Prostaglandin Inhibition for Emphysema

The Prostaglandin Inhibition for Emphysema (PIE) study will determine if a currently
available therapy, ibuprofen 600 mg three times daily, can block PGE production in the lower
respiratory tract and if this results in improvement in measures of lung repair function.
This is a proof-of-concept study. The PIE study will set the stage for novel therapy to
modify the course of chronic obstructive pulmonary disease (COPD).

COPD is the third leading cause of death in the United States. No currently available
treatment can meaningfully restore lung function that is lost in this disease. Emphysema is a
major component of COPD and results when lung damage exceeds the ability of the lung to
repair. Recent evidence indicates that the repair processes present in the normal lung are
deficient in patients with emphysema and that this is due, in part, to suppression of repair
by an inflammatory mediator: prostaglandin E (PGE). Currently available therapies can block
PGE production, but whether this can be achieved in the lung in COPD is unknown. The PIE
study will answer that question.

This will be accomplished by performing a randomized, double blind, placebo-controlled,
parallel group study that will compare a widely used and well-tolerated non-steroidal
anti-inflammatory drug, ibuprofen 600 mg three times daily, with placebo. PGE will be
measured directly in the lower respiratory tract by sampling the lung with the technique of
bronchoalveolar lavage. Secondary measures will be made, quantifying PGE in induced sputum
and quantifying PGE metabolites in blood and urine. In addition, the current proposal will
determine if biochemical measures of lung repair are restored by treatments that block PGE
production. Additional outcomes will also be assessed including the effect of treatment on
PGD and other eicosanoids and assessing IL-8 and neutrophils in sputum and BAL fluid and
selected inflammatory biomarkers present in serum that may be associated with lung function
decline. Finally, in an accompanying Ancillary Study, the current proposal will determine if
alveolar macrophages over-produce PGE and/or PGD in COPD and will determine if the microRNA
miR-146a modulates the production of these prostaglandins, as we have demonstrated for lung
fibroblasts. The Ancillary Study will also determine if genetic variation in a miR-146a is
related to differential expression.

The proposed research will, therefore, determine if inhibition of PGE production can be
achieved in the lung, if this appears to restore lung repair mechanisms and will help
determine who would benefit from such a therapeutic approach. This is a highly novel approach
to the treatment of emphysema and has the potential to restore lost lung function, a crucial
unmet medical need for a major public health problem.

Inclusion Criteria:

- Age > 45 years

- Emphysema (>5% of voxels <950 Hounsfield Units determined on the CT scan performed as
part of the COPDGene study as quantified at the COPDGene radiology center). An
equivalent scan as determined by the radiology center is also acceptable.

- Post-bronchodilator FEV1 > 35% predicted)

- Smoker or ex-smoker (10 pack years minimum)

Exclusion Criteria:

- Contraindication to bronchoscopy or other study procedures

- Pregnancy of plans to become pregnant within six months

- Aspirin-sensitive asthma

- Regular use of systemic glucocorticoid

- Regular use of an NSAID (low dose aspirin for cardiac disease is acceptable and
subjects taking only this regularly will be eligible)

- Unstable medical condition

- History of myocardial infarction or unstable angina within six months

- Allergy to or history of adverse effect from ibuprofen or other NSAID

- History of gastrointestinal bleeding within one year

- Any condition that, in the opinion of the investigator, places the subject at untoward
risk

- Inability to provide informed consent