title: A potential new target for asthma therapy: a disintegrin and metalloprotease 10 (ADAM10) involvement in murine experimental asthma.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Mathews
authors.forename: J
authors.initials: J
authors.lastname: Ford
authors.forename: S
authors.initials: S
authors.lastname: Norton
authors.forename: D
authors.initials: D
authors.lastname: Kang
authors.forename: A
authors.initials: A
authors.lastname: Dellinger
authors.forename: D R
authors.initials: DR
authors.lastname: Gibb
authors.forename: A Q
authors.initials: AQ
authors.lastname: Ford
authors.forename: H
authors.initials: H
authors.lastname: Massay
authors.forename: C L
authors.initials: CL
authors.lastname: Kepley
authors.forename: P
authors.initials: P
authors.lastname: Scherle
authors.forename: A D
authors.initials: AD
authors.lastname: Keegan
authors.forename: D H
authors.initials: DH
authors.lastname: Conrad
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011014:Pneumonia / Q000276:immunology / Q000473:pathology; D017455:Receptors, IgE / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D017455:Receptors, IgE; D007073:Immunoglobulin E; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse