乌司他丁防治术后认知功能障碍机制的研究进展
Research Progress of Ulinastatin in Preventing and Treating Postoperative Cognitive Dysfunction
摘要: 乌司他丁是人体内的生理性抑炎物质，相对分子量约67 kD，是一种典型的Kunitz型蛋白酶抑制剂，此外其在体内的代谢产物也具有较强的酶抑作用。其临床药理学作用可能包括：稳定细胞溶酶体膜结构、抑制体内多种促炎介质的释放、对抗体内产生的过多氧自由基、改善局部循环与灌注等。近年来，临床研究发现乌司他丁应用于临床具有很好脑保护作用。因此，本文就近年来使用乌司他丁预防患者术后认知功能障碍的机制做一综述，为POCD的防治提供科学理论指导。
Abstract: Ulinastatin is a physiological anti-inflammatory substance in the human body with a relative molecular weight of about 67 kD. It is a typical Kunitz protease inhibitor. In addition, its metabolites in the body also have a strong enzyme inhibitory effect. Its clinical pharmacological effects may include: stabilizing cell lysosomal membrane structure, inhibiting the release of various pro-inflammatory mediators in the body, fighting against excessive oxygen free radicals produced in the body, improving local circulation and perfusion, etc. In recent years, clinical studies have found that Ulinastatin has a good brain protection effect in clinical applications. Therefore, this article reviews the mechanism of using Ulinastatin to prevent postoperative cognitive dysfunction in patients in recent years, and provides scientific theoretical guidance for the prevention and treatment of POCD.
文章引用：陈学英, 解健, 余喜亚. 乌司他丁防治术后认知功能障碍机制的研究进展[J]. 临床医学进展, 2021, 11(8): 3758-3764. https://doi.org/10.12677/ACM.2021.118552

参考文献

[1] Hou, R., Wang, H., Chen, L., Qiu, Y. and Li, S. (2018) POCD in Patients Receiving Total Knee Replacement under Deep vs. Light Anesthesia: A Randomized Controlled Trial. Brain and Behavior, 8, Article No. e910. [Google Scholar] [CrossRef] [PubMed]
[2] 凌成亮. 乌司他丁临床研究进展[J]. 现代临床医学, 2013, 39(4): 243-244+248.
[3] 廖培军, 李忠勇, 金仙珍. 血必净联用乌司他丁治疗重症脓毒症有效性的系统评价[J]. 中国实验方剂学杂志, 2014, 20(22): 232-237.
[4] Jiang, X.M., Hu, J.H., Wang, L.L., Ma, C., Wang, X. and Liu, X.-L. (2018) Ulinastatin Alleviates Neurological Deficiencies Evoked by Transient Cerebral Ischemia via Improving Autophagy, Nrf-2-ARE and Apoptosis Signals in Hippocampus. Physiological Research, 67, 637-646. [Google Scholar] [CrossRef] [PubMed]
[5] Kahraman, A., Barreyro, F.J., Bronk, S.F, Werneburg, N.W., Mott, J.L., Akazawa, Y., et al. (2008) TRAIL Mediates Liver Injury by the Innate Immune System in the Bile Duct-Ligated Mouse. Hepatology, 47, 1317-1330. [Google Scholar] [CrossRef] [PubMed]
[6] Benchoua, A., Braudeau, J., Reis, A., Couriaud, C. and Onténiente, B. (2004) Activation of Proinflammatory Caspases by Cathepsin B in Focal Cerebral Ischemia. Journal of Cerebral Blood Flow & Metabolism, 24, 1272-1279. [Google Scholar] [CrossRef] 
[7] 曹宝萍, 张磊, 苏宁, 王凯, 边寰, 费舟, 等. 乌司他丁对创伤性脑损伤的保护作用研究[J]. 中华神经外科疾病研究杂志, 2013, 12(3): 244-246.
[8] 戴春美, 汪丽娟, 王铁均, 郦文泽, 任希. 乌司他丁对重型颅脑损伤患者C-反应蛋白的影响[J]. 海峡药学, 2013, 25(6): 114-115.
[9] 万秋清, 袁爱群, 柯江维. 乌司他丁治疗儿童重型颅脑损伤的疗效及其作用机制[J]. 南昌大学学报(医学版), 2013, 53(3): 51-54.
