Effects Of Paclitaxel On Vascular Remodeling And Peripheral Inflammation In Rats With Pulmonary Hypertension

Objective: To investigate the therapeutic effects of different doses of paclitaxel on pulmonary artery pressure,pulmonary vascular remodeling and pulmonary perivascular inflammation in pulmonary hypertension rats treated with monocrotaline(MCT).Meanwhile,the effects of paclitaxel on the expression of FoxO1 around pulmonary vessels,Cyclin D1 expression in lung tissue were also investigated.Methods: 100 male Sprague-Dawley rats were randomly allocated into 4 groups with 25 rats in each group: control group,MCT group,paclitaxel interventional groups(group PTX-2 or PTX-3).The rats received subcutaneous injection of 60 mg/kg monocrotaline in MCT group and paclitaxel interventional groups,while the same volume of DMSO was injected instead of MCT in control group.4 weeks following the MCT insult,the rats were subjected to intravenous administration of paclitaxel at 2 mg/kg or 3 mg/kg every other 3 days for 3 times in the 14-day observational period in group PTX-2 and group PTX-3 respectively,whereas the equal volume of normal saline were substituted of paclitaxel in MCT group.At the end of experiment,the rats were anesthetized to undergo left thoracotomy for the exposure of the right ventricle of rats.The mean pulmonary arterial pressure(m PAP)was measured with a catheter inserted into pulmonary trunk connecting to the pressure transducer.The rats were euthanized by intravenous injection of 10 % potassium chloride thereafter.The lung tissue was exercised and fixed in 10 % neutral formaldehyde for vasculature morphological and perivascular inflammation assessment.The immunohistochemistry assay was used to evaluate the expression of FoxO1,?-smooth muscle actin in media tunica of pulmonary arterioles.The macrophage surface marker of CD163 was applied to identify the phenotype of interstitial macrophages.The rest part of lung tissue was stored in a refrigerator at-80°C,and the expression of Cyclin D1 was determined by Western Blot method to analyze the thickening of pulmonary vessels.Results: Compared with control rats,MCT insult caused significant rise in mean PAP,percentage of media tunica thickening,the ratio of lymphoid follicles on Day 28.The decrease of mean PAP,the attenuation of medial tunica thickening or the ratio of lymphoid follicles was observed in PTX-2 group,moreover,the higher dose of PTX(3 mg/kg)was identified to be more effective in decrease of mean PAP,the attenuation of medial tunica thickening or the ratio of lymphoid follicles compared with PTX at dose of 2 mg/kg(P <0.05).The expression of CD163 on macrophages was significantly increased in MCT group compared with control group,the rescue of PTX significantly repress the accumulation of perivascular macrophages and the polarization to M2 macrophages.The expression of FoxO1 was significantly decreased in MCT group compared with control group.The intervention of PTX increased the expression of FoxO1 in PASMCs,whereas,the higher dose of PTX(3 mg/kg)was identified to be more effective in increase of FoxO1 expression.Western Blot results showed that PTX intervention could significantly reduce the expression of Cyclin D1 and media thickening(P <0.05),and PTX-3 group could improve the medial thickening of pulmonary arterioles wall.(P <0.05).Conclusion: Paclitaxel elicits the therapeutic effect on pulmonary vascular remodeling and decreases the pulmonary arterial pressure,which is associated with the upregulation of FoxO1 expression and inhibition of M2 macrophages accumulation in perivascular areas of lung interstitium.