Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation.
BACKGROUND
Bronchial asthma is characterized by airway structural changes, including mucosal inflammation and subepithelial collagen deposition. An imbalance between the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) is thought to play a critical role in the synthesis or degradation of the extracellular matrix of the airway architecture. However, the relationship between subepithelial basement membrane thickness and these enzymes in asthma has not been determined.


OBJECTIVE
We compared the thickness of collagen and tenascin deposition and the expression of MMP-9 and TIMP-1 in bronchial biopsy specimens from subjects with asthma and control subjects.


METHODS
Bronchial biopsy specimens were obtained from 25 subjects with asthma and 10 healthy control subjects to estimate the extent of collagen and tenascin deposition in subepithelial reticular basement membrane by immunohistochemical staining. Using a computer-assisted image analysis system, we quantitated expression of both epithelial and submucosal MMP-9 and TIMP-1. The numbers of inflammatory cells were also determined.


RESULTS
Subjects with asthma exhibited greater thickness of collagen III (P <.01), collagen V (P <.01), and tenascin (P <.01) deposition in reticular basement membrane than did control subjects. The proportions of epithelium and submucosa immunoreactive to MMP-9 and TIMP-1 were significantly higher in the subjects with asthma than in the control subjects (each P <.001). Submucosal expression of MMP-9 was significantly higher than that of TIMP-1 in subjects with asthma (P <.01). Significant correlations were found between the number of myofibroblasts and thicknesses of collagen III (rs = 0. 70, P <.001), collagen V (rs = 0.67, P <.001), and tenascin (rs = 0. 58, P <.01) in subjects with asthma. On the other hand, the number of eosinophils was correlated with degree of mucosal expression of MMP-9 (rs = 0.43, P <.05) and TIMP-1 (rs = 0.69, P <.001). In subjects with asthma, a significant inverse correlation was found between subepithelial fibrosis and FEV1 (type III collagen, rs = -0. 89, P <.001; type V collagen, rs = -0.90, P <.001; tenascin, rs = -0. 88, P <.001), and airway responsiveness (type III collagen, rs = -0. 59, P <.01; type V collagen, rs = -0.47, P <.05; tenascin, rs = -0. 48, P <.05).


CONCLUSIONS
These findings suggest that collagen III, collagen V, and tenascin deposition in basement membrane in subjects with bronchial asthma are associated with increased expression of MMP-9, which may be produced by eosinophils, and that airway remodeling in subjects with asthma may be related to air-flow obstruction and airway hyperresponsiveness.
Hoshino
M
M
Second Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan.
Nakamura
Y
Y
Sim
J
J
Shimojo
J
J
Isogai
S
S
D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000503:physiopathology*; D001485:Basement Membrane / Q000473:pathology; D001706:Biopsy; D001980:Bronchi / Q000473:pathology*; D001991:Bronchitis / Q000201:enzymology*; D002452:Cell Count; D017364:Collagenases / Q000096:biosynthesis* / Q000276:immunology; D005260:Female; D005355:Fibrosis; D006801:Humans; D008168:Lung / Q000502:physiology; D008297:Male; D008407:Mast Cells / Q000166:cytology; D020780:Matrix Metalloproteinase 9; D008875:Middle Aged; D009092:Mucous Membrane / Q000737:chemistry; D013601:T-Lymphocytes / Q000166:cytology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000276:immunology
D019715:Tissue Inhibitor of Metalloproteinase-1; D017364:Collagenases; D020780:Matrix Metalloproteinase 9