prostaglandin inhibition for emphysema

Conditions: Emphysema

Summary: 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.

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.

Eligibility criteria:
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

Keywords: emphysema prostaglandin e bronchoalveolar lavage