A small molecule inhibitor of redox-regulated NF-kappa B and activator protein-1 transcription blocks allergic airway inflammation in a mouse asthma model.
An oxidant/antioxidant imbalance is seen in the lungs of patients with asthma. This oxidative stress in asthmatic airways may lead to activation of redox-sensitive transcription factors, NF-kappaB and AP-1. We examined the effect of the small molecule inhibitor of redox-regulated NF-kappaB and AP-1 transcription, MOL 294 on airway inflammation and airway hyperreactivity (AHR) in a mouse model of asthma. MOL 294 is a potent nonpeptide inhibitor of NF-kappaB and AP-1 based upon a beta-strand template that binds to and inhibits the cellular redox protein thioredoxin. BALB/c mice after i.p. OVA sensitization (day 0) were challenged with intranasal OVA on days 14, 25, 26, and 27. MOL 294, administered intranasal on days 25-27, blocked the airway inflammatory response to OVA assessed 24 h after the last OVA challenge on day 28. MOL 294 reduced eosinophil, IL-13, and eotaxin levels in bronchoalveolar lavage fluid and airway tissue eosinophilia and mucus hypersecretion. MOL 294 also decreased AHR in vivo to methacholine. These results support redox-regulated transcription as a therapeutic target in asthma and demonstrate that selective inhibitors can reduce allergic airway inflammation and AHR.
Henderson
William R
WR
Department of Medicine, University Washington, Seattle 98195, USA. joangb@u.washington.edu
Chi
Emil Y
EY
Teo
Jia-Ling
JL
Nguyen
Cu
C
Kahn
Michael
M
D000281:Administration, Intranasal; D000485:Allergens / Q000008:administration & dosage*; D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D016535:Bronchial Hyperreactivity / Q000517:prevention & control; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000096:biosynthesis; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D018793:Interleukin-13 / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010084:Oxidation-Reduction / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D013879:Thioredoxins / Q000037:antagonists & inhibitors; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000485:Allergens; C515456:CCL11 protein, human; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D018793:Interleukin-13; C468870:MOL 294; D016328:NF-kappa B; D011724:Pyridazines; D018808:Transcription Factor AP-1; D014230:Triazoles; D013879:Thioredoxins; D010047:Ovalbumin