

FOLLOWUS
Department of Pathophysiology, School of Medicine, Nantong University, Nantong 226001, Jiangsu, China
Department of Critical Care, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
Department of Pathology, the First Hospital of Lanzhou University, Lanzhou 730000, China
*Yang Lu, marineluyang@ntu.edu.cn;
Ren-Fang Mao, maorenfang@ntu.edu.cn
Received:25 July 2025,
Accepted:16 March 2026,
Published:2026-04
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Jiang YH, Li XJ, Ma DC, Chen YL, Shi YY, Lu Y, et al. Endothelial barrier and sepsis: mechanisms and potential therapeutic strategies. Mil Med Res. 2026;13(1):100013.
Jiang YH, Li XJ, Ma DC, Chen YL, Shi YY, Lu Y, et al. Endothelial barrier and sepsis: mechanisms and potential therapeutic strategies. Mil Med Res. 2026;13(1):100013. DOI: 10.1016/j.mmr.2026.100013.
Sepsis is a life-threatening condition characterized by an exaggerated and uncontrolled immune response
leading to widespread inflammation throughout the body. This immune response can compromise the integrity of the endothelial barrier
resulting in increased vascular permeability. The degree of vascular permeability in septic shock patients correlates with disease severity and significantly influences the outcomes of resuscitation and prognosis. This review systematically examines the structural regulation of the endothelial barrier and the dynamic mechanisms of its injury in subgroups of sepsis. In response to these mechanisms
emerging therapeutic strategies focus on glycocalyx protection
signal pathway modulation
cytoskeleton stability
and immune regulation
aiming to restore endothelial barrier function through multi-target synergism. In the future
combining analysis of endothelial barrier function and the dynamic regulation mechanism provides a new perspective for the precise treatment of sepsis.
Singer M , Deutschman CS , Seymour CW , Shankar-Hari M , Annane D , Bauer M , et al . The third international consensus definitions for sepsis and septic shock (sepsis-3) . JAMA . 2016 ; 315 ( 8 ): 801 - 10 .
GBD 2023 Causes of Death Collaborators . Global burden of 292 causes of death in 204 countries and territories and 660 subnational locations, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023 . Lancet . 2025 ; 406 ( 10513 ): 1811 - 72 .
Cecconi M , Evans L , Levy M , Rhodes A . Sepsis and septic shock . Lancet . 2018 ; 392 ( 10141 ): 75 - 87 .
Joffre J , Hellman J , Ince C , Ait-Oufella H . Endothelial responses in sepsis . Am J Respir Crit Care Med . 2020 ; 202 ( 3 ): 361 - 70 .
Girardis M , David S , Ferrer R , Helms J , Juffermans NP , Martin-Loeches I , et al . Understanding, assessing and treating immune, endothelial and haemostasis dysfunctions in bacterial sepsis . Intensive Care Med . 2024 ; 50 ( 10 ): 1580 - 92 .
Bode C , Weis S , Sauer A , Wendel-Garcia P , David S . Targeting the host response in sepsis: current approaches and future evidence . Crit Care . 2023 ; 27 ( 1 ): 478 .
Stasi A , Castellano G , Ranieri E , Infante B , Stallone G , Gesualdo L , et al . SARS-CoV-2 and viral sepsis: immune dysfunction and implications in kidney failure . J Clin Med . 2020 ; 9 ( 12 ): 4057 .
Wu M , Yan Y , Xie X , Bai J , Ma C , Du X . Effect of endothelial responses on sepsis-associated organ dysfunction . Chin Med J (Engl) . 2024 ; 137 ( 23 ): 2782 - 92 .
Druey KM , Arnaud L , Parikh SM . Systemic capillary leak syndrome . Nat Rev Dis Primers . 2024 ; 10 ( 1 ): 86 .
Zhuang C , Kang M , Lee M . Delivery systems of therapeutic nucleic acids for the treatment of acute lung injury/acute respiratory distress syndrome . J Control Release . 2023 ; 360 : 1 - 14 .
Joffre J , Radermacher P , Kallel H , Marangon I , Rutault A , Levy Y , et al . Vascular leakage during circulatory failure: physiopathology, impact and treatments . Ann Intensive Care . 2025 ; 15 ( 1 ): 79 .
Claesson-Welsh L , Dejana E , McDonald DM . Permeability of the endothelial barrier: identifying and reconciling controversies . Trends Mol Med . 2021 ; 27 ( 4 ): 314 - 31 .
Radeva MY , Waschke J . Mind the gap: mechanisms regulating the endothelial barrier . Acta Physiol (Oxf) . 2018 ; 222 ( 1 ). doi: 10.1111/apha.12860 https://doi.org/10.1111/apha.12860 .
Yu J , Xue J , Liu C , Zhang A , Qin L , Liu J , et al . MiR-146a-5p accelerates sepsis through dendritic cell activation and glycolysis via targeting ATG7 . J Biochem Mol Toxicol . 2022 ; 36 ( 10 ): e23151 .
