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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Anti-inflammatory effect of a selective IkappaB kinase-beta inhibitor in rat lung in response to LPS and cigarette smoke.

Authors: Rajendrasozhan, Saravanan; Hwang, Jae-Woong; Yao, Hongwei; Kishore, Nandini; Rahman, Irfan

Published In Pulm Pharmacol Ther, (2010 Jun)

Abstract: IkappaB kinase (IKK) activates NF-kappaB which plays a pivotal role in pro-inflammatory response in the lung. NF-kappaB 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 IKKbeta/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.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; 2h 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-kappaB activation were measured.Oral administration of IKKbeta/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-1beta 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-kappaB in response to LPS or CS.These results suggest that IKKbeta/IKK2 inhibitor PHA-408 is a powerful anti-inflammatory agent against LPS- and CS-mediated lung inflammation.

PubMed ID: 20080200 Exiting the NIEHS site

MeSH Terms: Animals; Bronchoalveolar Lavage Fluid/immunology; Dose-Response Relationship, Drug; I-kappa B Kinase/antagonists & inhibitors*; Indazoles/pharmacology*; Inflammation Mediators/metabolism; Isonicotinic Acids/pharmacology*; Lipopolysaccharides/adverse effects*; Lung/drug effects*; Male; NF-kappa B/metabolism; Rats; Rats, Sprague-Dawley; Smoking/adverse effects*

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