Comparison of Alveolar Macrophages in Healthy Individuals Versus Individuals With COPD

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

Innate and Adaptive Immunity in COPD Exacerbations: Bronchoscopies on Healthy Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00281203
• Other study ID #: 1327
• Secondary ID: R01HL082480
• Status: Completed
• Phase: N/A
• First received: January 20, 2006
• Last updated: July 15, 2013
• Start date: September 2005
• Est. completion date: July 2010

Study information

• Verified date: July 2013
• Source: University of Michigan
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Observational

Clinical Trial Summary

This study group forms the normal subject control group in an experiment designed to determine whether the alveolar macrophages (AMø) of patients with chronic obstructive pulmonary disease (COPD) show abnormal responsiveness to bacterial and viral products. Specifically, the study will determine the dose-response characteristics of AMø 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. Results of the AMø from these healthy volunteers will be compared with AMø of COPD patients and smokers (or ex-smokers) with normal pulmonary function; those samples are being obtained during clinically indicated bronchoscopies under a separate consent form.

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:

Bronchoscopies will be performed on healthy volunteers. Subjects are reimbursed $30 for the initial visit and $150 at completion of the bronchoscopy to help defray travel expenses and for the time spent participating as a volunteer.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: July 2010
• Est. primary completion date: July 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion criteria:

• Healthy individuals with normal pulmonary function as defined by AmericanThoracic Society criteria (entry spirometry)

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-Only, 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 on the entry visit and will starting the intravenous (IV) line on the day of bronchoscopy
• fiberoptic bronchoscopy
A flexible instrument will be passed through the mouth and into the lungs. Portions of the lungs will be washed, by injecting and immediately suctioning out a small amount of fluid. The entire return will be used for research purposes, and no results will be reported to the participant. Bronchoscopy is performed once.

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 (8)

Curtis JL, Freeman CM, Hogg JC. The immunopathogenesis of chronic obstructive pulmonary disease: insights from recent research. Proc Am Thorac Soc. 2007 Oct 1;4(7):512-21. Review. — View Citation

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

Han MK, Agusti A, Calverley PM, Celli BR, Criner G, Curtis JL, Fabbri LM, Goldin JG, Jones PW, Macnee W, Make BJ, Rabe KF, Rennard SI, Sciurba FC, Silverman EK, Vestbo J, Washko GR, Wouters EF, Martinez FJ. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med. 2010 Sep 1;182(5):598-604. doi: 10.1164/rccm.200912-1843CC. Epub 2010 Jun 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

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
•   University of Michigan-Peking University Joint Initiative for Clinical & Translational Research