Lee WL , Slutsky AS . Sepsis and endothelial permeability . 2010 ; 363 ( 7 ): 689 - 91 .
Reglero-Real N , Colom B , Bodkin JV , Nourshargh S . Endothelial cell junctional adhesion molecules: role and regulation of expression in inflammation . Arterioscler Thromb Vasc Biol . 2016 ; 36 ( 10 ): 2048 - 57 .
Hellenthal KEM , Brabenec L , Wagner NM . Regulation and dysregulation of endothelial permeability during systemic inflammation . Cells . 2022 ; 11 ( 12 ): 1935 .
Barry M , Pati S . Targeting repair of the vascular endothelium and glycocalyx after traumatic injury with plasma and platelet resuscitation . Matrix Biol Plus . 2022 ; 14 : 100107 .
Dolmatova EV , Wang K , Mandavilli R , Griendling KK . The effects of sepsis on endothelium and clinical implications . Cardiovasc Res . 2021 ; 117 ( 1 ): 60 - 73 .
Kinlay S , Behrendt D , Wainstein M , Beltrame J , Fang JC , Creager MA , et al . Role of endothelin-1 in the active constriction of human atherosclerotic coronary arteries . Circulation . 2001 ; 104 ( 10 ): 1114 - 8 .
Esmon CT . The protein C anticoagulant pathway . Arterioscler Thromb . 1992 ; 12 ( 2 ): 135 - 45 .
Ince C , Mayeux PR , Nguyen T , Gomez H , Kellum JA , Ospina-Tascón GA , et al . The endothelium in sepsis . Shock . 2016 ; 45 ( 3 ): 259 - 70 .
Augustin HG , Koh GY . A systems view of the vascular endothelium in health and disease . Cell . 2024 ; 187 ( 18 ): 4833 - 58 .
Gane J , Stockley R . Mechanisms of neutrophil transmigration across the vascular endothelium in COPD . Thorax . 2012 ; 67 ( 6 ): 553 - 61 .
Aird WC . Phenotypic heterogeneity of the endothelium: II. Representative vascular beds . Circ Res . 2007 ; 100 ( 2 ): 174 - 90 .
Klijn E , Den Uil CA , Bakker J , Ince C . The heterogeneity of the microcirculation in critical illness . Clin Chest Med . 2008 ; 29 ( 4 ): 643 - 54,viii .
Matsuoka RL , Buck LD , Vajrala KP , Quick RE , Card OA . Historical and current perspectives on blood endothelial cell heterogeneity in the brain . Cell Mol Life Sci . 2022 ; 79 ( 7 ): 372 .
Reitsma S , Slaaf DW , Vink H , van Zandvoort MA , oude Egbrink MG . The endothelial glycocalyx: composition, functions, and visualization . Pflugers Arch . 2007 ; 454 ( 3 ): 345 - 59 .
Lipowsky HH . Microvascular rheology and hemodynamics . Microcirculation . 2005 ; 12 ( 1 ): 5 - 15 .
Jiang XZ , Ventikos Y , Luo KH . Microvascular ion transport through endothelial glycocalyx layer: new mechanism and improved Starling principle . Am J Physiol Heart Circ Physiol . 2019 ; 317 ( 1 ): H104 - H13 .
Michel CC , Woodcock TE , Curry FE . Understanding and extending the Starling principle . Acta Anaesthesiol Scand . 2020 ; 64 ( 8 ): 1032 - 7 .
Woodcock TE , Woodcock TM . Revised starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy . Br J Anaesth . 2012 ; 108 ( 3 ): 384 - 94 .
Aldecoa C , Llau JV , Nuvials X , Artigas A . Role of albumin in the preservation of endothelial glycocalyx integrity and the microcirculation: a review . Ann Intensive Care . 2020 ; 10 ( 1 ): 85 .
Yazdani S , Jaldin-Fincati JR , Pereira RVS , Klip A . Endothelial cell barriers: transport of molecules between blood and tissues . Traffic . 2019 ; 20 ( 6 ): 390 - 403 .
Uchimido R , Schmidt EP , Shapiro NI . The glycocalyx: a novel diagnostic and therapeutic target in sepsis . Crit Care . 2019 ; 23 ( 1 ): 16 .
Iba T , Levy JH . Derangement of the endothelial glycocalyx in sepsis . J Thromb Haemost . 2019 ; 17 ( 2 ): 283 - 94 .
Mironov AA , Mironov A , Sanavio B , Krol S , Beznoussenko GV . Intracellular membrane transport in vascular endothelial cells . Int J Mol Sci . 2023 ; 24 ( 6 ): 5791 .
Sukriti S , Tauseef M , Yazbeck P , Mehta D . Mechanisms regulating endothelial permeability . Pulm Circ . 2014 ; 4 ( 4 ): 535 - 51 .
