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目的观察多廿烷醇对野百合碱诱导的肺动脉高压(PAH)大鼠的平均肺动脉压(MPAP)与肺动脉重构的影响及可能的机制。方法雄性SD大鼠60只随机数字法分为正常对照组、PAH组、多廿烷醇组,每组20只。野百合碱(40mg/kg)一次性腹腔注射建立大鼠PAH模型,多廿烷醇组以多廿烷醇[10 mg/(kg·d)]灌胃,对照组和PAH组给予等量的生理盐水灌胃4周。肺动脉导管法测定大鼠MPAP;称重法测右心室肥厚指数(RVHI);HE染色观察肺小动脉病理形态改变,测定肺小动脉管壁厚度占血管外径的百分比(WT%)、肺小动脉管壁总面积占血管总面积的百分比(WA%);TUNEL染色法观察肺小动脉内皮细胞凋亡情况;Western blot法测肺组织凋亡相关蛋白Bax、Bcl-2表达;酶联免疫吸附试验测定血清白细胞介素6(IL-6)和肿瘤坏死因子α(TNF-α)水平。结果与正常对照组相比,PAH组MPAP[(33.91±4.72)比(17.57±3.44)mm Hg]、RVHI[(69.25±8.42)%比(24.91±2.82)%]、肺小动脉WT%[(66.53±10.01)%比(32.08±4.98)%]和WA%[(86.52±4.97)%比(52.96±6.65)%]增加(均P<0.01);与PAH组相比,多廿烷醇组MPAP[(26.94±6.02)比(33.91±4.72)mm Hg]、RVHI[(55.27±9.89)%比(69.25±8.42)%]、肺小动脉WT%[(41.66±10.47)%比(66.53±10.01)%]和WA%[(64.10±12.80)%比(86.52±4.97)%]减少(均P<0.01)。与正常对照组相比,PAH组大鼠肺小动脉内皮细胞凋亡增多,PAH组肺组织凋亡蛋白Bax表达增加,抗凋亡蛋白Bcl-2表达减少,Bax与Bcl-2比值增加;与PAH组相比,多廿烷醇组大鼠肺小动脉内皮细胞凋亡减少,肺组织Bax表达减少,Bcl-2表达增加,Bax与Bcl-2比值减少(均P<0.01)。与正常对照组相比,PAH组大鼠血清细胞因子IL-6、TNF-α水平升高;与PAH组相比,多廿烷醇组血清IL-6、TNF-α水平降低(均P<0.01)。结论多廿烷醇改善野百合碱诱导的PAH大鼠的MPAP及肺血管重构,可能与其减少细胞凋亡、抑制炎症反应有关。
Objective To investigate the effects of policosanol on the mean pulmonary arterial pressure (MPAP) and pulmonary remodeling induced by monocrotaline in pulmonary hypertension (PAH) rats and its possible mechanism. Methods Sixty female SD rats were randomly divided into normal control group, PAH group and policosanol group, 20 rats in each group. PAH model was established by intraperitoneal injection of monocrotaline (40mg / kg), policosanol [10 mg / (kg · d)] in policosanol group and control group and PAH group Saline gavage for 4 weeks. Pulmonary artery catheterization was used to measure MPAP in rats. Right ventricular hypertrophy index (RVHI) was measured by weighing method. Pathological changes of pulmonary arterioles were observed with HE staining. The percentage of pulmonary arterioles to vascular diameter (WT%), The percentage of total vascular wall area (WA%) in total vessel area was observed. The apoptosis of pulmonary arterioles was observed by TUNEL staining. The expressions of Bax and Bcl-2 in lung tissue were detected by Western blot. The levels of serum interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were measured. Results Compared with the normal control group, the MPAP in the PAH group was significantly higher than that in the PAH group (33.91 ± 4.72 vs 17.57 ± 3.44 mm Hg), RVHI (69.25 ± 8.42)% vs 24.91 ± 2.82% (66.53 ± 10.01)% (32.08 ± 4.98)%] and WA% [(86.52 ± 4.97)% vs (52.96 ± 6.65)%] (all P <0.01). Compared with PAH group, policosanol The mean arterial pressure of MPAP group was (26.94 ± 6.02) vs (33.91 ± 4.72) mm Hg, RVHI was (55.27 ± 9.89)% vs (69.25 ± 8.42)%, pulmonary arterioles WT% was (41.66 ± 10.47)% ± 10.01%] and WA% [(64.10 ± 12.80)% vs (86.52 ± 4.97%)] (all P <0.01). Compared with the normal control group, the apoptosis of pulmonary arterioles in PAH group increased, the expression of Bax protein in lung tissue of PAH group increased, the expression of anti-apoptotic protein Bcl-2 decreased, and the ratio of Bax to Bcl-2 increased Compared with PAH group, the apoptosis of pulmonary arterioles in the policosanol group decreased, the expression of Bax decreased, the expression of Bcl-2 increased and the ratio of Bax to Bcl-2 decreased (all P <0.01). Compared with the normal control group, the levels of serum cytokines IL-6 and TNF-α in PAH group were significantly increased, while the levels of IL-6 and TNF-α in the policosanol group were lower than those in the PAH group (all P < 0.01). Conclusion Policosanol can improve the MPAP and pulmonary vascular remodeling induced by monocrotaline in PAH rats, which may be related to the decrease of apoptosis and the inhibition of inflammatory reaction.