脓毒症诊治中Ang/Tie信号通路的研究进展
收稿日期: 2023-05-01
网络出版日期: 2024-05-30
基金资助
国家自然科学基金面上项目(81970127);国家自然科学基金面上项目(82270128)
Advances in the study on Ang/Tie signaling pathway in diagnosis and treatment of sepsis
Received date: 2023-05-01
Online published: 2024-05-30
脓毒症以及伴随的多器官功能障碍是一组常见的临床综合征,其患病率随着人口老龄化逐年上升。全球每年发生2 000万例脓毒症,死亡率为26%。早期准确诊断脓毒症,有利于及时采取针对性的治疗策略,这是降低病死率的关键。内皮细胞是外源病原体或内源性损伤信号的早期作用对象。研究提示,内皮细胞的结构改变与功能活化在脓毒症的发生、发展中发挥重要作用。作为内皮细胞专属信号通路,血管生成素(angiopoietin, Ang)/酪氨酸激酶受体(tyrosine kinase receptor, Tie)在内皮细胞的异常激活和损伤中发挥重要作用。Ang/Tie信号通路主要包括2种位于内皮细胞中的酪氨酸激酶受体(Tie1、Tie2)和4种分泌性糖蛋白配体(Ang-1、Ang-2、Ang-3、Ang-4)。机制研究方面,Ang-1可持续性激活Tie2受体,维持细胞与细胞、细胞与基质间的相互作用,支持血管内皮细胞正常的生理功能;Ang-2是Ang-1拮抗剂,可竞争性阻断Ang-1与Tie2受体结合。脓毒症环境下,Ang-1下降,Ang-2升高,Ang-1/Ang-2的比值下降。Ang-2竞争性阻断Ang-1与可溶性Tie2受体结合,内皮细胞处于严重异常激活状态。Ang-2介导肝素酶的释放导致糖萼损伤,可引起血管通透性增加;Ang-2可促进炎症反应;Ang/Tie信号系统失调介导凝血功能障碍,Ang-2升高是弥散性血管内凝血的前哨性事件。临床病情监测方面,Ang-2>5.61 ng/mL,诊断脓毒症的灵敏度为74.36%; Ang-2持续升高,提示内皮功能难以恢复,器官发生功能性改变。早期动态监测Ang-2可用于预测脓毒症相关肺损伤、急性肾损伤。Ang-2/Ang-1比值上升、Ang1/可溶性Tie2比值下降可预测脓毒症患者90 d病死率(ROC曲线面积分别为0.787和0.704)。Ang-2和可溶性Tie-2水平下降,则提示脓毒症血浆置换有效。靶向Ang/Tie信号通路的动物实验获得一定成功,但目前临床试验未能获得有价值的结果。脓毒症相关Ang/Tie信号通路有待于进一步深入研究。
关键词: 脓毒症; 血管生成素; 酪氨酸激酶受体Ang/Tie
杨航, 戴菁, 王学锋 . 脓毒症诊治中Ang/Tie信号通路的研究进展[J]. 诊断学理论与实践, 2024 , 23(01) : 90 -95 . DOI: 10.16150/j.1671-2870.2024.01.012
Sepsis and concomitant multiorgan dysfunction are a group of common clinical syndromes, and their prevalence are increasing year by year due to the increase of the aging population. It reveals that 20 million cases of sepsis occur globally every year, with a mortality rate of 26%. Early diagnosis of sepsis facilitates the adoption of timely and targeted therapeutic strategies, which is a key element in reducing mortality. Endothelial cells (EC) are the early targets of exogenous pathogens and endogenous injury signals, and numerous studies suggest that structural changes and functional activation of EC play an important role in the development of sepsis. As an endothelial-exclusive signaling pathway, the angiopoietin (Ang)/tyrosine kinase receptor (Tie) signaling pathway plays an important role in the abnormal activation and injury of EC, and plays a central role in the regulation of dysfunctional changes in the disease process. The Ang/Tie signaling pathway mainly includes two tyrosine kinase receptors (Tie1, Tie2) located in EC and four secreted glycoprotein ligands (Ang-1, Ang-2, Ang-3, Ang-4). Ang-1 sustainably activates the Tie2 receptor, maintaining function between cells, and between cell and matrix, supporting the normal physiological functions of vascular EC. Ang-2 is an Ang-1 antagonist, competitively blocking the binding of Ang-1 to the Tie2 receptor. In a sepsis environment, the ratio of Ang-1/Ang-2 decreases (Ang-1 decreases, while Ang-2 increases). Ang-2 competitively blocks the binding of Ang-1 to Tie2 receptors, resulting in severe abnormal activation of EC. Ang-2 mediates the release of heparinase (HPSE), resulting in glycocalyx damage and an increase of vascular permeability. Ang-2 increase may promote inflammatory response. Ang/Tie signaling system dysfunction results in coagulation dysfunction, and Ang-2 elevation is a sentinel event in disseminated intravascular coagulation. In terms of disease monitoring, the sensitivity of Ang-2>5.61 ng/mL for diagnosing sepsis is 74.36%. Continuing rise of Ang-2 indicates that patients are in difficulty with restoring endothelial function and normal function in organs. Early dynamic mornitoring of Ang-2 can be used to predict sepsis related lung injury and acute kidney injury. The increase in Ang-2/Ang-1 ratio and Ang-2/soluble Tie ratio are independently correlated with the 90 d- mortality rate of sepsis patients(area under ROC curve is 0.787 and 0.704, respectively). Decrease of Ang-2 and / or Tie-2 in levels indicates good efficay of plasma exchange in sepsis patients. Targeting the Ang/Tie signaling pathway have achieved certain success in animal experiments, but currently clinical trials have not yielded valuable results. Further in-depth research is needed on the Ang/Tie signaling pathway related to sepsis.