Vandenbroucke E , Mehta D , Minshall R , Malik AB . Regulation of endothelial junctional permeability . Ann N Y Acad Sci . 2008 ; 1123 : 134 - 45 .
Giannotta M , Trani M , Dejana E . VE-cadherin and endothelial adherens junctions: active guardians of vascular integrity . Dev Cell . 2013 ; 26 ( 5 ): 441 - 54 .
Zihni C , Mills C , Matter K , Balda MS . Tight junctions: from simple barriers to multifunctional molecular gates . Nat Rev Mol Cell Biol . 2016 ; 17 ( 9 ): 564 - 80 .
Dörfel MJ , Westphal JK , Bellmann C , Krug SM , Cording J , Mittag S , et al . CK2-dependent phosphorylation of occludin regulates the interaction with ZO-proteins and tight junction integrity . Cell Commun Signal . 2013 ; 11 ( 1 ): 40 .
Goldenberg NM , Steinberg BE , Slutsky AS , Lee WL . Broken barriers: a new take on sepsis pathogenesis . Sci Transl Med . 2011 ; 3 ( 88 ): 88ps25 .
Dejana E , Giampietro C . Vascular endothelial-cadherin and vascular stability . Curr Opin Hematol . 2012 ; 19 ( 3 ): 218 - 23 .
Dejana E , Orsenigo F . Endothelial adherens junctions at a glance . J Cell Sci . 2013 ; 126 ( Pt 12 ): 2545 - 9 .
Liao S , Lin Y , Liu L , Yang S , Lin Y , He J , et al . ADAM10-a "multitasker" in sepsis: focus on its posttranslational target . Inflamm Res . 2023 ; 72 ( 3 ): 395 - 423 .
Blaise S , Polena H , Vilgrain I . Soluble vascular endothelial-cadherin and auto-antibodies to human vascular endothelial-cadherin in human diseases: two new biomarkers of endothelial dysfunction . Vasc Med . 2015 ; 20 ( 6 ): 557 - 65 .
Dejana E , Orsenigo F , Lampugnani MG . The role of adherens junctions and VE-cadherin in the control of vascular permeability . J Cell Sci . 2008 ; 121 ( Pt 13 ): 2115 - 22 .
Stiehl T , Thamm K , Kaufmann J , Schaeper U , Kirsch T , Haller H , et al . Lung-targeted RNA interference against angiopoietin-2 ameliorates multiple organ dysfunction and death in sepsis . Crit Care Med . 2014 ; 42 ( 10 ): e654 - 62 .
Yu WK , McNeil JB , Wickersham NE , Shaver CM , Bastarache JA , Ware LB . Angiopoietin-2 outperforms other endothelial biomarkers associated with severe acute kidney injury in patients with severe sepsis and respiratory failure . Crit Care . 2021 ; 25 ( 1 ): 48 .
Lu YN , Wang XH , Xu BC , Zheng YF , Zhang X , Liu Y , et al . Urinary trypsin inhibitor exerts multifaceted regulation of angiopoietin 2 in septic cardiomyopathy . Eur J Pharmacol . 2025 ; 1003 : 177944 .
Joussen AM , Ricci F , Paris LP , Korn C , Quezada-Ruiz C , Zarbin M . Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data . Eye (Lond) . 2021 ; 35 ( 5 ): 1305 - 16 .
Korhonen EA , Lampinen A , Giri H , Anisimov A , Kim M , Allen B , et al . Tie1 controls angiopoietin function in vascular remodeling and inflammation . J Clin Invest . 2016 ; 126 ( 9 ): 3495 - 510 .
Chang L , Goldman RD . Intermediate filaments mediate cytoskeletal crosstalk . Nat Rev Mol Cell Biol . 2004 ; 5 ( 8 ): 601 - 13 .
Vogel SM , Malik AB . Cytoskeletal dynamics and lung fluid balance . Compr Physiol . 2012 ; 2 ( 1 ): 449 - 78 .
Garnier O , Vilgrain I . Dialogue between VE-cadherin and sphingosine 1 phosphate receptor1 (s1pr1) for protecting endothelial functions . Int J Mol Sci . 2023 ; 24 ( 4 ): 4018 .
Gao M , Zhu X , Gao X , Yang H , Li H , Du Y , et al . Kaempferol mitigates sepsis-induced acute lung injury by modulating the SphK1/S1P/S1PR1/MLC2 signaling pathway to restore the integrity of the pulmonary endothelial cell barrier . Chem Biol Interact . 2024 ; 398 : 111085 .
Moolenaar WH , Kranenburg O , Postma FR , Zondag GC . Lysophosphatidic acid: G-protein signalling and cellular responses . Curr Opin Cell Biol . 1997 ; 9 ( 2 ): 168 - 73 .
Wilkerson BA , Argraves KM . The role of sphingosine-1-phosphate in endothelial barrier function . Biochim Biophys Acta . 2014 ; 1841 ( 10 ): 1403 - 12 .