[10] Lin, G.X., Wang, T., Chen, M.H., Hu, Z.-H. and Ouyang, W. (2014) Serum High-Mobility Group Box 1 Protein Correlates with Cognitive Decline after Gastrointestinal Surgery. Acta Anaesthesiologica Scandinavica, 58, 668-674. [Google Scholar] [CrossRef] [PubMed]
[11] Cibelli, M., Fidalgo, A.R., Terrando, N., Ma, D., Monaco, C., Feldmann, M., et al. (2010) Role of Interleukin-1β in Postoperative Cognitive Dysfunction. Annals of Neurology, 68, 360-368. [Google Scholar] [CrossRef] [PubMed]
[12] Yang, N., Liang, Y., Yang P., Wang, W., Zhang, X. and (2016) TNF-α Receptor Antagonist Attenuates Isoflurane-Induced Cognitive Impairment in Aged Rats. Experimental and Therapeutic Medicine, 12, 463-468. [Google Scholar] [CrossRef] [PubMed]
[13] Dilger, R.N. and Johnson, R.W. (2008) Aging, Microglial Cell Priming, and the Discordant Central Inflammatory Response to Signals from the Peripheral Immune System. Journal of Leukocyte Biology, 84, 932-939. [Google Scholar] [CrossRef] [PubMed]
[14] Norden, D.M. and Godbout, J.P. (2013) Review: Microglia of the Aged Brain: Primed to Be Activated and Resistant to Regulation. Neuropathology and Applied Neurobiology, 39, 19-34. [Google Scholar] [CrossRef] [PubMed]
[15] Geng, Y.J., Wu, Q.H. and Zhang, R.Q. (2017) Effect of Propofol, Sevoflurane, and Isoflurane on Postoperative Cognitive Dysfunction Following Laparoscopic Cholecystectomy in Elderly Patients: A Randomized Controlled Trial. Journal of Clinical Anesthesia, 38, 165-171. [Google Scholar] [CrossRef] [PubMed]
[16] Ding, Y., Shi, C., Chen, L., Ma, P., Li, K., Jin, J., et al. (2017) Effects of Andrographolide on Postoperative Cognitive Dysfunction and the Association with NF-κB/MAPK Pathway. Oncology Letters, 14, 7367-7373. [Google Scholar] [CrossRef] [PubMed]
[17] Terrando, N., Eriksson, L.I., Ryu, J.K., Yang, T., Monaco, C., Feldmann, M., et al. (2011) Resolving Postoperative Neuroinflammation and Cognitive Decline. Annals of Neurology, 70, 986-995. [Google Scholar] [CrossRef] [PubMed]
[18] Varvel, N.H., Neher, J.J., Bosch, A., Wang, W., Ransohoff, R.M., Miller, R.J., et al. (2016) Infiltrating Monocytes Promote Brain Inflammation and Exacerbate neuronal Damage after Status Epilepticus. Proceedings of the National Academy of Sciences of the United States of America, 113, E5665-E5674. [Google Scholar] [CrossRef] [PubMed]
[19] Laye, S., Bluthe, R.M., Kent, S., Combe, C., Medina, C., Parnet, P., et al. (1995) Subdiaphragmatic Vagotomy Blocks Induction of IL-1 Beta mRNA in Mice Brain in Response to Peripheral LPS. American Journal of Physiology, 268, R1327-R1331. [Google Scholar] [CrossRef] 
[20] Siddiqui, N.T., Fischer, H., Guerina, L. and Friedman, Z. (2014) Effect of a Preoperative Gabapentin on Postoperative Analgesia in Patients with Inflammatory Bowel Disease Following Major Bowel Surgery: A Randomized, Placebo-Controlled Trial. Pain Practice, 14, 132-139. [Google Scholar] [CrossRef] [PubMed]
[21] Chen, X., Wang, Y., Luo, H., Luo, Z., Liu, L., Xu, W., et al. (2013) Ulinastatin Reduces Urinary Sepsisrelated Inflammation by Upregulating IL10 and Downregulating TNFα Levels. Molecular Medicine Reports, 8, 29-34. [Google Scholar] [CrossRef] [PubMed]
[22] Wang, K.Y., Yang, Q.Y., Tang, P., Li, H.-X., Zhao, H.-W. and Ren, X.-B. (2017) Effects of Ulinastatin on Early Postoperative Cognitive Function after One-Lung Ventilation Surgery in Elderly Patients Receiving Neoadjuvant Chemotherapy. Metabolic Brain Disease, 32, 427-435. [Google Scholar] [CrossRef] [PubMed]
[23] 林柏松, 张秀和, 张柏民, 姜亦忠, 李哲. 乌司他丁对首次单纯二尖瓣机械瓣置换患者术后早期认知功能的影响[J]. 中风与神经疾病杂志, 2009, 26(6): 693-696.
