Comparison of Alveolar Macrophages in Individuals With COPD Versus Smokers With Normal Pulmonary Function

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

Innate and Adaptive Immunity in COPD Exacerbations: Clinically-Indicated Bronchoscopies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00281190
• Other study ID #: 1326
• Secondary ID: R01HL082480
• Status: Completed
• Phase: N/A
• First received: January 20, 2006
• Last updated: December 12, 2014
• Start date: September 2005
• Est. completion date: October 2014

Study information

• Verified date: December 2014
• Source: University of Michigan
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: October 2014
• Est. primary completion date: October 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 40 Years and older

Eligibility

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

Study Design

Observational Model: Case Control, Time Perspective: Prospective

Related Conditions & MeSH terms

• Chronic Disease
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Procedure:
• 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.

Locations

Country	Name	City	State
United States	University of Michigan at Ann Arbor	Ann Arbor	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
University of Michigan	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (7)

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;14:2631-46. Review. — View Citation

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: 1 — View Citation

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. Epub 2007 Jul 19. — View Citation

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. — View Citation

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. — View Citation

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 — View Citation

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;14:33. doi: — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	alveolar macrophage functions in vitro		day of bronchoscopy	No

External Links

•   COPD Foundation
•   Curtis Laboratory
•   Graduate Program in Immunology
•   Training Grant in Lung Diseases
•   University of Michigan research site for participants