| Background Pulmonary thromboembolism (PTE) is a clinical and physiopathologic syndrom of pulmonary disorder caused by endogenous or exogenous pulmonary thromboembolus. PTE is a disease that of high morbidity, high mortality and high morbidity.It is the third cause of death after malignant tumor and myocardial infarction, and is also the primary death cause in postpartum women. Now PTE has become an international health care. It has been reported that the mortality rate of untreated PTEis as high as30%, while the rate of misdiagnosis and missed diagnosis is extremely high,70%inEurope and the United States, and90%in China. The majority of patients can not get timely treatment, so most of the patients whth acute PTEcan not returned to normalin anatomy and hemodynamics, and a few patients developed into chronic thromboembolic pulmonary hypertension with poor prognosis. Theprocess is accompanied with pulmonary vascular remodeling characterized by medial wall thickness of muscular arteriesand muscularization of peripheral arteries, which may result from increased migration to intima and proliferation of smoothmuscle cells (SMC).Low molecular weight heparin (LMWH) have been shown to inhibit theproliferation of SMC. And urokinase (UK) may have some effects on vascular endothelial cells. At present the research on the mechanism behind the LMWH, UK and pulmonary artery intimal hyperplasia after acute PTE is few.Objective1.To investigate the pathologic characteristics of lung tissus and intimal hyperplasia of pulmonary artery after acute PTE. To study changes of ET-1and MMP-9in lung tissue, and explore their roles in neointima formation associated with acute PTE.2.To investigate the effect of LMWH and UK onintimal hyperplasiaafter acute PTE.Methods 1.124male Sprague-Dawley rats were randomly divided into sham group(n=30), PTE group(n=30),low molecular weight heparin group(LMWH group, n=30) and Urokinase group (UK group, n=30). Experimental pulmonary thromboembolism was induced in94rats by injection of auto-blood clots into jugular vein, and an additional30rats underwent sham operations. after inductionrats received either low molecular weight heparin (LMWH group, LMWH0.01ml/Kg, Q12h), Urokinase group (UK group, UK20000IU/Kg+LMWH0.01ml/Kg, Q12h) or saline (Sham and PTE group)subcutaneously for7days. Animals were sacrificed at2,4,6hours and1,4,7days after PTE. Five animals were killed for each group at each time point.2.Mean pulmonary arterial pressure (mPAP) and right ventricular pressure(RVP) were determined by right heart catheterization.3.Pressure of artery blood oxygen(PaO2), the changes of ET-1and MMP-9were detected by right jugular veinintubation.4. To investigate the pathologic characteristics of lung tissus and intimal hyperplasia of pulmonary artery after acute PTE in lung biopsy by HE staining.5.Immunohistochemical analysis was used to study the changes of ET-1and MMP-9.6. The MMP-9protein content in lung tissue were determined by Western blot.Results1.Induction of PTE was attempted in94rats, with90rats (95.7%) succeeded. Of the4rats died,4died within2hours owing to thrombus retained in the right ventricle of the heart. Increasing of respiratory and heart rate was found in rats after injecting thrombus.2.mPAP in PTE, LMWH and UKgroup were significantly increased.mPAP in PTE group was increased in time points of h2、h4、h6、d1、d4and there were significant differences between PTE and Sham group (p<0.05).There were significant differences in time points of h2、h4、h6、d1between LMWH and Sham group (p<0.05),and there were significant differences in time points ofdl between LMWH and PTE group (p<0.05).There were significant differences in time points of h2、h4、h6between UK and Sham group (p<0.05).There were significant differences in time points of h6、d1、d4between UK and PTE group (p<0.05).There were significant differences in time points of h6、d1between UK and LMWH group (p<0.05). 3.RVP in PTE, LMWH and UKgroup were significantly increased after PTE.RVP in PTE and LMWH group was increased in time points of h2、h4、h6、d1and there were significant differences compared with Sham group (p<0.05).There were significant differences in time point of h2between UK and Sham group (p<0.05).There were significant differences in time point of h6、d1between UK and PTE roup (p<0.05).There were significant differences in time point of h6、d1between UK and LMWH group (p<0.05).4.Pressure of artery blood oxygen(PaO2) in PTE group was decreased in all time points,and there were significant differences compared with Sham group (p<0.05).There were significant differences in time points of h2、h4、h6、d1、d4between LMWH and Sham group (p<0.05).There were significant differences in time point of d4、d7between LMWH and PTE roup (p<0.05).There were significant differences in time point of h2、h4、h6、d1between UK and Sham group (p<0.05).There were significant differences in time point of h6、d1、d4between UK and LMWH group (p<0.05).There were no significant differences between the4groups in PaCO2.5.The level of MMP-9were significantly increased in PTE、LMWH and UK group.There were significant differences in time points of h2、h4、h6between PTE and LMWH group (p<0.05).There were significant differences in time point of d4、 d7between LMWH and Sham roup (p<0.05).There were significant differences in time point of h2、h4、h6between UK and Sham roup (p<0.05).There were significant differences in time point of h4、h6、d7between UK and PTE roup (p<0.05).There were significant differences in time point of h4、h6between UK and LMWH roup (p<0.05).6.The level of MMP-9were significantly increased in PTE、LMWH and UK group.There were significant differences in all the time points between PTE and Sham group (p<0.05).There were significant differences in Sham group in time points of h2、h4、h6、d1compared with PTE and Sham group (p<0.05).There were significant differences in time point of d4、d7between LMWH and PTE roup (p<0.05).There were significant differences in time point of d1、d4、d7between UK and PTE roup (p<0.05).7.Immunohistochemical analysis indicated that ET-1was expressed predominantly in pulmonary vascular smooth muscle cells, macrophages endothelial cells andneointimal smooth muscle cells. ET-1overexpression in PTE group was present on after PTE. ET-1were expressed weakly in LMWH and UK group. MMP-9is expressed in pulmonary vascular smooth muscle cells macrophages, neointimal smooth musclecellsand monocyte-macrophages. The MMP-9expression in PTE group was graduallyenhanced after PTE. MMP-9were expressed weakly in LMWH and UK group.8.In PTE group, MMP-9protein expression increase (P<0.05). In LMWH and UK group, MMP-9protein expression were lower than PTE group (P<0.05), yet the levels of MMP-9protein were higher than those in Sham group.Conclusions1.Rat model of acute pulmonary embolism can be established by injecting autologous blood clots into jugular vein.2.Pulmonary arterial intimal hyperplasia was present at day4and continued to exist after acute PTE in rats.3.ET-1and MMP-9contribute importantly to the process of neointima formation associated with acute PTE.4.LMWH and Urokinase prevents intimal hyperplasia after acute PTE in rats. |
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