Abstract
Rationale: Neutrophil elastase (NE) plays a central role in inflammation and tissue degradation in airway diseases, e.g. alpha-1 antitrypsin deficiency, cystic fibrosis and chronic obstructive pulmonary disease. Its inhibition might therefore be of use to improve the current treatments for those diseases.
Objective: The aim of the study was to evaluate the effect of a direct lung application of POL6014, a potent NE inhibitor, in a 4 day TS model in mice.
Methods: POL6014 (0.1, 0.5, 2 and 10 mg/kg) or a positive control, p38 inhibitor (0.1 mg/kg) were intranasally administered daily 1 h before each TS exposure in C57BL/6j mice for 4 days. The bronchoalveolar lavage (BAL) fluid was collected 24 h after the end of the last TS exposure and the total and differential cell counts were determined. Plasma and lung compound levels were also measured.
Results: POL6014 dose-dependently and significantly reduced the number of macrophages, epithelial cells, neutrophils and lymphocytes recovered in BAL. The maximum inhibition was reached at 2 mg/kg in reducing neutrophils by 65% (p<0.001), epithelial cells by 68% (p<0.001), macrophages by 33% (p<0.001) and lymphocytes by 77% (p<0.001).
At 0.1 mg/kg POL6014 already showed significant inhibition on neutrophils by 50% (p<0.001).
POL6014 showed dose-related exposures with substantial lung and low plasma levels and no accumulation after repeated administration.
Conclusion: POL6014 significantly and dose-dependently reduced TS-induced inflammation. It might provide a new therapeutic approach for the treatment of NE-driven lung diseases.
- © 2013 ERS