Enhancement of gelatinase activity during development of subepithelial fibrosis in a murine model of asthma.
BACKGROUND
Chronic asthma is characterized by inflammatory cell infiltration and tissue remodelling leading to subepithelial fibrosis. Metalloproteinases (MMPs) are involved in degradation of extracellular matrix in most chronic inflammatory diseases.


OBJECTIVE
The aim of this study was to investigate the expression of MMPs in the development of inflammatory processes associated or not with the concomitant development of subepithelial fibrosis in an experimental model of asthma.


METHODS
Sensitized BP2 mice were challenged with ovalbumin (OA) every 2 weeks during 8 months. Several mice were removed once a month and bronchoalveolar lavages (BAL) or lung biopsies were performed.


RESULTS
Lung sections stained with picrosirius and hydroxyproline measurements showed a significant collagen deposition after 16 weeks of OA challenge, demonstrating the development of subepithelial fibrosis. Pulmonary inflammation was present from the first OA challenge and was consistent throughout the 8 months of the study. Moreover, an up-regulation and activation of MMP-9 and, to a less extent, MMP-2 were observed in BAL fluid from challenged mice. The level of tissue inhibitor of metalloproteinases (TIMP)-1 increased after 12 weeks of OA challenge vs. control mice.


CONCLUSIONS
This study reveals that a decrease in the activation of the MMP-9 due to the increase in TIMP-1, could contribute to excessive collagen deposition following repeated antigen challenge in sensitized mice.
Corbel
M
M
INSERM U 456, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1 and Anatomie Pathologie B, CHR Pontchaillou, Rennes, France.
Caulet-Maugendre
S
S
Germain
N
N
Lagente
V
V
Boichot
E
E
D000818:Animals; D001249:Asthma / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D018093:Gelatinases / Q000378:metabolism*; D006909:Hydroxyproline / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D016207:Cytokines; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D010047:Ovalbumin; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D006909:Hydroxyproline