Neubauer K , Zieger B . Endothelial cells and coagulation . Cell Tissue Res . 2022 ; 387 ( 3 ): 391 - 8 .
Levi M , van der Poll T . Disseminated intravascular coagulation: a review for the internist . Intern Emerg Med . 2013 ; 8 ( 1 ): 23 - 32 .
Studt JD , Kremer Hovinga JA , Antoine G , Hermann M , Rieger M , Scheiflinger F , et al . Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin . Blood . 2005 ; 105 ( 2 ): 542 - 4 .
Nguyen TC , Han YY , Kiss JE , Hall MW , Hassett AC , Jaffe R , et al . Intensive plasma exchange increases a disintegrin and metalloprotease with thrombospondin motifs-13 activity and reverses organ dysfunction in children with thrombocytopenia-associated multiple organ failure . Crit Care Med . 2008 ; 36 ( 10 ): 2878 - 87 .
Nguyen TC , Liu A , Liu L , Ball C , Choi H , May WS , et al . Acquired ADAMTS-13 deficiency in pediatric patients with severe sepsis . Haematologica . 2007 ; 92 ( 1 ): 121 - 4 .
Williams B , Zou L , Pittet JF , Chao W . Sepsis-induced coagulopathy: a comprehensive narrative review of pathophysiology, clinical presentation, diagnosis, and management strategies . Anesth Analg . 2024 ; 138 ( 4 ): 696 - 711 .
Iba T , Helms J , Neal MD , Levy JH . Mechanisms and management of the coagulopathy of trauma and sepsis: trauma-induced coagulopathy, sepsis-induced coagulopathy, and disseminated intravascular coagulation . J Thromb Haemost . 2023 ; 21 ( 12 ): 3360 - 70 .
Madoiwa S , Nunomiya S , Ono T , Shintani Y , Ohmori T , Mimuro J , et al . Plasminogen activator inhibitor 1 promotes a poor prognosis in sepsis-induced disseminated intravascular coagulation . Int J Hematol . 2006 ; 84 ( 5 ): 398 - 405 .
Levi M , ten Cate H , van der Poll T . Endothelium: interface between coagulation and inflammation . Crit Care Med . 2002 ; 30 ( 5 Suppl ): S220 - S4 .
Gando S , Levi M , Toh CH . Disseminated intravascular coagulation . J Intensive Care . 2025 ; 13 ( 1 ): 32 .
Naime ACA , Ganaes JOF , Lopes-Pires ME . Sepsis: the involvement of platelets and the current treatments . Curr Mol Pharmacol . 2018 ; 11 ( 4 ): 261 - 9 .
Soriano AO , Jy W , Chirinos JA , Valdivia MA , Velasquez HS , Jimenez JJ , et al . Levels of endothelial and platelet microparticles and their interactions with leukocytes negatively correlate with organ dysfunction and predict mortality in severe sepsis . Crit Care Med . 2005 ; 33 ( 11 ): 2540 - 6 .
Piagnerelli M , Boudjeltia KZ , Brohee D , Piro P , Carlier E , Vincent JL , et al . Alterations of red blood cell shape and sialic acid membrane content in septic patients . Crit Care Med . 2003 ; 31 ( 8 ): 2156 - 62 .
Donadello K , Piagnerelli M , Reggiori G , Gottin L , Scolletta S , Occhipinti G , et al . Reduced red blood cell deformability over time is associated with a poor outcome in septic patients . Microvasc Res . 2015 ; 101 : 8 - 14 .
Aird WC . The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome . Blood . 2003 ; 101 ( 10 ): 3765 - 77 .
Jr Janeway CA, ., Medzhitov R . Innate immune recognition . Annu Rev Immunol . 2002 ; 20 : 197 - 216 .
Wu HP , Chen CK , Chung K , Tseng JC , Hua CC , Liu YC , et al . Serial cytokine levels in patients with severe sepsis . Inflamm Res . 2009 ; 58 ( 7 ): 385 - 93 .
Zhang H , Wang Y , Qu M , Li W , Wu D , Cata JP , et al . Neutrophil, neutrophil extracellular traps and endothelial cell dysfunction in sepsis . Clin Transl Med . 2023 ; 13 ( 1 ): e1170 .
Puy C , Moellmer SA , Pang J , Vu HH , Melrose AR , Lorentz CU , et al . Coagulation factor XI regulates endothelial cell permeability and barrier function in vitro and in vivo . Blood . 2024 ; 144 ( 17 ): 1821 - 33 .
Ding J , Li Z , Li L , Ding Y , Wang D , Meng S , et al . Myosin light chain kinase inhibitor ML7 improves vascular endothelial dysfunction and permeability via the mitogen-activated protein kinase pathway in a rabbit model of atherosclerosis . Biomed Pharmacother . 2020 ; 128 : 110258 .
