STUDY_CHAIR
University of Michigan at Ann Arbor
Locations
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University of Michigan at Ann Arbor
Ann Arbor, Michigan, United States
Countries
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References
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Freeman CM, Curtis JL, Chensue SW. CC chemokine receptor 5 and CXC chemokine receptor 6 expression by lung CD8+ cells correlates with chronic obstructive pulmonary disease severity. Am J Pathol. 2007 Sep;171(3):767-76. doi: 10.2353/ajpath.2007.061177. Epub 2007 Jul 19.
Freeman CM, Han MK, Martinez FJ, Murray S, Liu LX, Chensue SW, Polak TJ, Sonstein J, Todt JC, Ames TM, Arenberg DA, Meldrum CA, Getty C, McCloskey L, Curtis JL. Cytotoxic potential of lung CD8(+) T cells increases with chronic obstructive pulmonary disease severity and with in vitro stimulation by IL-18 or IL-15. J Immunol. 2010 Jun 1;184(11):6504-13. doi: 10.4049/jimmunol.1000006. Epub 2010 Apr 28.
Freeman CM, Martinez FJ, Han MK, Ames TM, Chensue SW, Todt JC, Arenberg DA, Meldrum CA, Getty C, McCloskey L, Curtis JL. Lung dendritic cell expression of maturation molecules increases with worsening chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009 Dec 15;180(12):1179-88. doi: 10.1164/rccm.200904-0552OC. Epub 2009 Sep 3.
Curtis JL, Todt JC, Hu B, Osterholzer JJ, Freeman CM. Tyro3 receptor tyrosine kinases in the heterogeneity of apoptotic cell uptake. Front Biosci (Landmark Ed). 2009 Jan 1;14(7):2631-46. doi: 10.2741/3401.
Punturieri A, Copper P, Polak T, Christensen PJ, Curtis JL. Conserved nontypeable Haemophilus influenzae-derived TLR2-binding lipopeptides synergize with IFN-beta to increase cytokine production by resident murine and human alveolar macrophages. J Immunol. 2006 Jul 1;177(1):673-80. doi: 10.4049/jimmunol.177.1.673.
Erb-Downward JR, Thompson DL, Han MK, Freeman CM, McCloskey L, Schmidt LA, Young VB, Toews GB, Curtis JL, Sundaram B, Martinez FJ, Huffnagle GB. Analysis of the lung microbiome in the "healthy" smoker and in COPD. PLoS One. 2011 Feb 22;6(2):e16384. doi: 10.1371/journal.pone.0016384.
Todt JC, Freeman CM, Brown JP, Sonstein J, Ames TM, McCubbrey AL, Martinez FJ, Chensue SW, Beck JM, Curtis JL. Smoking decreases the response of human lung macrophages to double-stranded RNA by reducing TLR3 expression. Respir Res. 2013 Mar 9;14(1):33. doi: 10.1186/1465-9921-14-33.
Related Links
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COPD Foundation
Training Grant in Lung Diseases
Graduate Program in Immunology
Other Identifiers
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1326
Identifier Type: -
Identifier Source: org_study_id