title: A mouse model of otitis media identifies HB-EGF as a mediator of inflammation-induced mucosal proliferation.
abstract: OBJECTIVE
  Otitis media is one of the most common pediatric infections. While it is usually treated without difficulty, up to 20% of children may progress to long-term complications that include hearing loss, impaired speech and language development, academic underachievement, and irreversible disease. Hyperplasia of middle ear mucosa contributes to the sequelae of acute otitis media and is of important clinical significance. Understanding the role of growth factors in the mediation of mucosal hyperplasia could lead to the development of new therapeutic interventions for this disease and its sequelae.
  
  
  METHODS
  From a whole genome gene array analysis of mRNA expression during acute otitis media, we identified growth factors with expression kinetics temporally related to hyperplasia. We then tested these factors for their ability to stimulate mucosal epithelial growth in vitro, and determined protein levels and histological distribution in vivo for active factors.
  
  
  RESULTS
  From the gene array, we identified seven candidate growth factors with upregulation of mRNA expression kinetics related to mucosal hyperplasia. Of the seven, only HB-EGF (heparin-binding-epidermal growth factor) induced significant mucosal epithelial hyperplasia in vitro. Subsequent quantification of HB-EGF protein expression in vivo via Western blot analysis confirmed that the protein is highly expressed from 6 hours to 24 hours after bacterial inoculation, while immunohistochemistry revealed production by middle ear epithelial cells and infiltrating lymphocytes.
  
  
  CONCLUSIONS
  Our data suggest an active role for HB-EGF in the hyperplasia of the middle ear mucosal epithelium during otitis media. These results imply that therapies targeting HB-EGF could ameliorate mucosal growth during otitis media, and thereby reduce detrimental sequelae of this childhood disease.
authors.affiliation: Division of Otolaryngology, University of California, San Diego School of Medicine and VA Medical Center, La Jolla, California, United States of America.
authors.forename: Keigo
authors.initials: K
authors.lastname: Suzukawa
authors.affiliation: Division of Otolaryngology, University of California, San Diego School of Medicine and VA Medical Center, La Jolla, California, United States of America.
authors.forename: Julia
authors.initials: J
authors.lastname: Tomlin
authors.affiliation: Division of Otolaryngology, University of California, San Diego School of Medicine and VA Medical Center, La Jolla, California, United States of America.
authors.forename: Kwang
authors.initials: K
authors.lastname: Pak
authors.affiliation: Division of Otolaryngology, University of California, San Diego School of Medicine and VA Medical Center, La Jolla, California, United States of America.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Chavez
authors.affiliation: Division of Otolaryngology, University of California, San Diego School of Medicine and VA Medical Center, La Jolla, California, United States of America.
authors.forename: Arwa
authors.initials: A
authors.lastname: Kurabi
authors.affiliation: Division of Trauma, Department of Surgery, University of California, San Diego School of Medicine and VA Medical Center, La Jolla, California, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Baird
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, University of California, San Diego School of Medicine and VA Medical Center, La Jolla, California, United States of America.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Wasserman
authors.affiliation: Division of Otolaryngology, University of California, San Diego School of Medicine and VA Medical Center, La Jolla, California, United States of America.
authors.forename: Allen F
authors.initials: AF
authors.lastname: Ryan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004432:Ear, Middle / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism*; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000378:metabolism* / Q000473:pathology*; D010033:Otitis Media / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: D066257:Heparin-binding EGF-like Growth Factor; D012333:RNA, Messenger; D004815:Epidermal Growth Factor