Transplant Immunology Laboratory, Hanson Institute, Adelaide, SA, Australia.
Br J Pharmacol. 2012 May;166(1):194-209. doi: 10.1111/j.1476-5381.2011.01590.x.
Renal ischaemia-reperfusion (IR) injury is an inevitable consequence of renal transplantation, causing significant graft injury, increasing the risk of rejection and contributing to poor long-term graft outcome. Renal injury is mediated by cytokine and chemokine synthesis, inflammation and oxidative stress resulting from activation of the NF-κB pathway.
We utilized liposomal incorporation of a potent inhibitor of the NF-κB pathway, curcumin, to target delivery to renal tubular epithelial and antigen-presenting cells. Liposomes containing curcumin were administered before bilateral renal ischaemia in C57/B6 mice, with subsequent reperfusion. Renal function was assessed from plasma levels of urea and creatinine, 4 and 24 h after reperfusion. Renal tissue was examined for NF-κB activity and oxidative stress (histology, immunostaining) and for apoptosis (TUNEL). Cytokines and chemokines were measured by RT-PCR and Western blotting.
Liposomal curcumin significantly improved serum creatinine, reduced histological injury and cellular apoptosis and lowered Toll-like receptor-4, heat shock protein-70 and TNF-α mRNA expression. Liposomal curcumin also reduced neutrophil infiltration and diminished inflammatory chemokine expression. Curcumin liposomes reduced intracellular superoxide generation and increased superoxide dismutase levels, decreased inducible NOS mRNA expression and 3-nitrotyrosine staining consistent with limitations in nitrosative stress and inhibited renal tubular mRNA and protein expression of thioredoxin-interacting protein. These actions of curcumin were mediated by inhibition of NF-κB, MAPK and phospho-S6 ribosomal protein.
Liposomal delivery of curcumin promoted effective, targeted delivery of this non-toxic compound that provided cytoprotection via anti-inflammatory and multiple antioxidant mechanisms following renal IR injury.
肾缺血再灌注(IR)损伤是肾移植不可避免的后果,导致严重的移植物损伤,增加排斥反应的风险,并导致移植物预后不良。肾损伤是由细胞因子和趋化因子的合成、炎症和氧化应激介导的,这些都是 NF-κB 通路激活的结果。
我们利用 NF-κB 通路的一种强效抑制剂姜黄素的脂质体包封,将其靶向递送至肾小管上皮细胞和抗原呈递细胞。在 C57/B6 小鼠双侧肾缺血前给予含有姜黄素的脂质体,然后再进行再灌注。再灌注后 4 和 24 小时,通过血浆尿素和肌酐水平评估肾功能。用组织学、免疫染色和 TUNEL 检测评估肾组织 NF-κB 活性和氧化应激以及细胞凋亡。通过 RT-PCR 和 Western blot 检测细胞因子和趋化因子。
脂质体姜黄素显著改善了血清肌酐,减轻了组织学损伤和细胞凋亡,降低了 Toll 样受体-4、热休克蛋白-70 和 TNF-α 的 mRNA 表达。脂质体姜黄素还减少了中性粒细胞浸润和炎症趋化因子的表达。姜黄素脂质体减少了细胞内超氧阴离子的产生,增加了超氧化物歧化酶的水平,降低了诱导型一氧化氮合酶的 mRNA 表达和 3-硝基酪氨酸染色,这与减少硝化应激和抑制肾小管硫氧还蛋白相互作用蛋白的 mRNA 和蛋白表达一致。姜黄素的这些作用是通过抑制 NF-κB、MAPK 和磷酸化 S6 核糖体蛋白来介导的。
姜黄素的脂质体递送促进了这种无毒化合物的有效、靶向递送,在肾 IR 损伤后通过抗炎和多种抗氧化机制提供了细胞保护作用。