The effect of extracellular matrix remodeling on airflow obstruction in a rat model of chronic obstructive pulmonary disease.
OBJECTIVE
To study the nature of extracellular matirx (ECM) remodeling and its role in airflow obstruction in a rat model of chronic obstructive pulmonary disease (COPD), and to observe the role of nacetylcystein (NAC), protein kinase C (H(7)) and TGF-beta monocolonal antibody in the regulation of extracellular matrix remodeling in the airway wall.


METHODS
Fifty-three Wistar rats were randomly divided into 5 groups: the healthy control group, the COPD model group, the NAC group, the H(7) group and the TGF-beta monocolonal antibody group. Pathologic study of the airway and lung tissue, lung function test and blood gas analysis were performed. Fibroblasts and lymphocytes of the bronchial wall and alveolar macrophages were counted. Areas of the epithelial layer, the smooth muscle layer and the lamina propria were measured by image analyzer. The level of hydroxyproline in bronchial and lung homogenates was determined by biochemistry method. The serum levels of laminin (LN) and hyaluronic acid (HA) were determined by RIA method.


RESULTS
The changes in histopathology, lung function and blood gas in the animal model were similar to those in COPD patients. The collagen, mainly type I collagen, in airway walls was significantly increased. The areas of the epithelial layer (21 114 micro m(2)) and the smooth muscle layer (16 061 micro m(2)) were significantly increased in the COPD model as compared to the control group (13 056 micro m(2) and 6 692 micro m(2), respectively) (P < 0.01). In the drug intervention groups these parameters were significantly decreased compared to the control group. The numbers of fibroblasts (13.6 +/- 4.2), lymphocytes (35.6 +/- 6.4) and alveolar macrophages (14.8 +/- 1.1) in the model group, were significantly increased compared to the control group (6.8 +/- 1.4, 6.1 +/- 1.2 and 3.5 +/- 1.2, respectively) (P < 0.01, 0.001, 0.001), while in the drug intervention groups the cells were significantly decreased except for fibroblasts in the H(7) group. The hydroxyproline level of the model group (111.5 +/- 2.3) pg/ml was significantly increased as compared to the control group (47.8 +/- 9.7) pg/ml (P < 0.05) and was negatively correlated with FEV(0.3)/FVC (P < 0.001) and positively correlated with airflow resistance (P < 0.01). The number of fibroblasts was also positively correlated with the level of hydroxyproline (P < 0.001). The serum levels of LN (26 +/- 4) micro m/L and HA (19.4 +/- 1.4) micro g/L in the model group were significantly increased compared to the control group (15 +/- 3) micro g/L, and (10.9 +/- 2.9) micro g/L, respectively (P < 0.05). Hydroxyproline in the NAC group (83.1 +/- 41.7) pg/ml and the TGF-beta monoclonal antibody group (71.2 +/- 20.3) pg/ml was significantly decreased, while in the H(7) group (160.6 +/- 41.7) pg/ml it was significantly increased.


CONCLUSIONS
Excessive deposition of ECM, mainly of type I collagen, and proliferation of functionally activated fibroblasts were important pathological changes in airway remodeling and the important causes of airflow obstruction. TGF-beta monoclonal antibody and NAC can modulate airway extracellular matrix remodeling. H(7) can increase collagen deposition in the airway wall but the underlining mechanisms need to be elucidated.
Li
Hongmei
H
Division of Respiratory Medicine, The 304th Hospital Chinese PLA, Beijing 100037, China.
Cui
Dejian
D
Ma
Nan
N
Lu
Lianrong
L
Gao
Yabing
Y
Cui
Xuemei
X
Wang
Dewen
D
D000818:Animals; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D008168:Lung; D029424:Pulmonary Disease, Chronic Obstructive; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016212:Transforming Growth Factor beta