Effect of Inhibition of the Ubiquitin-Proteasome-System and IκB Kinase on Airway Inflammation and Hyperresponsiveness in a Murine Model of Asthma

Abstract

The current treatment of asthma is far from optimal and there is a need for novel therapeutic approaches. NFkB has recently been highlighted as an important pro-inflammatory transcriptional factor and its blockade is believed to represent a new therapeutic approach for asthma. The purpose of this study is to investigate the effects of blocking the actions of NFkB, through inhibition of the ubiquitin-proteasome system (UPS) or IkB kinase (IKK), in a murine model of asthma. Treatment with the UPS inhibitor, MG-132 (0.03 and 0.1 mg/kg), did not significantly affect the ovalbumin-induced increase in total and differential cell numbers, histological changes such as perivascular and peribronchial inflammatory cell infiltration, perivascular and peribronchial fibrosis or the increased Penh to methacholine. In contrast, treatment of mice with the IKK inhibitor, BAY 11-7085, (3 and 10 mg/kg) dose-dependently inhibited the ovalbumin-induced increase in airway leukocyte influx and decreased the percentage of airway lymphocytes, neutrophils and eosinophils. Also, BAY 11-7085-treated (10 mg/kg) mice showed a significant decrease in the histologically assessed inflammatory indices as well as a significant reduction in the ovalbumin-induced increase in Penh to inhaled methacholine. Furthermore, BAY 11-7085 significantly inhibited the ovalbumin-induced increase in the level of phosphorylation of IkBalpha and extracellular regulated kinases (ERK) 1/2, whilst MG-132 significantly increased the phosphorylation of (ERK) 1/2. These findings confirm the critical role that NFkB plays in airway inflammation, highlight the importance of IKK in regulating the pro-inflammatory activity of NFkB and also suggest that UPS may not be a useful drug target for asthma treatment.