Inhibition of matrix metalloproteinases prevents allergen-induced airway inflammation in a murine model of asthma.
Although matrix metalloproteinases (MMPs) have been reported to play crucial roles in the migration of inflammatory cells through basement membrane components in vitro, the role of MMPs in the in vivo accumulation of the cells to the site of inflammation in bronchial asthma is still obscure. In this study, we investigated the role of MMPs in the pathogenesis of bronchial asthma, using a murine model of allergic asthma. In this model, we observed the increase of the release of MMP-2 and MMP-9 in bronchoalveolar lavage fluids after Ag inhalation in the mice sensitized with OVA, which was accompanied by the infiltration of lymphocytes and eosinophils. Administration of tissue inhibitor of metalloproteinase-2 to airways inhibited the Ag-induced infiltration of lymphocytes and eosinophils to airway wall and lumen, reduced Ag-induced airway hyperresponsiveness, and increased the numbers of eosinophils and lymphocytes in peripheral blood. The inhibition of cellular infiltration to airway lumen was observed also with tissue inhibitor of metalloproteinase-1 and a synthetic matrix metalloproteinase inhibitor. These data suggest that MMPs, especially MMP-2 and MMP-9, are crucial for the infiltration of inflammatory cells and the induction of airway hyperresponsiveness, which are pathophysiologic features of bronchial asthma, and further raise the possibility of the inhibition of MMPs as a therapeutic strategy of bronchial asthma.
Kumagai
K
K
First Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Ohno
I
I
Okada
S
S
Ohkawara
Y
Y
Suzuki
K
K
Shinya
T
T
Nagase
H
H
Iwata
K
K
Shirato
K
K
D000280:Administration, Inhalation; D000485:Allergens / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000201:enzymology* / Q000276:immunology / Q000628:therapy; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D017252:CD3 Complex / Q000378:metabolism; D017364:Collagenases / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000201:enzymology; D005260:Female; D018093:Gelatinases / Q000037:antagonists & inhibitors; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000628:therapy; D015848:Interleukin-5 / Q000378:metabolism; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology / Q000473:pathology*; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011994:Recombinant Proteins / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000502:physiology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism / Q000502:physiology; D014132:Trachea
D000485:Allergens; D017252:CD3 Complex; D015848:Interleukin-5; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D010047:Ovalbumin; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9