免疫检查点程序性死亡受体-1 介导腹主动脉瘤和假性动脉瘤的进展。
Immune checkpoint programmed death-1 mediates abdominal aortic aneurysm and pseudoaneurysm progression.
机构信息
Department of Vascular and Endovascular Surgery, First Affiliated Hospital of Zhengzhou University, 450052 Henan, China.
Emergency Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, 450052 Henan, China.
出版信息
Biomed Pharmacother. 2021 Oct;142:111955. doi: 10.1016/j.biopha.2021.111955. Epub 2021 Jul 30.
PURPOSE
The causes and pathogenetic mechanisms underlying abdominal aortic aneurysms (AAAs) and pseudoaneurysms are not fully understood. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease AAA and pseudoaneurysm formation in mouse and rat models.
METHODS
Human AAA samples were examined in conjunction with an adventitial calcium chloride (CaCl) application mouse model and an aortic patch angioplasty rat model. Single-dose PD-1 antibody (4 mg/kg) or BMS-1 (PD-1 inhibitor-1) (1 mg/kg) was administered by intraperitoneal (IP) or intraluminal injection. In the intramural injection group, PD-1 antibody was injected after CaCl incubation. The rats were divided into three groups: (1) the control group was only decellularized without other special treatment, (2) the PD-1 antibody-coated patch group, and (3) the BMS-1 coated patch group. Patches implanted in the rat abdominal aorta were harvested on day 14 after implantation and analyzed.
RESULTS
Immunohistochemical analysis showed PD-1-positive cells, PD-1 and CD3, PD-1 and CD68, and PD-1 and α-actin co-expressed in the human AAA samples. Intraperitoneal (IP) injection or intraluminal injection of PD-1antibody/BMS-1 significantly inhibited AAA progression. PD-1 antibody and BMS-1 were each successfully conjugated to decellularized rat thoracic artery patches, respectively, by hyaluronic acid. Patches coated with either humanized PD-1 antibody or BMS-1 can also inhibit pseudoaneurysm progression and inflammatory cell infiltration.
CONCLUSION
PD-1 pathway inhibition may be a promising therapeutic strategy for inhibiting AAA and pseudoaneurysm progression.
目的
腹主动脉瘤（AAA）和假性动脉瘤的病因和发病机制尚未完全阐明。我们假设抑制程序性死亡-1（PD-1）可以减少小鼠和大鼠模型中的 AAA 和假性动脉瘤形成。
方法
结合外膜氯化钙（CaCl）应用小鼠模型和主动脉补片血管成形术大鼠模型，检查人 AAA 样本。通过腹腔内（IP）或腔内注射给予单次剂量 PD-1 抗体（4mg/kg）或 BMS-1（PD-1 抑制剂-1）（1mg/kg）。在壁内注射组中，在 CaCl 孵育后注射 PD-1 抗体。大鼠分为三组：（1）对照组仅去细胞化而无其他特殊处理，（2）PD-1 抗体包被的补片组，和（3）BMS-1 包被的补片组。植入大鼠腹主动脉的补片在植入后第 14 天收获并进行分析。
结果
免疫组织化学分析显示人 AAA 样本中 PD-1 阳性细胞、PD-1 和 CD3、PD-1 和 CD68 以及 PD-1 和 α-肌动蛋白共表达。PD-1 抗体/ BMS-1 的腹腔内（IP）注射或腔内注射显著抑制 AAA 进展。PD-1 抗体和 BMS-1 分别通过透明质酸成功地连接到去细胞化的大鼠胸主动脉补片上。包被有人源化 PD-1 抗体或 BMS-1 的补片也可以抑制假性动脉瘤的进展和炎症细胞浸润。
结论
PD-1 通路抑制可能是抑制 AAA 和假性动脉瘤进展的一种有前途的治疗策略。
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