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


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; 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.


RESULTS
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.


CONCLUSIONS
These results suggest that IKKbeta/IKK2 inhibitor PHA-408 is a powerful anti-inflammatory agent against LPS- and CS-mediated lung inflammation.
Rajendrasozhan
Saravanan
S
Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, NY 14642, USA.
Hwang
Jae-Woong
JW
Yao
Hongwei
H
Kishore
Nandini
N
Rahman
Irfan
I
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D007191:Indazoles / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007539:Isonicotinic Acids / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012907:Smoking / Q000009:adverse effects*
D007191:Indazoles; D018836:Inflammation Mediators; D007539:Isonicotinic Acids; D008070:Lipopolysaccharides; D016328:NF-kappa B; C548309:PHA 408; D051550:I-kappa B Kinase