Collins SR , Blank RS , Deatherage LS , Dull RO . Special article: the endothelial glycocalyx: emerging concepts in pulmonary edema and acute lung injury . Anesth Analg . 2013 ; 117 ( 3 ): 664 - 74 .
Zhang Y , Liang X , Bao X , Xiao W , Chen G . Toll-like receptor 4 (TLR4) inhibitors: current research and prospective . Eur J Med Chem . 2022 ; 235 : 114291 .
Hu D , Sheeja Prabhakaran H , Zhang YY , Luo G , He W , Liou YC . Mitochondrial dysfunction in sepsis: mechanisms and therapeutic perspectives . Crit Care . 2024 ; 28 ( 1 ): 292 .
Ciesielska A , Matyjek M , Kwiatkowska K . TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling . Cell Mol Life Sci . 2021 ; 78 ( 4 ): 1233 - 61 .
Chan YH , Harith HH , Israf DA , Tham CL . Differential regulation of LPS-mediated VE-cadherin disruption in human endothelial cells and the underlying signaling pathways: a mini review . Front Cell Dev Biol . 2019 ; 7 : 280 .
Chichger H , Duong H , Braza J , Harrington EO . P18, a novel adaptor protein, regulates pulmonary endothelial barrier function via enhanced endocytic recycling of VE-cadherin . FASEB J . 2015 ; 29 ( 3 ): 868 - 81 .
Huang Y , Tan Q , Chen R , Cao B , Li W . Sevoflurane prevents lipopolysaccharide-induced barrier dysfunction in human lung microvascular endothelial cells: Rho-mediated alterations of VE-cadherin . Biochem Biophys Res Commun . 2015 ; 468 ( 1-2 ): 119 - 24 .
Liu H , Yu X , Yu S , Kou J . Molecular mechanisms in lipopolysaccharide-induced pulmonary endothelial barrier dysfunction . Int Immunopharmacol . 2015 ; 29 ( 2 ): 937 - 46 .
Chattopadhyay R , Raghavan S , Rao GN . Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier function . Redox Biol . 2017 ; 12 : 438 - 55 .
Xu JQ , Zhang WY , Fu JJ , Fang XZ , Gao CG , Li C , et al . Viral sepsis: diagnosis, clinical features, pathogenesis, and clinical considerations . Mil Med Res . 2024 ; 11 ( 1 ): 78 .
Sharma A , Kontodimas K , Bosmann M . The mavs immune recognition pathway in viral infection and sepsis . Antioxid Redox Signal . 2021 ; 35 ( 16 ): 1376 - 92 .
Tang A , Shi Y , Dong Q , Wang S , Ge Y , Wang C , et al . Prognostic differences in sepsis caused by gram-negative bacteria and gram-positive bacteria: a systematic review and meta-analysis . Crit Care . 2023 ; 27 ( 1 ): 467 .
Ramachandran G . Gram-positive and gram-negative bacterial toxins in sepsis: a brief review . Virulence . 2014 ; 5 ( 1 ): 213 - 8 .
Holmes D , Colaneri M , Palomba E , Gori A . Exploring post-sepsis and post-COVID-19 syndromes: crossovers from pathophysiology to therapeutic approach . Front Med (Lausanne) . 2023 ; 10 : 1280951 .
Siti-Zubaidah MZ , Harafinova HS , Liba AN , Nordin ML , Hambali KA , Siti HN . Exploring bradykinin: a common mediator in the pathophysiology of sepsis and atherosclerotic cardiovascular disease . Vascul Pharmacol . 2024 ; 156 : 107414 .
Malavige GN , Ogg GS . Pathogenesis of vascular leak in dengue virus infection . Immunology . 2017 ; 151 ( 3 ): 261 - 9 .
Raghavan S , Kenchappa DB , Leo MD . SARS-CoV-2 spike protein induces degradation of junctional proteins that maintain endothelial barrier integrity . Front Cardiovasc Med . 2021 ; 8 : 687783 .
Biering SB , Akey DL , Wong MP , Brown WC , Lo NTN , Puerta-Guardo H , et al . Structural basis for antibody inhibition of flavivirus NS1-triggered endothelial dysfunction . Science . 2021 ; 371 ( 6525 ): 194 - 200 .
Krishnan J , Hennen EM , Ao M , Kirabo A , Ahmad T , de la Visitación N , et al . Netosis drives blood pressure elevation and vascular dysfunction in hypertension . Circ Res . 2024 ; 134 ( 11 ): 1483 - 94 .
Yanaka M , Honma T , Sato K , Shinohara N , Ito J , Tanaka Y , et al . Increased monocytic adhesion by senescence in human umbilical vein endothelial cells . Biosci Biotechnol Biochem . 2011 ; 75 ( 6 ): 1098 - 103 .
Honda S , Ikeda K , Urata R , Yamazaki E , Emoto N , Matoba S . Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis . Sci Rep . 2021 ; 11 ( 1 ): 14608 .
