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

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.

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