[24] Rhee, K.Y., Sung, T.Y., Kim, J.D., Kang, H., Mohamad, N. and Kim, T.-Y. (2018) High-Dose Ulinastatin Improves Postoperative Oxygenation in Patients Undergoing Aortic Valve Surgery with Cardiopulmonary Bypass: A Retrospective Study. Journal of International Medical Research, 46, 1238-1248. [Google Scholar] [CrossRef] 
[25] Hu, X., Zhang, M., Leak, R.K., Gan, Y., Li, P., Gao, Y., et al. (2012) Delivery of Neurotherapeutics across the Blood Brain Barrier in Stroke. Current Pharmaceutical Design, 18, 3704-3720. [Google Scholar] [CrossRef] [PubMed]
[26] Bruno, M.A., Mufson, E.J., Wuu, J. and Claudio Cuello, A. (2009) Increased Matrix Metalloproteinase 9 Activity in Mild Cognitive Impairment. Journal of Neuropathology & Experimental Neurology, 68, 1309-1318. [Google Scholar] [CrossRef] 
[27] Li, X.F., Zhang, X.J., Zhang, C., Wang, L.-N., Li, Y.-R., Zhang, Y., et al. (2018) Ulinastatin Protects Brain Against Cerebral Ischemia/Reperfusion Injury through Inhibiting MMP-9 and Alleviating Loss of ZO-1 and Occludin Proteins in Mice. Experimental Neurology, 302, 68-74. [Google Scholar] [CrossRef] [PubMed]
[28] Hu, H.X., Xu, D.H., Ju, W.N., Ma, C., Wang, X. and Liu, X.L. (2018) Neuroprotection of Ulinastatin on Transient Cerebral Ischemia via Antioxidative Mechanisms. Journal of Biological Regulators and Homeostatic Agents, 32, 283-288.
[29] Hu, H.X., Zhu, M.Q., Sun, Y.C., Ma, C., Wang, X., Liu, X.L. (2018) Xuebijing Enhances Neuroprotective Effects of Ulinastatin on Transient Cerebral Ischemia via Nrf2-Are Signal Pathways in the Hippocampus. Journal of Biological Regulators and Homeostatic Agents, 32, 1143-1149.
[30] Xu, L., Hu, Z. and Shen, J. (2013) A Preliminary Study of the Effects of Ulinastatin on Early Postoperative Cognition Function in Patients Undergoing Abdominal Surgery. Neuroscience Letters, 541, 15-19. [Google Scholar] [CrossRef] [PubMed]
[31] Wu, J., Yan, X. and Jin, G. (2018) Ulinastatin Protects Rats from Sepsis-Induced Acute Lung Injury by Suppressing the JAK-STAT3 Pathway. Journal of Cellular Biochemistry, 120, 2554-2559. [Google Scholar] [CrossRef] [PubMed]
[32] Fang, M., Zhong, W.H., Song, W.L., Deng, Y.-Y., Yang, D.-M., Xiong, B., et al. (2018) Ulinastatin Ameliorates Pulmonary Capillary Endothelial Permeability Induced by Sepsis through Protection of Tight Junctions via Inhibition of TNF-Alpha and Related Pathways. Frontiers in Pharmacology, 9, Article No. 823. [Google Scholar] [CrossRef] [PubMed]
[33] Xu, C.E., Zou, C.W., Zhang, M.Y. and Guo, L. (2013) Effects of High-Dose Ulinastatin on Inflammatory Response and Pulmonary Function in Patients with Type-A Aortic Dissection after Cardiopulmonary Bypass under Deep Hypothermic Circulatory Arrest. Journal of Cardiothoracic and Vascular Anesthesia, 27, 479-484. [Google Scholar] [CrossRef] [PubMed]
[34] Kohman, R.A., Tarr, A.J., Byler, S.L. and Boehm, G.W. (2007) Age Increases Vulnerability to Bacterial Endotoxin-Induced Behavioral Decrements. Physiology & Behavior, 91, 561-565. [Google Scholar] [CrossRef] [PubMed]
[35] Rhee, S.H. (2014) Lipopolysaccharide: Basic Biochemistry, Intracellular Signaling, and Physiological Impacts in the Gut. Intestinal Research, 12, 90-95. [Google Scholar] [CrossRef] [PubMed]
[36] Brun, P., Castagliuolo, I., Di Leo, V., Buda, A., Pinzani, M., Palù, G., et al. (2007) Increased Intestinal Permeability in Obese Mice: New Evidence in the Pathogenesis of Nonalcoholic Steatohepatitis. American Journal of Physiology-Gastrointestinal and Liver Physiology, 292, G518-G525. [Google Scholar] [CrossRef] [PubMed]
[37] Zhang, M., Zhang, Y.H., Fu, H.Q., Zhang, Q.-M. and Wang, T.-L. (2018) Ulinastatin May Significantly Improve Postoperative Cognitive Function of Elderly Patients Undergoing Spinal Surgery by Reducing the Translocation of Lipopolysaccharide and Systemic Inflammation. Frontiers in Pharmacology, 9, Article No. 1007. [Google Scholar] [CrossRef] [PubMed]

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