Ikonomidis I , Voumvourakis A , Makavos G , Triantafyllidi H , Pavlidis G , Katogiannis K , et al . Association of impaired endothelial glycocalyx with arterial stiffness, coronary microcirculatory dysfunction, and abnormal myocardial deformation in untreated hypertensives . J Clin Hypertens (Greenwich) . 2018 ; 20 ( 4 ): 672 - 9 .
Csiszar A , Wang M , Lakatta EG , Ungvari Z . Inflammation and endothelial dysfunction during aging: role of NF-kappaB . J Appl Physiol (1985) . 2008 ; 105 ( 4 ): 1333 - 41 .
Kim KS , Kim JE , Choi KJ , Bae S , Kim DH . Characterization of DNA damage-induced cellular senescence by ionizing radiation in endothelial cells . Int J Radiat Biol . 2014 ; 90 ( 1 ): 71 - 80 .
Krouwer VJ , Hekking LH , Langelaar-Makkinje M , Regan-Klapisz E , Post JA . Endothelial cell senescence is associated with disrupted cell-cell junctions and increased monolayer permeability . Vasc Cell . 2012 ; 4 ( 1 ): 12 .
Morgan RG , Walker AE , Trott DW , Machin DR , Henson GD , Reihl KD , et al . Induced Trf2 deletion leads to aging vascular phenotype in mice associated with arterial telomere uncapping, senescence signaling, and oxidative stress . J Mol Cell Cardiol . 2019 ; 127 : 74 - 82 .
Michels EHA , Butler JM , Reijnders TDY , Cremer OL , Scicluna BP , Uhel F , et al . Association between age and the host response in critically ill patients with sepsis . Crit Care . 2022 ; 26 ( 1 ): 385 .
Renema P , Pittet JF , Brandon AP , Jr Leal SM , Gu S , Promer G , et al . Tau and aβ42 in lavage fluid of pneumonia patients are associated with end-organ dysfunction: a prospective exploratory study . PLoS One . 2024 ; 19 ( 2 ): e0298816 .
Huang X , Hu H , Sun T , Zhu W , Tian H , Hao D , et al . Plasma endothelial glycocalyx components as a potential biomarker for predicting the development of disseminated intravascular coagulation in patients with sepsis . J Intensive Care Med . 2021 ; 36 ( 11 ): 1286 - 95 .
Csipo T , Cassidy BR , Balasubramanian P , Drevets DA , Ungvari ZI , Yabluchanskiy A . Endothelial dysfunction and impaired neurovascular coupling responses precede cognitive impairment in a mouse model of geriatric sepsis . Front Aging Neurosci . 2021 ; 13 : 644733 .
Lavarti R , Cai L , Alvarez-Diaz T , Medina-Rodriguez T , Bombin S , Raju RP . Senescence landscape in the liver following sepsis and senolytics as potential therapeutics . Aging Cell . 2025 ; 24 ( 1 ): e14354 .
Victorelli S , Salmonowicz H , Chapman J , Martini H , Vizioli MG , Riley JS , et al . Apoptotic stress causes mtDNA release during senescence and drives the sasp . Nature . 2023 ; 622 ( 7983 ): 627 - 36 .
Li X , Chen M , Chen X , He X , Li X , Wei H , et al . TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation . Eur Heart J . 2024 ; 45 ( 39 ): 4219 - 35 .
Strunk T , Molloy EJ , Mishra A , Bhutta ZA . Neonatal bacterial sepsis . Lancet . 2024 ; 404 ( 10449 ): 277 - 93 .
Palma-Barqueros V , Torregrosa JM , Caparrós-Pérez E , Mota-Pérez N , Bohdan N , Llanos MDC , et al . Developmental differences in platelet inhibition response to prostaglandin E1 . Neonatology . 2020 ; 117 ( 1 ): 15 - 23 .
Sitaru AG , Holzhauer S , Speer CP , Singer D , Obergfell A , Walter U , et al . Neonatal platelets from cord blood and peripheral blood . Platelets . 2005 ; 16 ( 3-4 ): 203 - 10 .
Toulon P , Berruyer M , Brionne-François M , Grand F , Lasne D , Telion C , et al . Age dependency for coagulation parameters in paediatric populations. Results of a multicentre study aimed at defining the age-specific reference ranges . Thromb Haemost . 2016 ; 116 ( 1 ): 9 - 16 .
Eschborn S , Weitkamp JH . Procalcitonin versus C-reactive protein: review of kinetics and performance for diagnosis of neonatal sepsis . J Perinatol . 2019 ; 39 ( 7 ): 893 - 903 .
Ng PC , Li K , Leung TF , Wong RP , Li G , Chui KM , et al . Early prediction of sepsis-induced disseminated intravascular coagulation with interleukin-10, interleukin-6, and RANTES in preterm infants . Clin Chem . 2006 ; 52 ( 6 ): 1181 - 9 .
