The investigators are investigating the effects of traffic-related diesel exhaust on lung function and the immune system in those at risk for COPD. The individual will be exposed to either filtered air (FA) or carefully controlled levels of diesel exhaust (DE) in our exposure chamber. Post exposure the individual will complete a steady state exercise test. 24h later, a procedure called bronchoscopy (whereby a thin, flexible tube is placed down the throat and into the lungs) will be used so that samples can be collected from the lungs. After 1 month the entire procedure will be repeated with the alternative exposure.

1. Purpose:

   To study the effects of traffic related diesel exhaust on people at risk for developing COPD.

2. Hypotheses:

   Hypothesis 1: An increase in proteins, in the exposed lung and blood, that are associated with the pathophysiology of COPD.

   Hypothesis 2: Air trapping, dyspnea, and impaired exercise tolerance. Such increases will be more pronounced in those with COPD than in control subjects.

3. Justification:

   The use of diesel engines is increasing because they are more fuel-efficient than gasoline engines. However, diesel engines produce different emissions than gasoline engines. Diesel exhaust is emitted from the tailpipe of both "on-road" diesel engine vehicles (diesel cars, buses and trucks) and "non-road" diesel engines (locomotives, marine vessels and some construction equipment). Diesel exhaust consists of both gaseous and particulate air pollutants. People with COPD may be sensitive to air pollution; we would like to know how diesel exhaust (DE) can affects the respiratory and immune systems. We are not expecting that responses will be noticeable to the participant; we are expecting that any responses that may occur will only be detectable through careful examination of cells and tissues (e.g., bronchoalveolar lavage (fluid from lungs), blood). Understanding these subtle changes will help us prevent health problems associated with air pollution in the future.

4. Objectives To provide biological plausibility and deepen mechanistic understanding of the emerging epidemiology suggesting a strong role for air pollution in COPD.

5. Research Methods:

This is a blinded crossover experiment between two conditions (300 µg/m³ diesel exhaust or filtered air), randomized and counter-balanced to order. Data collection for each condition will be separated by a 4-week washout period.

Prior to the exposure participants will: 1) complete some questionnaires, 2) undergo a set of lung function tests (breathing tests), 3) undergo an incremental exercise test and 4) receive a physical exam by the primary investigator. A small sample of blood and spirometry measurements will also be collected for analysis.

After the exposure another series of exercise and lung function tests will be performed. Blood, spirometry measurements, bronchoalveolar lavage (BAL), endobronchial brushings and biopsies will also be collected for examination of cellular, functional and immunological changes influencing the airways.

Inclusion Criteria:

1. Age between 40-75 years of age

2. Free of cardiovascular disease

3. Free of insulin-dependent diabetes

4. Study participants must agree to adhere to the following medication intake protocol 24 hours prior to study visits:

   • participants will be asked to withhold:
   • short-acting beta2-agonists (SABAs) for 4 hours prior to testing
   • long-acting beta2-agonists (LABAs) for 12 hours prior to testing if taken in an individual inhaler (different inhaler from inhaled corticosteroid inhaler)
   • LABAs and ICS for 24hrs, if those two medication groups are combined in one inhaler
   • ICS (if taken alone as a mono-therapy, or if taken with either a LABA or SABA, but in two separate inhaler), for 24 hrs.

Overall, we are looking for 15 healthy controls without a history of smoking; 20 individuals with a history of smoking, but who have been non-smokers for at least 6 months prior to study participation; and 15 mild-moderate COPD patients (GOLD I and GOLD II).

Exclusion Criteria:

• Not between the ages of 40-65 years.
• Are pregnant, breast-feeding, or planning to get pregnant in the following 12 months.
• Are currently using inhaled corticosteroids.
• Are allergic to salbutamol, lidocaine, fentanyl or midazolam.
• Are currently participating in another study that involves taking medications.
• Have unstable COPD symptoms.
• Have clinically significant comorbidities (i.e., coronary artery disease).
• Have a history/clinical evidence of asthma.
• Have contraindications to exercise testing.
• Have a body mass index <18.5.
• Regularly use of antihistamines, non-steroidal anti-inflammatories, anticoagulants, acetylsalicylic acid (ASA) or decongestants.