Department of Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Fuzhou Children's Hospital of Fujian Province Affiliated with Fujian Medical University, 145-817-Middle Road, Gulou, Fuzhou, 350005, Fujian, China.
BMC Pulm Med. 2021 Nov 20;21(1):377. doi: 10.1186/s12890-021-01710-4.
Preventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH). Causes of PH include pulmonary vasoconstriction and inflammation. This study aimed to determine whether cilostazol (CLZ), a phosphodiesterase-3 inhibitor, prevents monocrotaline (MCT)- and chronic hypoxia (CH)-induced PH development in rats.
Fifty-one male Sprague-Dawley rats were fed rat chow with (0.3% CLZ) or without CLZ for 21 days after a single injection of MCT (60 mg/kg) or saline. Forty-eight rats were fed rat chow with and without CLZ for 14 days under ambient or hypobaric (air at 380 mmHg) CH exposure. The mean pulmonary artery pressure (mPAP), the right ventricle weight-to-left ventricle + septum weight ratio (RV/LV + S), percentages of muscularized peripheral pulmonary arteries (%Muscularization) and medial wall thickness of small muscular arteries (%MWT) were assessed. Levels of the endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), AKT, pAKT and IκB proteins in lung tissue were measured using Western blotting. Monocyte chemotactic protein (MCP)-1 mRNA in lung tissue was also assessed.
mPAP [35.1 ± 1.7 mmHg (MCT) (n = 9) vs. 16.6 ± 0.7 (control) (n = 9) (P < 0.05); 29.1 ± 1.5 mmHg (CH) (n = 10) vs. 17.5 ± 0.5 (control) (n = 10) (P < 0.05)], RV/LV + S [0.40 ± 0.01 (MCT) (n = 18) vs. 0.24 ± 0.01 (control) (n = 10) (P < 0.05); 0.41 ± 0.03 (CH) (n = 13) vs. 0.27 ± 0.06 (control) (n = 10) (P < 0.05)], and %Muscularization and %MWT were increased by MCT injection and CH exposure. CLZ significantly attenuated these changes in the MCT model [mPAP 25.1 ± 1.1 mmHg (n = 11) (P < 0.05), RV/LV + S 0.30 ± 0.01 (n = 14) (P < 0.05)]. In contrast, these CLZ effects were not observed in the CH model. Lung eNOS protein expression was unchanged in the MCT model and increased in the CH model. Lung protein expression of AKT, phosphorylated AKT, and IκB was downregulated by MCT, which was attenuated by CLZ; the CH model did not change these proteins. Lung MCP-1 mRNA levels were increased in MCT rats but not CH rats.
We found model differences in the effect of CLZ on PH development. CLZ might exert a preventive effect on PH development in an inflammatory PH model but not in a vascular structural change model of PH preceded by vasoconstriction. Thus, the preventive effect of CLZ on PH development might depend on the PH etiology.
预防肺血管重构是肺动脉高压（PH）的关键策略。PH 的病因包括肺血管收缩和炎症。本研究旨在确定磷酸二酯酶-3 抑制剂西洛他唑（CLZ）是否可预防野百合碱（MCT）和慢性低氧（CH）诱导的大鼠 PH 发展。
51 只雄性 Sprague-Dawley 大鼠在单次注射 MCT（60mg/kg）或生理盐水后，用含（0.3% CLZ）或不含 CLZ 的大鼠饲料喂养 21 天。48 只大鼠在常压低氧（空气 380mmHg）或常氧环境下用含或不含 CLZ 的大鼠饲料喂养 14 天。评估平均肺动脉压（mPAP）、右心室重量与左心室+室间隔重量比（RV/LV+S）、肌化外周肺动脉百分比（%Muscularization）和小动脉中层厚度（%MWT）。采用 Western blot 法检测肺组织内皮型一氧化氮合酶（eNOS）、磷酸化 eNOS（peNOS）、AKT、pAKT 和 IκB 蛋白水平。还评估了肺组织中单核细胞趋化蛋白-1（MCP-1）mRNA 的水平。
mPAP[35.1±1.7mmHg（MCT）（n=9）与 16.6±0.7mmHg（对照）（n=9）（P<0.05）；29.1±1.5mmHg（CH）（n=10）与 17.5±0.5mmHg（对照）（n=10）（P<0.05）]、RV/LV+S[0.40±0.01（MCT）（n=18）与 0.24±0.01（对照）（n=10）（P<0.05）；0.41±0.03（CH）（n=13）与 0.27±0.06（对照）（n=10）（P<0.05）]和%Muscularization 和%MWT 增加，MCT 注射和 CH 暴露。CLZ 可显著减弱 MCT 模型中的这些变化[mPAP 25.1±1.1mmHg（n=11）（P<0.05），RV/LV+S 0.30±0.01（n=14）（P<0.05）]。相反，在 CH 模型中未观察到 CLZ 的这些作用。MCT 模型中肺 eNOS 蛋白表达不变，CH 模型中肺 eNOS 蛋白表达增加。肺 AKT、磷酸化 AKT 和 IκB 蛋白表达被 MCT 下调，CLZ 可减轻这种下调；CH 模型未改变这些蛋白。MCT 大鼠肺 MCP-1mRNA 水平升高，但 CH 大鼠未升高。
我们发现 CLZ 对 PH 发展的影响存在模型差异。CLZ 可能对炎症性 PH 模型中的 PH 发展具有预防作用，但对先前存在血管收缩的 PH 血管结构变化模型无作用。因此，CLZ 对 PH 发展的预防作用可能取决于 PH 的病因。
