Protective effects and mechanisms of bilirubin nanomedicine against acute pancreatitis
Protective effects and mechanisms of bilirubin nanomedicine against acute pancreatitis
复制标题
胆红素纳米药物对急性胰腺炎的保护作用及机制
DOI：
10.1016/j.jconrel.2020.03.034
复制
发表时间：
2020
影响因子：
10.8
通讯作者：
Zhao Ying-Zheng
中科院分区：
文献类型：
--
作者：
Yao Qing;Jiang Xue;Zhai Yuan-Yuan;Luo Lan-Zi;Xu He-Lin;Xiao Jian;Kou Longfa;Zhao Ying-Zheng
急性胰腺炎（acute pancreatic，AP）是一种突发性炎症反应，由胰腺中的胰酶激活引起，严重时可导致全身炎症和多器官功能衰竭。氧化应激促进炎症的进一步恶化，并在AP的发展中发挥重要作用。胆红素在一系列伴有高水平氧化应激的疾病中具有抗氧化、抗炎和抗凋亡作用。然而，胆红素对AP管理的治疗效果尚未得到证实。此外，胆红素的溶解性差和潜在的毒性也限制了其应用。因此，我们开发了胆红素包裹的丝纤维蛋白纳米颗粒（BRSNPs），以研究胆红素纳米药物治疗AP的保护作用和机制。BRSNPs可以选择性地传递到胰腺的炎症病变，并以酶反应的方式释放胆红素。在由L-精氨酸过度刺激引起的AP模型中，BRSNPs通过减少氧化应激、降低促炎细胞因子的表达以及损害巨噬细胞和中性粒细胞的募集来对AP发挥强的治疗作用。BRSNPs可能通过抑制NF-κB通路和激活Nrf 2/HO-1通路来保护腺泡细胞免受广泛的氧化损伤和炎症反应。总之，本研究首次证明胆红素纳米药物（BRSNPs）对实验性急性胰腺炎具有有效的缓解作用，其机制与抑制NF-κB调节的促炎信号传导和激活Nrf 2调节的细胞保护蛋白表达有关。
Acute pancreatitis (AP) is a sudden inflammatory reaction, caused by the activation of pancreatic enzymes in the pancreas, and in severe cases can lead to systemic inflammation and multiple organ failure. Oxidative stress contributed to the further deterioration of inflammation and played an important role in AP development. Bilirubin has been found to exert antioxidative, anti-inflammatory, and anti-apoptotic effects in a series of diseases accompanied by a high level of oxidative stress. However, the therapeutic effects of bilirubin for AP management have not yet been demonstrated. Additionally, the poor solubility and potential toxicity of bilirubin also limit its application. Thus, we developed bilirubin encapsulated silk fibrin nanoparticles (BRSNPs) to study the protective effects and mechanisms of bilirubin nanomedicine for the treatment of AP. BRSNPs could selectively delivery to the inflammatory lesion of the pancreas and release bilirubin in an enzyme-responsive manner. In the model of AP caused by L-Arginine hyperstimulation, BRSNPs exerted strong therapeutic effects against AP by the reduction of oxidative stress, decreased expression of pro-inflammatory cytokines, and impaired recruitment of macrophages and neutrophils. The mechanism study indicated that BRSNPs protected acinar cells against extensive oxidative damage and inflammation through inhibiting NF-κB pathway and activating the Nrf2/HO-1 pathway. Collectively, for the first time, this study demonstrated that bilirubin nanomedicine, BRSNPs, are effective in alleviating experimental acute pancreatitis, and the mechanisms are associated with its inhibition of NF-κB regulated pro-inflammatory signaling and activation of Nrf2-regulated cytoprotective protein expression.