Eicosanoid Lipids by Airway Cells During Infection With Human Rhinoviruses

Theinvestigators and others have shown that airway epithelial cell infection with human
rhinovirus (HRV) is a major risk factor for subsequent exacerbation. Additionally, the
investigators have shown that the nucleotide receptor, P2X7, is an important host factor in
the prevention of exacerbations, and have data to suggest that this may occur at the level of
the alveolar macrophage. Alveolar macrophages facilitate the resolution of inflammation in
part by generating eicosanoid metabolites of arachidonic acid including prostaglandin E2
(PGE2) and lipoxin A4 (LXA4). Patients with severe asthma have a reduced capacity to generate
PGE2 and LXA4 when compared to those with non-severe asthma, despite alveolar macrophage
expression of two of the key enzymes involved in their production. These and other data
suggest that pro-resolving eicosanoid metabolism is most efficient when airway epithelial
cells are in communication with alveolar macrophages, and that these pathways may be
defective in patients with severe asthma. Moreover, inoculation experiments with human
rhinovirus (HRV) demonstrate that alveolar macrophages express cox-2 during resolution. These
and other data have led to the central hypothesis that transcellular generation of PGE2 and
lipoxins is regulated by P2X7-induced cox-2 expression in alveolar macrophages, and that this
process facilitates resolution of an HRV-triggered exacerbation.

Inclusion Criteria:

- Age 18-55 years

- Diagnosis of mild asthma

- Pre-albuterol forced expiratory volume in the first second (FEV1) of >70% predicted.

- Confirmation of asthma diagnosis by either an improvement in FEV1 after four puffs of
albuterol by ≥ 12%, or a decline in FEV1 by ≥ 20% after a graded challenge with
inhaled methacholine with a provocative concentration causing a 20% fall ≤ 8 mg/mL

- Documented negative Tuberculin skin test (PPD) within the last 12 months or a medical
history that is consistent with a low probability of exposure to tuberculosis (i.e.
the subject is not a health worker, has not traveled to endemic areas, and has no
pre-existing medical or social risk factors for tuberculosis).

- Safety laboratory assessments within normal ranges (labs to include complete blood
count with differential and platelet count, PT/INR, creatinine, ALT)

- Women of child-bearing potential (WCBP) must have a negative urine pregnancy test
(urine HCG) within 48 hours of the methacholine challenge at Visit 2, within 48 hours
of the bronchoscopy at Visit 3 and within 48 hrs of Visit 4. WCBP must agree to use a
reliable method of birth control for the duration of the study (reliable methods of
birth control can include abstinence, barrier methods, oral contraceptives, injection
contraceptives or skin absorption contraceptives).

- In the opinion of the investigator, capable and willing to grant written informed
consent and cooperate with study procedures and requirements.

Exclusion Criteria:

- Major health problems such as autoimmune disease, heart disease, type I and II
diabetes, uncontrolled hypertension or lung diseases other than asthma. The listed
health problems are definitive exclusion but decisions regarding major health problems
not listed will be based upon the judgment of the investigator.

- No pre-existing chronic infectious disease.

- Any condition for which, in the opinion of the investigator, transient oxyhemoglobin
desaturation is inadvisable.

- Pregnant or lactating females or has a planned pregnancy during the course of the
study.

- Asthma maintenance therapy other than inhaled short acting beta-agonists within 1
month of screening. This includes but is not limited to inhaled or oral
corticosteroids, long acting beta-agonists and leukotriene receptor antagonists.

- Upper or lower respiratory infection within 1 month of screening.

- Unstable asthma as indicated by self-report of increased symptoms or increased
beta-agonist use over the 2 weeks preceding the screening visit.

- Current smokers (defined as smoked within the last year) or a former smoker with a
history of >10 pack years.

- Morbid obesity as defined by a Body Mass Index (BMI) > 40.

- Use of an investigational drug within 30 days of entering the study

- History of noncompliance with medical regiments or subjects who are considered
unreliable including those with a psychiatric history that, in the opinion of the
investigator, may interfere with the conduct of study procedures.