组织型纤溶酶原激活物在脓毒症相关疾病中的应用及其靶向给药的研究进展
Advances in the Application of Tissue-Type Plasminogen Activator in Sepsis-Related Diseases and Its Targeted Delivery
DOI: 10.12677/acm.2024.1441379, PDF,   
作者: 郭 飞, 单 亮*：青岛大学附属医院重症医学科，山东 青岛
关键词: 脓毒症；组织型纤溶酶原激活剂；靶向给药；Sepsis； Tissue-Type Plasminogen Activator； Targeted Delivery
摘要: 脓毒症是由于感染引起的机体反应失调，进而导致的严重的器官功能障碍，据估计每年可造成全球约500万人死亡。它是由宿主对感染的反应失调引起的，主要以炎症反应、免疫功能失调和凝血功能紊乱为特征。目前，炎症反应和凝血障碍被认为是促进脓毒症和脓毒症休克患者器官功能障碍的两个驱动因素，且研究显示，由于凝血功能的异常，脓毒症患者体内微循环中常常伴随着微血栓的形成，加重器官功能障碍的进展。组织型纤溶酶原激活剂是一种溶栓剂，目前被广泛应用于脑卒中和急性心梗的溶栓治疗，但其应用受到短半衰期、全身出血风险等副作用的限制，针对其副作用，不少学者考虑以靶向给药的方式降低其副作用的限制。本文将对组织型纤溶酶原激活剂在脓毒症相关疾病中的应用及其靶向给药策略进行探讨，为脓毒症治疗及靶向用药提供新思路。
Abstract: Sepsis is a serious organ dysfunction caused by a dysregulated host response to infection, estimated to result in approximately 5 million deaths worldwide annually. It is characterized by dysregulation of the host response to infection, often accompanied by inflammatory response, immune dysfunction and coagulation dysfunction. Currently, inflammation and coagulation are considered as two driving factors promoting organ dysfunction in sepsis and septic shock patients. Studies have shown that sepsis patients often have microthrombi formation in the microcirculation due to abnormalities in coagulation function. Tissue-type plasminogen activator (tPA) is widely used in thrombolytic therapy for acute stroke and acute myocardial infarction, but its application is limited by side effects such as short half-life and systemic bleeding risk. In response to its side effects, many researchers consider targeted drug delivery as a means to reduce its adverse effects. This paper will discuss the application of tissue-type plasminogen activator in sepsis-related diseases and its targeted drug delivery strategies, providing new ideas for sepsis treatment and targeted drug delivery.
文章引用：郭飞, 单亮. 组织型纤溶酶原激活物在脓毒症相关疾病中的应用及其靶向给药的研究进展[J]. 临床医学进展, 2024, 14(4): 2971-2977. https://doi.org/10.12677/acm.2024.1441379

参考文献

[1] Seymour, C.W., Liu, V.X., Iwashyna, T.J., et al. (2016) Assessment of Clinical Criteria for Sepsis. JAMA, 315, 762-774. [Google Scholar] [CrossRef] [PubMed]
[2] Van Der Poll, T., Schultz, M. and Levi, M. (2013) Sepsis and Thrombosis. Seminars in Thrombosis and Hemostasis, 39, 559-566. [Google Scholar] [CrossRef] [PubMed]
[3] Colucci, M., Semeraro, F., Ammollo, C., et al. (2015) Coagulopathy of Acute Sepsis. Seminars in Thrombosis and Hemostasis, 41, 650-658. [Google Scholar] [CrossRef] [PubMed]
[4] Giustozzi, M., Ehrlinder, H., Bongiovanni, D., et al. (2021) Coagulopathy and Sepsis: Pathophysiology, Clinical Manifestations and Treatment. Blood Reviews, 50, Article ID: 100864. [Google Scholar] [CrossRef] [PubMed]
[5] Ince, C. (2005) The Microcirculation Is the Motor of Sepsis. Critical Care, 9, S13-S19. [Google Scholar] [CrossRef] [PubMed]
[6] Walborn, A., Rondina, M., Mosier, M., et al. (2019) Endothelial Dysfunction Is Associated with Mortality and Severity of Coagulopathy in Patients with Sepsis and Disseminated Intravascular Coagulation. Clinical and Applied Thrombosis/Hemostasis, 25. [Google Scholar] [CrossRef] [PubMed]
[7] Iba, T. and Levy, J.H. (2018) Inflammation and Thrombosis: Roles of Neutrophils, Platelets and Endothelial Cells and Their Interactions in Thrombus Formation during Sepsis. Journal of Thrombosis and Haemostasis, 16, 231-241. [Google Scholar] [CrossRef] [PubMed]
[8] Evans, C.E., Spier, A.B. and Zhao, Y.Y. (2018) Sepsis-Induced Thrombus Formation and Cell-Specific HIFs. Thrombosis Research, 171, 187-189. [Google Scholar] [CrossRef] [PubMed]
[9] Iba, T., Levi, M. and Levy, J.H. (2020) Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation. Seminars in Thrombosis and Hemostasis, 46, 89-95. [Google Scholar] [CrossRef] [PubMed]
