A Study Of Rat Model With Pulmonary Hypertension From Chronic Bronchitis And Emphysema

OBJECTIVE: (1)To establish a rat model with pulmonary hypertension from chronic bronchitis and emphysema by simulating the pathogenesis of human chronic obstructive pulmonary disease (COPD). (2)To study the role of matrix metalloproteinases (MMP-2 and MMP-9) in airway and pulmonary vascular remodeling.METHODS: 41 Wistar rats were divided into 5 groups randomly. Group A was a model with hypoxic pulmonary hypertension (n=10). Rats were exposed to chronic hypoxia [inspiratory O2 fraction(FiO2)=0.10] 8h/d , 6d/w for 2 weeks. Group B is one with pulmonary hypertension from chronic bronchitis and emphysema (n=7). 200μg lipopolysaccharide(LPS) was instilled intratracheally once at first and forteenth day and the rats were exposed to cigarette smoke 2h/d for 6 weeks. In last 2 weeks chronic hypoxia (FiO2=0.18) 8h/d were performed simultaneously. Group C(n=8), 200μg LPS was instilled intratracheally once at first and forteenth day for all rats. Then these rats were exposed to cigarette smoke 2h/d for 6 weeks. Group D(n=8), rats were exposed to chronic hypoxia(FiO2=0.18) 8h/d for 2 weeks. Healthy control ,group E(n=8), rats were bred for 6 weeks in normal circumstance. We studied blood gas analysis and pulmonary hemodynamic changes, observed the morphology changes of airways and pulmonary vascular structure. Total cell counts and their differentiation in bronchoalveocar lavage fluids (BALF) were done . The expression and enzymatic activity of MMP-2 and MMP-9 in lung tissue were detected by immunohistochemistry . RESULTS: (1) Compared to the group E, the PaO2 in group A and B were significantly decreased (p <0.05), while blood gas analysis didn't change in other groups (p >0.05). (2) The RVSP , mPAP, RV/LV+S were higher in group A, B, C than group E. The muscularization of intra-alceolar arteries in group A, B, and C were significantly apparent compared with group E(p <0.05) . The cross-sectional medial vascular wall area of pulmonary arteries were increased significantly in group A and group B compared with group E(p <0.05). (3) The number of white cell and neutrophils in BALF obtained from group B and C were significantly higher than group E(p <0.05). Only percentage of alveolar macrophage elevated could be found in BALF of group A. (4)The rats of group B showed the same pathological features in trachea, bronchi and lung tissues as human being with COPD. There had shown an increased number of inflammatory cells, in particular, lymphocytes in the airways of rats of group B. But changes like those could not be seen in rats of groups A. (5) By using image analyzer , immunoreactivity of MMP-9 were significantly increased in epithelial cells and inflammatory cells , which of MMP-2 were also increased in inflammatory cells in group B compared with group E and group A (p <0.05). CONCLUSIONS: A rat model with pulmonary hypertension from chronic bronchitis and emphysema was successfully established by passive cigarette smoking , intratracheal instillation of LPS plus chronic hypoxia(FiO2=0.18). It was a better animal model than hypoxic pulmonary hypertension, to which mimiced the same pathologic changes of human pulmonary hypertension from COPD . The increased expression of MMPs , especially from inflammatory cells , may interfere in the repair of airway , and contribute to the remodeling of airway and pulmonary vascular in chronic bronchitis and emphysema .