Nanomedicine: Nanotechnology, Biology and Medicine ( IF 5.4 ) Pub Date : 2021-07-23 , DOI: 10.1016/j.nano.2021.102449 Ian Vargas 1 , Daniel J Stephenson 2 , Margaret Baldwin 3 , Joseph P Gaut 4 , Charles E Chalfant 5 , Hua Pan 1 , Samuel A Wickline 1
Acute kidney injury (AKI) management remains mainly supportive as no specific therapeutic agents directed at singular signaling pathways have succeeded in clinical trials. Here, we report that inhibition of thrombin-driven clotting and inflammatory signaling with use of locally-acting thrombin-targeted perfluorocarbon nanoparticles (PFC NP) protects renal vasculature and broadly modulates diverse inflammatory processes that cause renal ischemia reperfusion injury. Each PFC NP was complexed with ~13,650 copies of the direct thrombin inhibitor, PPACK (proline-phenylalanine-arginine-chloromethyl-ketone). Mice treated after the onset of AKI with PPACK PFC NP exhibited downregulated VCAM-1, ICAM-1, PGD2 prostanoid, M-CSF, IL-6, and mast cell infiltrates. Microvascular architecture, tubular basement membranes, and brush border components were better preserved. Non-reperfusion was reduced as indicated by reduced red blood cell trapping and non-heme iron. Kidney function and tubular necrosis improved at 24 hours versus the untreated control group, suggesting a benefit for dual inhibition of thrombosis and inflammation by PPACK PFC NP.
中文翻译:
凝血酶的持续局部抑制可在急性肾损伤发作后保留肾脏微结构和功能
急性肾损伤 (AKI) 管理仍然主要是支持性的,因为没有针对单一信号通路的特定治疗药物在临床试验中取得成功。在这里,我们报告了使用局部作用的凝血酶靶向全氟化碳纳米颗粒 (PFC NP) 抑制凝血酶驱动的凝血和炎症信号传导可保护肾血管系统并广泛调节导致肾缺血再灌注损伤的各种炎症过程。每个 PFC NP 都与约 13,650 份直接凝血酶抑制剂 PPACK(脯氨酸-苯丙氨酸-精氨酸-氯甲基-酮)复合。AKI 发作后用 PPACK PFC NP 治疗的小鼠表现出下调的 VCAM-1、ICAM-1、PGD2 前列腺素、M-CSF、IL-6 和肥大细胞浸润。微血管结构、管状基底膜、并且画笔边框组件得到了更好的保存。如减少的红细胞捕获和非血红素铁所示,非再灌注减少。与未治疗的对照组相比,肾功能和肾小管坏死在 24 小时时有所改善,这表明 PPACK PFC NP 对血栓形成和炎症的双重抑制有益。