[10] Seillier, C., Hélie, P., Petit, G., et al. (2022) Roles of the Tissue-Type Plasminogen Activator in Immune Response. Cellular Immunology, 371, Article ID: 104451. [Google Scholar] [CrossRef] [PubMed]
[11] Novokhatny, V.V., Ingham, K.C. and Medved, L.V. (1991) Domain Structure and Domain-Domain Interactions of Recombinant Tissue Plasminogen Activator. Journal of Biological Chemistry, 266, 12994-13002. [Google Scholar] [CrossRef] 
[12] Mehra, A., Ali, C., Parcq, J., et al. (2016) The Plasminogen Activation System in Neuroinflammation. Biochimica et Biophysica Acta, 1862, 395-402. [Google Scholar] [CrossRef] [PubMed]
[13] Van Zonneveld, A.J., Veerman, H., Macdonald, M.E., et al. (1986) Structure and Function of Human Tissue-Type Plasminogen Activator (T-PA). Journal of Cellular Biochemistry, 32, 169-178. [Google Scholar] [CrossRef] [PubMed]
[14] Lin, L. and Hu, K. (2014) Tissue Plasminogen Activator and Inflammation: From Phenotype to Signaling Mechanisms. American Journal of Clinical and Experimental Immunology, 3, 30-36.
[15] Zhang, C., An, J., Strickland, D.K., et al. (2009) The Low-Density Lipoprotein Receptor-Related Protein 1 Mediates Tissue-Type Plasminogen Activator-Induced Microglial Activation in the Ischemic Brain. The American Journal of Pathology, 174, 586-594. [Google Scholar] [CrossRef] [PubMed]
[16] Uhl, B., Zuchtriegel, G., Puhr-Westerheide, D., et al. (2014) Tissue Plasminogen Activator Promotes Postischemic Neutrophil Recruitment via Its Proteolytic and Nonproteolytic Properties. Arteriosclerosis, Thrombosis, and Vascular Biology, 34, 1495-1504. [Google Scholar] [CrossRef] 
[17] Lin, L., Wu, C. and Hu, K. (2012) Tissue Plasminogen Activator Activates NF-κB through a Pathway Involving Annexin A2/CD11b and Integrin-Linked Kinase. Journal of the American Society of Nephrology, 23, 1329-1338. [Google Scholar] [CrossRef] 
[18] Xiao, X., Zhang, H., Chen, H., et al. (2020) HSF1 Alleviates Microthrombosis and Multiple Organ Dysfunction in Mice with Sepsis by Upregulating the Transcription of Tissue-Type Plasminogen Activator. Thrombosis and Haemostasis, 121, 1066-1078. [Google Scholar] [CrossRef] [PubMed]
[19] Renckens, R., Roelofs, J., Florquin, S., et al. (2006) Endogenous Tissue-Type Plasminogen Activator Is Protective during Escherichia Coli-Induced Abdominal Sepsis in Mice. The Journal of Immunology, 177, 1189-1196. [Google Scholar] [CrossRef] [PubMed]
[20] Renckens, R., Roelofs, J., Stegenga, M.E., et al. (2008) Transgenic Tissue‐Type Plasminogen Activator Expression Improves Host Defense during Klebsiella Pneumonia. Journal of Thrombosis and Haemostasis, 6, 660-668. [Google Scholar] [CrossRef] [PubMed]
[21] Akol, H., Boon, E., Van Haren, F., et al. (2002) Successful Treatment of Fulminant Pneumococcal Sepsis with Recombinant Tissue Plasminogen Activator. European Journal of Internal Medicine, 13, 389-391. [Google Scholar] [CrossRef] 
[22] Aiuto, L.T., Barone, S.R., Cohen, P.S., et al. (1997) Recombinant Tissue Plasminogen Activator Restores Perfusion in Meningococcal Purpura Fulminans. Critical Care Medicine, 25, 1079-1082. [Google Scholar] [CrossRef] [PubMed]
[23] Zenz, W., Muntean, W., Gallistl, S., et al. (1995) Recombinant Tissue Plasminogen Activator Treatment in Two Infants with Fulminant Meningococcemia. Pediatrics, 96, 144-148. [Google Scholar] [CrossRef] 
[24] Powers, W.J., Rabinstein, A.A., Ackerson, T., et al. (2019) Guidelines for the Early Management of Patients with Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke, 50, E344-E418. [Google Scholar] [CrossRef] 
[25] Colucci, M., Paramo, J.A. and Collen, D. (1986) Inhibition of One-Chain and Two-Chain Forms of Human Tissue-Type Plasminogen Activator by the Fast-Acting Inhibitor of Plasminogen Activator in Vitro and in Vivo. Journal of Laboratory and Clinical Medicine, 108, 53-59.