Key words: Sepsis; Angiopoietins; Tyrosine kinase receptor Angli/Tie
[1] | PURCAREA A, SOVAILA S. Sepsis, a 2020 review for the internistJ[J]. Rom J Intern Med, 2020, 58(3):129-137. |
[2] | SINGER M, DEUTSCHMAN C S, SEYMOUR C W, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)[J]. JAMA, 2016, 315(8):801-810. |
[3] | KORHONEN E A, LAMPINEN A, GIRI H, et al. Tie1 controls angiopoietin function in vascular remodeling and inflammation[J]. J Clin Invest, 2016, 126(9):3495-3510. |
[4] | TEICHERT M, MILDE L, HOLM A, et al. Pericyte-expressed Tie2 controls angiogenesis and vessel maturation[J]. Nat Commun, 2017, 8:16106. |
[5] | BRAUN L J, ZINNHARDT M, VOCKEL M, et al. VE-PTP inhibition stabilizes endothelial junctions by activa-ting FGD5[J]. EMBO Rep, 2019, 20(7):e47046. |
[6] | LEE S J, LEE C K, KANG S, et al. Angiopoietin-2 exa-cerbates cardiac hypoxia and inflammation after myocardial infarction[J]. J Clin Invest, 2018, 128(11):5018-5033. |
[7] | SALIMI U, MENDEN H L, MABRY S M, et al. Angiopoie-tin-1 protects against endotoxin-induced neonatal lung injury and alveolar simplification in mice[J]. Pediatr Res, 2022, 91(6):1405-1415. |
[8] | ATREYA M R, CVIJANOVICH N Z, FITZGERALD J C, et al. Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1[J]. Crit Care, 2023, 27(1):250. |
[9] | YUAN H T, KHANKIN E V, KARUMANCHI S A, et al. Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium[J]. Mol Cell Biol, 2009, 29(8):2011-2022. |
[10] | ZIEGLER T, HORSTKOTTE J, SCHWAB C, et al. Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis. J Clin Invest, 2013, 123(8):3436-3445. |
[11] | RICHTER R P, ASHTEKAR A R, ZHENG L, et al. Glycocalyx heparan sulfate cleavage promotes endothelial cell angiopoietin-2 expression by impairing shear stress-related AMPK/FoxO1 signaling[J]. JCI Insight, 2022, 7(15):e155010. |
[12] | LUKASZ A, HILLGRUBER C, OBERLEITHNER H, et al. Endothelial glycocalyx breakdown is mediated by angiopoietin-2[J]. Cardiovasc Res, 2017, 113(6):671-680. |
[13] | DROST C C, ROVAS A, KUSCHE-VIHROG K, et al. Tie2 activation promotes protection and reconstitution of the endothelial glycocalyx in human sepsis[J]. Thromb Haemost, 2019, 119(11):1827-1838. |
[14] | 付绪哲, 柳英杰, 牛明明, 等. 脓毒症免疫抑制机制的研究进展[J]. 中国临床研究, 2023, 36(5):741-745. |
FU X Z, LIU Y J, NIU M M, et al. Research progress in immunosuppressive mechanism of sepsis[J]. Chin J Clin Res, 2023, 36(5):741-745. | |
[15] | SMADJA D M, GUERIN C L, CHOCRON R, et al. Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients[J]. Angiogenesis, 2020, 23(4):611-620. |
[16] | FIEDLER U, REISS Y, SCHARPFENECKER M, et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation[J]. Nat Med, 2006, 12(2):235-239. |
[17] | LASK A, GUTBIER B, KERSHAW O, et al. Adjunctive therapy with the Tie2 agonist Vasculotide reduces pulmonary permeability in Streptococcus pneumoniae infected and mechanically ventilated mice[J]. Sci Rep, 2022, 12(1):15531. |
[18] | IDOWU T O, ETZRODT V, SEELIGER B, et al. Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsis[J]. Elife, 2020, 9:e59520. |
[19] | 闫威威, 董思琴, 汪华学. 红细胞分布宽度与血小板计数比值对脓毒症患者预后的预测价值[J]. 安徽医学, 2022, 43(8):887-891. |
YAN W W, DONG S Q, WANG H X. The predictive value of the ratio of red blood cell distribution width to platelet count for the prognosis of sepsis patients[J]. Anhui Med J, 2022, 43(8):887-891. | |
[20] | HIGGINS S J, DE CEUNYNCK K, KELLUM J A, et al. Tie2 protects the vasculature against thrombus formation in systemic inflammation[J]. J Clin Invest, 2018, 128(4):1471-1484. |
