Targeting prolyl endopeptidase in chronic obstructive pulmonary disease

Introduction: Neutrophil influx and extracellular matrix remodeling and degradation leading to airway obstruction and inflammation are features of chronic obstructive pulmonary disease (COPD). Recently it has been shown that the neutrophil chemoattractant proline-glycine-proline (PGP) is elevated in bronchoalveolar lavage fluid (BALF) of COPD patients. The enzyme responsible for generating PGP, prolyl endopeptidase (PE), is also elevated in COPD. Therefore, PE inhibitors might lead to improvement of the disease. Methods: Different PE inhibitors were used in vitro (valproic acid (VPA), ZPP, S-17092) and in vivo (VPA) to measure PE activity, PGP generation and neutrophilic influx into the lungs. Neutrophil lysates were tested in PE activity assays . The PE inhibitors were used as competitor. Neutrophil lysates were incubated with collagen types I and II in presence of each of the PE inhibitors and PGP levels were measured. Using a whole body cigarette smoke exposure model, mice were exposed to cigarette smoke using 5 cigarettes twice daily for five consecutive days, except for the first day when they were exposed to 3 cigarettes. VPA was administered by oropharyngeal aspiration twice daily before and after smoke exposure during a week (8.6mM VPA in sterile PBS)) as treatment. Results: ZPP and S-17092 showed higher affinity to PE (both Ki of ∼1nM) where VPA was less potent (Ki of ∼1mM). This was also reflected in the PGP generation assays where 50mM VPA significantly (P