[26] Hacke, W., Kaste, M., Bluhmki, E., et al. (2008) Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. The New England Journal of Medicine, 359, 1317-1329. [Google Scholar] [CrossRef] 
[27] Zhang, S., Zhou, Y., Li, R., et al. (2022) Advanced Drug Delivery System against Ischemic Stroke. Journal of Controlled Release, 344, 173-201. [Google Scholar] [CrossRef] [PubMed]
[28] Correa-Paz, C., Navarro Poupard, M.F., Polo, E., et al. (2019) In Vivo Ultrasound-Activated Delivery of Recombinant Tissue Plasminogen Activator from the Cavity of Sub-Micrometric Capsules. Journal of Controlled Release, 308, 162-171. [Google Scholar] [CrossRef] [PubMed]
[29] Ma, Y.H., Wu, S.Y., Wu, T., et al. (2009) Magnetically Targeted Thrombolysis with Recombinant Tissue Plasminogen Activator Bound to Polyacrylic Acid-Coated Nanoparticles. Biomaterials, 30, 3343-3351. [Google Scholar] [CrossRef] [PubMed]
[30] Chen, J.P., Liu, C.H., Hsu, H.L., et al. (2016) Magnetically Controlled Release of Recombinant Tissue Plasminogen Activator from Chitosan Nanocomposites for Targeted Thrombolysis. Journal of Materials Chemistry B, 4, 2578-2590. [Google Scholar] [CrossRef] 
[31] Tadayon, A., Jamshidi, R. and Esmaeili, A. (2016) Targeted Thrombolysis of Tissue Plasminogen Activator and Streptokinase with Extracellular Biosynthesis Nanoparticles Using Optimized Streptococcus Equi Supernatant. International Journal of Pharmaceutics, 501, 300-310. [Google Scholar] [CrossRef] [PubMed]
[32] Hu, J., Huang, S., Zhu, L., et al. (2018) Tissue Plasminogen Activator-Porous Magnetic Microrods for Targeted Thrombolytic Therapy after Ischemic Stroke. ACS Applied Materials & Interfaces, 10, 32988-32997. [Google Scholar] [CrossRef] [PubMed]
[33] De Saint Victor, M., Barnsley, L.C., Carugo, D., et al. (2019) Sonothrombolysis with Magnetically Targeted Microbubbles. Ultrasound in Medicine and Biology, 45, 1151-1163. [Google Scholar] [CrossRef] [PubMed]
[34] Liu, C.H., Hsu, H.L., Chen, J.P., et al. (2019) Thrombolysis Induced by Intravenous Administration of Plasminogen Activator in Magnetoliposomes: Dual Targeting by Magnetic and Thermal Manipulation. Nanomedicine, 20, Article ID: 101992. [Google Scholar] [CrossRef] [PubMed]
[35] Zhang, B., Kim, H., Wu, H., et al. (2019) Sonothrombolysis with Magnetic Microbubbles under a Rotational Magnetic Field. Ultrasonics, 98, 62-71. [Google Scholar] [CrossRef] [PubMed]
[36] Yang, H.W., Hua, M.Y., Lin, K.J., et al. (2012) Bioconjugation of Recombinant Tissue Plasminogen Activator to Magnetic Nanocarriers for Targeted Thrombolysis. International Journal of Nanomedicine, 7, 5159-5173. [Google Scholar] [CrossRef] 
[37] Huang, L., Wang, J., Huang, S., et al. (2019) Polyacrylic Acid-Coated Nanoparticles Loaded with Recombinant Tissue Plasminogen Activator for the Treatment of Mice with Ischemic Stroke. Biochemical and Biophysical Research Communications, 516, 565-570. [Google Scholar] [CrossRef] [PubMed]
[38] Ma, H., Jiang, Z., Xu, J., et al. (2021) Targeted Nano-Delivery Strategies for Facilitating Thrombolysis Treatment in Ischemic Stroke. Drug Delivery, 28, 357-371. [Google Scholar] [CrossRef] [PubMed]

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