Effects of paclitaxel on vascular remodeling and peripheral inflammation in rats with pulmonary hypertension

Objective To explore the therapeutic effect of different doses of paclitaxel (PTX) on pulmonary artery pressure and pulmonary vascular remodeling in rats with pulmonary hypertension and its possible mechanism. Methods Twenty male Sprague-Dawley rats were randomly allocated into 4 groups with 5 rats in each group: control group(CON group), monocrotaline (MCT) group, and different doses of PTX groups (PTX-2 group and PTX-3 group). The rats received subcutaneous injection of 60 mg/kg MCT in MCT group and PTX interventional groups, while the same volume of DMSO was injected instead of MCT in control group. At 4 weeks following the MCT insult, the rats were subjected to intravenous administration of PTX at 2 mg/kg (PTX-2 group) or 3 mg/kg (PTX-3 group) at 4 day intervals (3 times in total), whereas the rats in the CON group and the MCT group were injected with the equal volume of normal saline through the tail vein. After measurement of pulmonary artery pressure, the rats were euthanized, the heart and lung tissues were stained with hematoxylin eosin, the proportion of middle membrane thickening (WT%) was measured, and the lymph follicle structure was evaluated. The expression of transcription factors FoxO1 and α-smooth muscle actin (α-SMA) were determined by immunohistochemistry, and the phenotype of macrophages in adventitia was analyzed. Results The mean pulmonary artery pressure (mPAP) in the MCT group was significantly higher than that in CON group (P<0.05). Compared with the MCT group, the mPAP in PTX-3 group was significantly reduced (P<0.05). Compared with the CON group, the expression of α - SMA and WT% in MCT group increased significantly (P<0.05). PTX intervention can significantly reduce the expression of α - SMA and the thickening of the middle membrane of the pulmonary vessels (P<0.05). The thickening of the middle membrane of the pulmonary vessels was further improved in the PTX-3 group (P<0.05). Compared with the CON group, the expression of FoxO1 in the lung tissue of rats in the MCT group decreased, and that in the PTX-2 group increased significantly (P<0.05). After MCT intervention, the peripheral lymphoid follicles and M2 phenotype macrophages (CD163⁺) increased significantly compared with the CON group (P<0.05). PTX intervention could reduce the ratio of lymphoid follicles and inhibit the aggregation of M2 pulmonary macrophages (P<0.05). Conclusions PTX (3 mg/kg) can significantly reduce the pressure of pulmonary artery in rats with pulmonary hypertension, improve the thickening of middle membrane of the pulmonary vessels, alleviate the inflammation around pulmonary artery, and effectively treat pulmonary hypertension.