吡非尼酮改善载脂蛋白E缺失小鼠晚期动脉粥样硬化

目的初步评估小分子药物吡非尼酮对晚期动脉粥样硬化的治疗作用。方法以普通饲料诱导载脂蛋白E缺失小鼠动脉粥样硬化病变,自40周龄开始给予吡非尼酮治疗,同时设厄贝沙坦给药组作为对照。给药18周后处死,检测血脂水平;取头臂干血管石蜡包埋,连续切片,分别行HE染色和Movat染色分析血管病变和斑块成分,统计分析平均斑块面积,最大管腔狭窄程度,斑块内坏死核心比重,中膜厚度,钙化发生率和斑块内平均钙化面积。此外使用天狼星红染色统计斑块内胶原含量,免疫组化染色半定量观察斑块内平滑肌细胞和巨噬细胞阳性面积。结果经过18周给药治疗,各组小鼠的血脂水平没有明显差异。吡非尼酮能够发挥与厄贝沙坦相似的治疗作用,显著减小头臂干血管斑块面积,改善管腔狭窄程度,降低斑块内坏死核心比重,增加最小中膜厚度,增加斑块内胶原含量,增加α-SMA＋平滑肌细胞表达,抑制巨噬细胞募集等,发挥减小和稳定晚期动脉粥样硬化斑块的作用。但是在斑块钙化发生率和平均钙化面积方面,吡非尼酮没有显著的改善作用。结论小分子药物吡非尼酮对载脂蛋白E缺失小鼠晚期动脉粥样硬化病变具有一定的治疗作用,虽然不能改善斑块钙化,但在减小和稳定斑块方面仍具有进一步开发和研究的潜力。

Pirfenidone improves advanced atherosclerosis in apolipoprotein E deficient mice

ObjectiveTo determine whether small compound pirfenidone has protective effect in advanced atherosclerosis in apolipoprotein E deficient mice.MethodsForty-week-old apolipoprotein E deficient mice with established atherosclerotic lesions were treated with or without pirfenidone（500 mg·kg^-1·d^-1） mixed in chow for eighteen weeks; and the mice of another group were treated with irbesartan（50 mg·kg^-1·d^-1） an antagonist of angiotensin Ⅱ type Ⅰ receptor as positive control.The aortas were collected and plasma lipids were analyzed.Brachiocephalic arteries from each mouse were embedded in paraffin and serially sectioned.Using HE and Movat staining,the morphology and composition of atherosclerotic plaques in brachiocephalic arteries were examined.The total collagen content in the plaques was detected with Sirius red-staining,and immunohistochemical stainings were used to determine the expression of smooth muscle cells and macrophages.ResultsAs compared with the untreated group,administration of pirfenidone or irbesartan significantly reduced lesion size and the percentage of stenosis of brachiocephalic arteries without lipid-lowering effects.In addition,pirfenidone or irbesartan stabilized the plaque as indicated by a reduction in the necrotic core size and the accumulation of macrophages,and by an increase in media thickness,collagen contents,and the expression of α-smooth muscle actins.rlowerer,unlike irbesartan,pirfenidone showed no significant effect on plaque calcification.ConclusionPirfenidone could reduce lesion size and promote plaque stability in apolipoprotein E deficient mice even when the lesions are established.Although its mechanism of action requires further study,pirfenidone offers the possibility of new pharmacological interventions in atherosclerosis.