Abstract
Rationale: I kappa B kinase (IKK) activates NF-kappa B which plays a pivotal role in pro-inflammatory response in the lung. NF-kappa B has been shown to be activated in alveolar macrophages and peripheral lungs of smokers and patients with chronic obstructive pulmonary disease. We investigated the anti-inflammatory effect of a highly selective and novel IKK beta/IKK2 inhibitor, PHA-408 [8-(5-chloro-2-(4-methylpiperazin-1-yl)isonicotinamido)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[gamma]indazole-3-carboxamide]. in lungs of rat in vivo.
Methods: Adult Sprague-Dawley rats were administered orally with PHA-408 (15 and 45 mg/kg) daily for 3 days and exposed to LPS aerosol (once on day 3, 2 h post-last PHA-408 administration) or cigarette smoke (CS; 2 h after PHA-408 administration for 3 days). Animals were sacrificed at 1, 4 and 24 h after the last exposure, and lung inflammatory response and NF-kappa B activation were measured.
Results: Oral administration of IKK beta/IKK2 inhibitor PHA-408 significantly inhibited LPS- and CS-mediated neutrophil influx in bronchoalveolar lavage (BAL) fluid of rats. The levels of pro-inflammatory mediators in BAL fluid (CINC-1) and lungs (IL-6, TNF-alpha, IL-1 beta and GM-CSF) were also reduced by PHA-408 administration in response to LPS or CS exposures. The reduced pro-inflammatory response in PHA-408-administered rats was associated with decreased nuclear translocation and DNA binding activity of NF-kappa B in response to LPS or CS.
Conclusion: These results suggest that IKK beta/IKK2 inhibitor PHA-408 is a powerful anti-inflammatory agent against LPS- and CS-mediated lung inflammation. (C) 2010 Elsevier Ltd. All rights reserved.