A potential new target for asthma therapy: A Disintegrin and Metalloprotease 10 (ADAM10) involvement in murine experimental asthma

• Published in: Allergy (Copenhagen) Vol. 66; no. 9; pp. 1193 - 1200
• Main Authors: Mathews, J. A., Ford, J., Norton, S., Kang, D., Dellinger, A., Gibb, D. R., Ford, A. Q., Massay, H., Kepley, C. L., Scherle, P., Keegan, A. D., Conrad, D. H.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2011; Blackwell
• Subjects: ADAM Proteins - antagonists & inhibitors; ADAM Proteins - genetics; ADAM Proteins - physiology; ADAM10; ADAM10 Protein; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - physiology; Animal models; Animals; Asthma; Asthma - immunology; Asthma - pathology; Asthma - therapy; Biological and medical sciences; CD23; CD23 antigen; Chemokines; Chronic obstructive pulmonary disease, asthma; Cytokines; Dermatology; Disease Models, Animal; Eosinophilia; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation - immunology; Helper cells; Hypersensitivity; IgE; Immunoglobulin E; Immunoglobulin E - immunology; Inflammation; Inhibitor drugs; Intranasal administration; Lung; Lymphocytes B; Lymphocytes T; Medical sciences; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - physiology; Metalloproteinase; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Pneumology; Pneumonia - immunology; Pneumonia - pathology; Receptors, IgE - genetics; Respiratory tract; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Th2; Disintegrin; FcεRII receptor; Targeted therapy; IgE; Immunology; Targeted drug; T-Lymphocyte; Bronchus disease; Th2 lymphocyte; Obstructive pulmonary disease; Th2; Lung disease; Immunopathology; Respiratory disease; Dermatology; Rodentia; ADAM10; Experimental study; Asthma; Vertebrata; Mammalia; Treatment; Mouse; Animal; CD23
• ISSN: 0105-4538; 1398-9995
• DOI: 10.1111/j.1398-9995.2011.02614.x

To cite this article: Mathews JA, Ford J, Norton S, Kang D, Dellinger A, Gibb DR, Ford AQ, Massay H, Kepley CL, Scherle P, Keegan AD, Conrad DH. A potential new target for asthma therapy: A Disintegrin and Metalloprotease 10 (ADAM10) involvement in murine experimental asthma. Allergy 2011; 66: 1193–1200. Background:  Elevated levels of CD23, a natural regulator of IgE production, have been shown to decrease the signs of lung inflammation in mice. The aim of this study was to study the involvement of ADAM10, the primary CD23 sheddase, in experimental asthma. Methods:  ADAM10 was blocked either by using mice with a B‐cell‐specific deletion of the protease or pharmacologically by intranasal administration of selective ADAM10 inhibitors. Airway hypersensitivity (AHR) and bronchoaveolar lavage fluid (BALF) eosinophilia and select BALF cytokine/chemokine levels were then determined. Results:  Using an IgE and mast cell–dependent mouse model, B‐cell‐specific ADAM10−/− mice (C57B/6 background) exhibited decreased eosinophilia and AHR when compared with littermate (LM) controls. Treatment of C57B/6 mice with selective inhibitors of ADAM10 resulted in an even further decrease in BALF eosinophilia, as compared with the ADAM10−/− animals. Even in the Th2 selective strain, Balb/c, BALF eosinophilia was reduced from 60% to 23% respectively. In contrast, when an IgE/mast cell–independent model of lung inflammation was used, the B‐cell ADAM10−/− animals and ADAM10 inhibitor treated animals had lung inflammation levels that were similar to the controls. Conclusions:  These results thus show that ADAM10 is important in the progression of IgE‐dependent lung inflammation. The use of the inhibitor further suggested that ADAM10 was important for maintaining Th2 levels in the lung. These results thus suggest that decreasing ADAM10 activity could be beneficial in controlling asthma and possibly other IgE‐dependent diseases.