Remodeling associated expression of matrix metalloproteinase 9 but not tissue inhibitor of metalloproteinase 1 in airway epithelium: modulation by immunostimulatory DNA.
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.
Cho
Jae Youn
JY
Department of Medicine, University of California San Diego, La Jolla 92093-0635, USA.
Miller
Marina
M
McElwain
Kirsti
K
McElwain
Shauna
S
Shim
Jung Yeon
JY
Raz
Eyal
E
Broide
David H
DH
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*
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