title: Remodeling associated expression of matrix metalloproteinase 9 but not tissue inhibitor of metalloproteinase 1 in airway epithelium: modulation by immunostimulatory DNA.
abstract: BACKGROUND
  Matrix metalloproteinase 9 (MMP-9) and its tissue inhibitor of metalloproteinase 1 (TIMP-1) are hypothesized to play a role in the pathogenesis of airway remodeling in asthma.
  
  
  OBJECTIVE
  We have used a mouse model of airway remodeling to determine the pattern of expression of MMP-9 and TIMP-1 in airway epithelium and peribronchial cells, and assess whether TIMP-1, an inhibitor of MMP-9, is expressed at the same sites in the airway. In addition, we have investigated whether immunostimulatory sequences (ISSs) of DNA modulate levels of expression of MMP-9, TIMP-1, and peribronchial fibrosis.
  
  
  METHODS
  Levels of lung MMP-9 and TIMP-1 were assessed by zymography, ELISA, and immunohistochemistry.
  
  
  RESULTS
  Repetitive ovalbumin challenge induced a significant increase in levels of MMP-9, TIMP-1, and peribronchial collagen deposition. The pattern of expression of MMP-9 and TIMP-1 in the remodeled airway was significantly different. MMP-9 but not TIMP-1 was expressed in airway epithelium, whereas both MMP-9 and TIMP-1 were expressed in peribronchial inflammatory cells. ISS significantly reduced expression of MMP-9 in airway epithelium (which immunostained positive for Toll receptor 9), as well as in peribronchial inflammatory cells. In vitro studies demonstrated that ISS inhibited bone marrow macrophage generation of MMP-9.
  
  
  CONCLUSIONS
  Allergen-induced peribronchial fibrosis is associated with expression of MMP-9 and TIMP-1 at different anatomical sites in the remodeled airway. The ability of ISS to inhibit the expression of MMP-9 in airway epithelium (a site where its inhibitor TIMP-1 is not induced by allergen challenge) may be important in determining whether ISS contributes to reductions in airway remodeling by reducing levels of MMP-9.
  
  
  CONCLUSIONS
  Immunostimulatory sequences of DNA, which are being investigated as novel therapeutics in asthma, inhibit airway remodeling in mice as well as epithelial expression of MMP-9, an enzyme that degrades the extracellular matrix proteins surrounding the airway.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla 92093-0635, USA.
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Marina
authors.initials: M
authors.lastname: Miller
authors.forename: Kirsti
authors.initials: K
authors.lastname: McElwain
authors.forename: Shauna
authors.initials: S
authors.lastname: McElwain
authors.forename: Jung Yeon
authors.initials: JY
authors.lastname: Shim
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000485:Allergens; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D003094:Collagen / Q000096:biosynthesis; D004247:DNA / Q000494:pharmacology*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000473:pathology; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010047:Ovalbumin; D020545:Respiratory Mucosa / Q000201:enzymology / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*
chemical_list: D000276:Adjuvants, Immunologic; D000485:Allergens; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D019715:Tissue Inhibitor of Metalloproteinase-1; D010047:Ovalbumin; D003094:Collagen; D004247:DNA; D020780:Matrix Metalloproteinase 9