Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Administration, Intranasal
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Allergens / administration & dosage*
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Animals
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Asthma / metabolism*
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Asthma / pathology
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Asthma / prevention & control*
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Bronchial Hyperreactivity / prevention & control
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Bronchoalveolar Lavage Fluid / cytology
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Bronchoalveolar Lavage Fluid / immunology
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Cell Movement / drug effects
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Cell Movement / immunology
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Chemokine CCL11
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Chemokines, CC / biosynthesis
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Disease Models, Animal
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Eosinophils / drug effects
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Eosinophils / pathology
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Female
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Humans
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Inflammation / metabolism
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Inflammation / prevention & control
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Interleukin-13 / biosynthesis
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Lung / drug effects
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Lung / immunology
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Lung / pathology*
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Mice
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Mice, Inbred BALB C
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Mucus / drug effects
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Mucus / immunology
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Mucus / metabolism
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / metabolism
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Ovalbumin / administration & dosage
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Ovalbumin / immunology
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Oxidation-Reduction / drug effects
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Pyridazines / pharmacology*
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Pyridazines / therapeutic use
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Thioredoxins / antagonists & inhibitors
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Transcription Factor AP-1 / antagonists & inhibitors*
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Transcription Factor AP-1 / metabolism
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Triazoles / pharmacology*
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Triazoles / therapeutic use
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Tumor Cells, Cultured
Substances
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Allergens
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CCL11 protein, human
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Ccl11 protein, mouse
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Chemokine CCL11
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Chemokines, CC
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Interleukin-13
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MOL 294
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NF-kappa B
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Pyridazines
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Transcription Factor AP-1
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Triazoles
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Thioredoxins
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Ovalbumin