A small molecule inhibitor of redox-regulated NF-kappa B and activator protein-1 transcription blocks allergic airway inflammation in a mouse asthma model.

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.

• Authors: William R Henderson Jr, Emil Y Chi, Jia-Ling Teo, Cu Nguyen, Michael Kahn
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 169 Issue 9 Pg. 5294-9 (Nov 01 2002) ISSN: 0022-1767 [Print] United States
• PMID: 12391249 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Allergens
• CCL11 protein, human
• Ccl11 protein, mouse
• Chemokine CCL11
• Chemokines, CC
• Interleukin-13
• MOL 294
• NF-kappa B
• Pyridazines
• Transcription Factor AP-1
• Triazoles
• Thioredoxins
• Ovalbumin

Topics

• Administration, Intranasal
• Allergens (administration & dosage)
• Animals
• Asthma (metabolism, pathology, prevention & control)
• Bronchial Hyperreactivity (prevention & control)
• Bronchoalveolar Lavage Fluid (cytology, immunology)
• Cell Movement (drug effects, immunology)
• Chemokine CCL11
• Chemokines, CC (biosynthesis)
• Disease Models, Animal
• Eosinophils (drug effects, pathology)
• Female
• Humans
• Inflammation (metabolism, prevention & control)
• Interleukin-13 (biosynthesis)
• Lung (drug effects, immunology, pathology)
• Mice
• Mice, Inbred BALB C
• Mucus (drug effects, immunology, metabolism)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Ovalbumin (administration & dosage, immunology)
• Oxidation-Reduction (drug effects)
• Pyridazines (pharmacology, therapeutic use)
• Thioredoxins (antagonists & inhibitors)
• Transcription Factor AP-1 (antagonists & inhibitors, metabolism)
• Triazoles (pharmacology, therapeutic use)
• Tumor Cells, Cultured