Suen Y , Chang M , Lee SM , Buzby JS , Cairo MS . Regulation of interleukin-11 protein and mRNA expression in neonatal and adult fibroblasts and endothelial cells . Blood . 1994 ; 84 ( 12 ): 4125 - 34 .
Ying J , Zhang C , Wang Y , Liu T , Yu Z , Wang K , et al . Sulodexide improves vascular permeability via glycocalyx remodelling in endothelial cells during sepsis . Front Immunol . 2023 ; 14 : 1172892 .
Xia S , Yu W , Menden H , Younger ST , Sampath V . FOXC2 autoregulates its expression in the pulmonary endothelium after endotoxin stimulation in a histone acetylation-dependent manner . Front Cell Dev Biol . 2021 ; 9 : 657662 .
Tang F , Zhao XL , Xu LY , Zhang JN , Ao H , Peng C . Endothelial dysfunction: pathophysiology and therapeutic targets for sepsis-induced multiple organ dysfunction syndrome . Biomed Pharmacother . 2024 ; 178 : 117180 .
Huang Y , Li G , Li D , Liu C , Chen M , Cai L , et al . Ethyl caffeate alleviates inflammatory response and promotes recovery in septic-acute lung injury via the TNF-α/NF-κB/MMP9 axis . Phytomedicine . 2025 ; 141 : 156700 .
Jiang J , Huang K , Xu S , Garcia JGN , Wang C , Cai H . Targeting NOX4 alleviates sepsis-induced acute lung injury via attenuation of redox-sensitive activation of CaMKII/ERK1/2/MLCK and endothelial cell barrier dysfunction . Redox Biol . 2020 ; 36 : 101638 .
Yoo H , Lee JY , Park J , Suh GY , Jeon K . Association of plasma levels of fas ligand with severity and outcome of sepsis . Shock . 2021 ; 56 ( 4 ): 544 - 50 .
Khongpraphan S , Sanongkiet S , Luangjindarat C , Thairat S , Munyoo B , Chabang N , et al . ECDD-S16, a synthetic derivative of cleistanthin a, suppresses pyroptosis in Burkholderia pseudomallei-infected U937 macrophages . PLoS One . 2025 ; 20 ( 7 ): e0327457 .
Vasudevan SO , Behl B , Rathinam VA . Pyroptosis-induced inflammation and tissue damage . Semin Immunol . 2023 ; 69 : 101781 .
Mussap M , Cibecchini F , Noto A , Fanos V . In search of biomarkers for diagnosing and managing neonatal sepsis: the role of angiopoietins . J Matern Fetal Neonatal Med . 2013 ; 26 Suppl 2 : 24 - 6 .
Richter RP , Russell RT , Hu PJ , Uhlich RM , Swain TA , Kerby JD , et al . Plasma angiopoietin-2/-1 ratio is elevated and angiopoietin-2 levels correlate with plasma syndecan-1 following pediatric trauma . Shock . 2019 ; 52 ( 3 ): 340 - 6 .
Jung B , Yagi H , Kuo A , Dorweiler TF , Aikawa M , Kasai T , et al . ApoM-bound S1P acts via endothelial S1PR1 to suppress choroidal neovascularization and vascular leakage . Angiogenesis . 2025 ; 28 ( 2 ): 24 .
Duan S , Kim SG , Bao J , Lim HJ , Kim JW , Yoon SI , et al . Persistent activation of sphingosine-1-phosphate receptor 1 by phytosphingosine-3,4-cyclic phosphate ameliorates sepsis by inhibiting hyperinflammation and vascular hyperpermeability . MedComm (2020) . 2025 ; 6 ( 6 ): e70238 .
Cannavo A , Liccardo D , Komici K , Corbi G , de Lucia C , Femminella GD , et al . Sphingosine kinases and sphingosine 1-phosphate receptors: signaling and actions in the cardiovascular system . Front Pharmacol . 2017 ; 8 : 556 .
Chen L , Li L , Song Y , Lv T . Blocking SphK1/S1P/S1PR1 signaling pathway alleviates lung injury caused by sepsis in acute ethanol intoxication mice . Inflammation . 2021 ; 44 ( 6 ): 2170 - 9 .
Wang R , Han Q , Fan J , Xu Z , Liu W , Liu D , et al . Sepsis-induced endothelial barrier dysfunction: mechanisms, pathology, and therapeutic advances . Research (Wash D C) . 2025 ; 8 : 0997 .
Zhan JH , Wei J , Liu YJ , Wang PX , Zhu XY . Sepsis-associated endothelial glycocalyx damage: a review of animal models, clinical evidence, and molecular mechanisms . Int J Biol Macromol . 2025 ; 295 : 139548 .
Delgadillo LF , Lomakina EB , Kuebel J , Waugh RE . Changes in endothelial glycocalyx layer protective ability after inflammatory stimulus . Am J Physiol Cell Physiol . 2021 ; 320 ( 2 ): C216 - c24 .
