SR1001抑制白细胞介素-17相关炎性反应减缓小鼠腹主动脉瘤进展的研究

SR1001 confers protection against the experimental abdominal aortic aneurysm induced by angiotensin Ⅱ in ApoE^-/- mice

目的探讨SR1001药物干预对血管紧张素Ⅱ（AngⅡ）诱导的载脂蛋白E（ApoE^-/-）小鼠实验性腹主动脉瘤模型的作用及其机制。方法45只雄性ApoE^-/-小鼠随机分为对照组（Sham组）、AngⅡ模型组（Control组）和AngⅡ＋SR1001治疗组（SR1001组）。所有小鼠从术前1～28d均接受0.5％二甲基亚砜（DMSO）或SR1001溶液腹腔注射治疗，各组小鼠分别于术后第0、14、28天对小鼠进行腹主动脉直径超声测量，评估腹主动脉瘤形成情况。术后第28天收取小鼠腹主动脉，进行弹性纤维染色（EVG）、免疫荧光染色[anti-CD4、白细胞介素-17（IL-17）]等组织学分析、Western blot蛋白检测相关炎性因子如IL-17、单核细胞趋化蛋白-1（MCP-1）、γ-干扰素（IFN-1）的表达。结果（1）与Control组比较，SR1001组的腹主动脉瘤的形成率显著降低（33.3％比73.3％，X^2=4.821，P=0.028）及腹主动脉直径显著减小[（1.39±0.06）mm比（1.98±0.11）mm，P=0.009]。与Sham组比较，SR1001组腹主动脉直径差异并无统计学意义[（1.39±0.06）mm比（1.07±0.08）mm，P=0.064]。（2）通过EVG染色组织学分析，与Control组比较，SR1001组通过SR1001药物干预明显地保护了血管壁结构（P=0.018）。（3）与Control组比较，SR1001组中腹主动脉组织中CD4^＋／IL-17^＋细胞（Th17细胞）的浸润明显地减少。（4）与Control组比较，SR100组炎性因子IL-17、MCP-1、IFN-1的蛋白表达得到明显抑制（分NP=0.008、0.016、0.023）。结论SR1001干预由AngⅡ诱导的ApoE^-/-小鼠实验性腹主动脉瘤模型可以有效抑制炎性因子的表达及炎性细胞浸润，有效地保护血管组织，减缓实验性腹主动脉瘤的发展。

Objective To investigate the effect and mechanism of SR1001 treatment in angiotensin ]I （Ang Ⅱ） induced experimental abdominal aortic aneurysm （EAAA） in apolipoprotein E （ApoE^-/-） mice. Methods Forty-five male apolipoprotein E-deficient （ApoE^-/-） mice were randomly divided into the following 3 groups： Sham group, AngⅡ model group （Control group）, AngⅡ ＋ SR1001 treatment group （SR1001 group）. All mice were treatment with 0. 5% dimethylsurfoxide （DMSO） or SR1001 by intraperitoneal injection. The aortic diameter was measured via ultrasound imaging, and the suprarenal aorta was chosen as the measuring point on days 0, 14, 28 thereafter. Twenty-eight days after Ang Ⅱ infusion, the abdominal aortic specimens were harvested. The elastica van Gieson （EVG） staining, and immunofluorescent staining were performed for histopathologic analysis. The protein levels of interleukin （IL）-17, monocyte chemotactic protein （MCP）-1, interferon （IFN）-γ were determined by Western blotting analysis. Results （ 1 ） Compared with the Control group, the AAA incidence in the SR1001 group was significantly reduced （33.3% vs. 73.3%, X^2 =4. 821, P=0. 028）, Abdominal aorta diameter （ 1.39±0. 06） mm vs. （ 1.98±0. 11 ） mm, P = 0. 009 ]. However, there was no significant difference in abdominal aorta diameter between the SR1001 group and Sham group [ （1.39±0. 06） mm vs. （1.07±0. 08） mm, P =0. 064]. （2） SR1001 treatment in SR1001 group preserves the structure of the aortic wall （P=0. 018）. （3） SR1001 treatment in SR1001 group attenuates local inflammatory cell infiltration in the EAAA model. （4） SR1001 treatment in SR1001 group suppresses the protein expression of pro-inflammatory mediators （IL-17, MCP-1, IFN-γ） in the EAAA model （P=0. 008, 0. 016, 0. 023, respectively）. Conclusion Treatment with SR1001 inhibits the Th17/IL-17A- related inflammatory responses, preserves the structure of the aortic wall, reduces local inflammatory cell infiltration and inflammatory factors expression, and attenuates the progression of abdominal aortic aneurysm.