[21] | SCHMAIER A A, PAJARES HURTADO G M, MANICKAS-HILL Z J, et al. Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19[J]. JCI Insight, 2021, 6(20):e151527. |
[22] | SZEDERJESI J, ALMASY E, LAZAR A, et al. The Role of Angiopoietine-2 in the Diagnosis and Prognosis of Sepsis[J]. J Crit Care Med (Targu Mures), 2015, 1(1):18-23. |
[23] | CALFEE C S, JANZ D R, BERNARD G R, et al. Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies[J]. Chest, 2015, 147(6):1539-1548. |
[24] | RICHTER R P, ZHENG L, ASHTEKAR A R, et al. Associations of Plasma Angiopoietins-1 and -2 and Angiopoie-tin-2/-1 Ratios With Measures of Organ Injury and Clinical Outcomes in Children With Sepsis: A Preliminary Report[J]. Pediatr Crit Care Med, 2020, 21(9):e874-e878. |
[25] | PRICE D R, BENEDETTI E, HOFFMAN K L, et al. Angiopoietin 2 is associated with vascular necroptosis induction in coronavirus disease 2019 acute respiratory distress syndrome[J]. Am J Pathol, 2022, 192(7):1001-1015. |
[26] | REILLY J P, WANG F, JONES T K, et al. Plasma angiopoietin-2 as a potential causal marker in sepsis-asso-ciated ARDS development: evidence from Mendelian randomization and mediation analysis[J]. Intensive Care Med, 2018, 44(11):1849-1858. |
[27] | ROSENBERGER C M, WICK K D, ZHUO H, et al. Early plasma angiopoietin-2 is prognostic for ARDS and morta-lity among critically ill patients with sepsis[J]. Crit Care, 2023, 27(1):234. |
[28] | YU W K, MCNEIL J B, WICKERSHAM N E, et al. Angiopoietin-2 outperforms other endothelial biomarkers associated with severe acute kidney injury in patients with severe sepsis and respiratory failure[J]. Crit Care, 2021, 25(1):48. |
[29] | ATREYA M R, CVIJANOVICH N Z, FITZGERALD J C, et al. Prognostic and predictive value of endothelial dysfunction biomarkers in sepsis-associated acute kidney injury: risk-stratified analysis from a prospective observational cohort of pediatric septic shock[J]. Crit Care, 2023, 27(1):260. |
[30] | FANG Y, LI C, SHAO R, et al. The role of biomarkers of endothelial activation in predicting morbidity and morta-lity in patients with severe sepsis and septic shock in intensive care: A prospective observational study[J]. Thromb Res, 2018, 171:149-154. |
[31] | KIM W Y, KWEON O J, CHA M J, et al. Dexamethasone may improve severe COVID-19 via ameliorating endothelial injury and inflammation: A preliminary pilot study[J]. PLoS One, 2021, 16(7):e0254167. |
[32] | KNAUP H, STAHL K, SCHMIDT B M W, et al. Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers[J]. Crit Care, 2018, 22(1):285. |
[33] | HOFMAENNER D A, DAVID S. From Angiopoietin-2 to basic chemistry: differential effects of statins on endothelial homeostasis in ARDS[J]. Crit Care, 2023, 27(1):183. |
[34] | JIANG S, LI S, HU J, et al. Combined delivery of angiopoietin-1 gene and simvastatin mediated by anti-intercellular adhesion molecule-1 antibody-conjugated ternary nanoparticles for acute lung injury therapy[J]. Nanomedicine, 2019, 15(1):25-36. |
[35] | JONES R S, SMITH P S, BERG P H, et al. Efficacy and safety of LY3127804, an anti-angiopoietin-2 antibody, in a randomized, double-blind, placebo-controlled clinical trial in patients hospitalized with pneumonia and presumed or confirmed COVID-19[J]. Clin Med Insights Circ Respir Pulm Med, 2022, 16:11795484221119316. |
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