[The role of matrix metalloproteinases in extracellular matrix remodelling in chronic obstructive pulmonary disease rat models].
OBJECTIVE
To study the role of metalloproteinases(MMPs) in the airway extracellular matrix (ECM) remodelling of chronic obstructive pulmonary disease (COPD) rat models.


METHODS
The COPD rat models which was established by intratracheal instillation of 200 microg lipopolysaccharide once for every two weeks(twice), and exposed to 5% smoke for 0.5 h/d for 4 weeks. The pathological changes were observed, lung function and blood gas changes were also deter mined. The fibroblasts, lymphocytes of bronchial walls and alveolar macrophages were counted. The hydroxyproline of bronchial lung tissue homogenates were deter mined by biochemistry method. The expression of MMP-9,MMP-2 and tissue inhibitor of metalloproteinase-1(TIMP-1) in bronchi and lung tissue was verfied by immunohistochemical analysis and by reverse transcription-polymerase chain reaction analysis. The gelatinolytic activities of MMPs of lung tissue were performed by gelatin zymographic analysis.


RESULTS
The pathological changes of bronchi and lung tissue, the changes of lung function and blood gas analysis were similar to those of the COPD patients. The number of fibroblasts, lymphocytes and alveolar macrophages of model group were significantly increased than those of control group (P < 0.001). The hydroxyproline of model group was significantly in creased than that of control group (P < 0.001). By using image analyzer, immunoreactivity of MMP-9, MMP-2,TIMP-1 were markedly increased in epithelial cells of bronchi, fibroblasts, macrophages, endothelial cells and pneumocytes in model group as compared with those of control group. The protein expressions of MMP-9, MMP-2 and TIMP-1 in model group were significantly increased than those in control group(P < 0.0001 or P < 0.01). The mRNA expression of MMP-2, MMP-9 and TIMP-1 in COPD model group (1.11 +/- 0.06,1.04 +/- 0.26 and 0.85 +/- 0.34,respectively) were significantly increased than those in control group (0.30 +/- 0.17,0.36 +/- 0.09 and 0.23 +/- 0.08,respectively) as well(P < 0.001 or P < "0.01). The relative gelatinolytic activities of 72 000 MMP-2, 92 000 MMP-9 in model group (3 263.5 +/- 665.1 and 1 338.4 +/- 241.2, respectively) were also significantly higher than those in the model group(388.6 +/- 60.8 and 116.1 +/- 49.8,respectively, P < 0.001).


CONCLUSIONS
The findings suggested that there were up regulations of MMP-9,MMP-2 and TIMP-1 of lung tissue in COPD model group which may contribute to the pathogenesis of airflow limitation through the airway remodelling and alveolar structure destruction(emphysema). The ECM degradation and deposition were imbalanced and abnormally activated. The evaluation of MMP-9,MMP-2 which are responsible for the inflammation and destruction process, and the evaluation of TIMP-1 which is responsible for the repair and remodelling process of the airways, may play an important role in the airway ECM remodelling in COPD.
Department of Respiratory Medicine, The 304th Hospital of Chinese PLA, Beijing 100037,China.
Hongmei
H
Li
Dejian
D
Cui
Xin
X
Tong
Nan
N
Ma
Yabing
Y
Gao
Xuemei
X
Cui
Lianrong
L
Lu
Dewen
D
Wang
Yanjie
Y
Liang
D000818:Animals; D001784:Blood Gas Analysis; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D005109:Extracellular Matrix / Q000378:metabolism; D005541:Forced Expiratory Volume; D015870:Gene Expression; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9