PMID- 21496385
OWN - NLM
STAT- MEDLINE
DCOM- 20110602
LR  - 20170214
IS  - 0394-6320 (Print)
IS  - 0394-6320 (Linking)
VI  - 24
IP  - 1
DP  - 2011 Jan-Mar
TI  - Effect of inhibition of the ubiquitin-proteasome-system and IkappaB kinase on airway 
      inflammation and hyperresponsiveness in a murine model of asthma.
PG  - 33-42
AB  - 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.
FAU - El-Hashim, A Z
AU  - El-Hashim AZ
AD  - Department of Applied Therapeutics, Kuwait University, Kuwait. 
      ahmed.elhashim@hsc.edu.kw
FAU - Renno, W M
AU  - Renno WM
FAU - Abduo, H T
AU  - Abduo HT
FAU - Jaffal, S M
AU  - Jaffal SM
FAU - Akhtar, S
AU  - Akhtar S
FAU - Benter, I F
AU  - Benter IF
LA  - eng
PT  - Journal Article
PL  - England
TA  - Int J Immunopathol Pharmacol
JT  - International journal of immunopathology and pharmacology
JID - 8911335
RN  - 0 (BAY 11-7085)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (Leupeptins)
RN  - 0 (Nfkbia protein, mouse)
RN  - 0 (Nitriles)
RN  - 0 (Proteasome Inhibitors)
RN  - 0 (Sulfones)
RN  - 0 (Ubiquitin)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - 9006-59-1 (Ovalbumin)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde)
SB  - IM
MH  - Animals
MH  - Asthma/*drug therapy
MH  - Bronchial Hyperreactivity/*drug therapy
MH  - Bronchoalveolar Lavage Fluid/cytology
MH  - Disease Models, Animal
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - I-kappa B Kinase/*antagonists & inhibitors
MH  - I-kappa B Proteins/metabolism
MH  - Leupeptins/*pharmacology
MH  - Lung/drug effects/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - NF-KappaB Inhibitor alpha
MH  - Nitriles/*pharmacology
MH  - Ovalbumin/immunology
MH  - *Proteasome Inhibitors
MH  - Sulfones/*pharmacology
MH  - Ubiquitin/*metabolism
EDAT- 2011/04/19 06:00
MHDA- 2011/06/03 06:00
CRDT- 2011/04/19 06:00
PHST- 2011/04/19 06:00 [entrez]
PHST- 2011/04/19 06:00 [pubmed]
PHST- 2011/06/03 06:00 [medline]
AID - 5 [pii]
AID - 10.1177/039463201102400105 [doi]
PST - ppublish
SO  - Int J Immunopathol Pharmacol. 2011 Jan-Mar;24(1):33-42. doi: 
      10.1177/039463201102400105.