Schmidt EP , Yang Y , Janssen WJ , Gandjeva A , Perez MJ , Barthel L , et al . The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis . Nat Med . 2012 ; 18 ( 8 ): 1217 - 23 .
Kataoka H , Ushiyama A , Akimoto Y , Matsubara S , Kawakami H , Iijima T . Structural behavior of the endothelial glycocalyx is associated with pathophysiologic status in septic mice: an integrated approach to analyzing the behavior and function of the glycocalyx using both electron and fluorescence intravital microscopy . Anesth Analg . 2017 ; 125 ( 3 ): 874 - 83 .
Baby S , Reljic T , Villalba N , Kumar A , Yuan SY . Endothelial glycocalyx-associated molecules as potential serological markers for sepsis-associated encephalopathy: a systematic review and meta-analysis . PLoS One . 2023 ; 18 ( 2 ): e0281941 .
Dogné S , Flamion B . Endothelial glycocalyx impairment in disease: focus on hyaluronan shedding . Am J Pathol . 2020 ; 190 ( 4 ): 768 - 80 .
Butler MJ , Down CJ , Foster RR , Satchell SC . The pathological relevance of increased endothelial glycocalyx permeability . Am J Pathol . 2020 ; 190 ( 4 ): 742 - 51 .
Fei Y , Huang X , Ning F , Qian T , Cui J , Wang X , et al . NETs induce ferroptosis of endothelial cells in LPS-ALI through SDC-1/HS and downstream pathways . Biomed Pharmacother . 2024 ; 175 : 116621 .
Nieuwdorp M , Meuwese MC , Mooij HL , van Lieshout MH , Hayden A , Levi M , et al . Tumor necrosis factor-alpha inhibition protects against endotoxin-induced endothelial glycocalyx perturbation . Atherosclerosis . 2009 ; 202 ( 1 ): 296 - 303 .
Drost CC , Rovas A , Osiaevi I , Schughart K , Lukasz A , Linke WA , et al . Interleukin-6 drives endothelial glycocalyx damage in COVID-19 and bacterial sepsis . Angiogenesis . 2024 ; 27 ( 3 ): 411 - 22 .
Zhang D , Li L , Chen Y , Ma J , Yang Y , Aodeng S , et al . Syndecan-1, an indicator of endothelial glycocalyx degradation, predicts outcome of patients admitted to an ICU with COVID-19 . Mol Med . 2021 ; 27 ( 1 ): 151 .
Fels B , Acharya S , Vahldieck C , Graf T , Käding N , Rupp J , et al . Mineralocorticoid receptor-antagonism prevents COVID-19-dependent glycocalyx damage . Pflugers Arch . 2022 ; 474 ( 10 ): 1069 - 76 .
Medeiros SK , Sharma N , Dwivedi D , Cani E , Zhou J , Dwivedi N , et al . The effects of DNAse I and low-molecular-weight heparin in a murine model of polymicrobial abdominal sepsis . Shock . 2023 ; 59 ( 4 ): 666 - 72 .
Chen TT , Lv JJ , Chen L , Li M , Liu LP . Heparanase inhibition leads to improvement in patients with acute gastrointestinal injuries induced by sepsis . World J Gastroenterol . 2023 ; 29 ( 35 ): 5154 - 65 .
Puskarich MA , Cornelius DC , Tharp J , Nandi U , Jones AE . Plasma syndecan-1 levels identify a cohort of patients with severe sepsis at high risk for intubation after large-volume intravenous fluid resuscitation . J Crit Care . 2016 ; 36 : 125 - 9 .
Saoraya J , Wongsamita L , Srisawat N , Musikatavorn K . Plasma syndecan-1 is associated with fluid requirements and clinical outcomes in emergency department patients with sepsis . Am J Emerg Med . 2021 ; 42 : 83 - 9 .
Immonen T , Jung E , Gallo DM , Diaz-Primera R , Gotsch F , Whittaker P , et al . Acute pyelonephritis in pregnancy and plasma syndecan-1: evidence of glycocalyx involvement . J Matern Fetal Neonatal Med . 2023 ; 36 ( 1 ): 2155041 .
Naggi A , Casu B , Perez M , Torri G , Cassinelli G , Penco S , et al . Modulation of the heparanase-inhibiting activity of heparin through selective desulfation, graded N-acetylation, and glycol splitting . J Biol Chem . 2005 ; 280 ( 13 ): 12103 - 13 .
Su X , Wang B , Zhou Z , Li Z , Tong S , Chen S , et al . A positive feedback loop of heparanase/syndecan1/nerve growth factor regulates cancer pain progression . Korean J Pain . 2023 ; 36 ( 1 ): 60 - 71 .
Ray U , Thirusangu P , Jin L , Xiao Y , Pathoulas CL , Staub J , et al . PG545 sensitizes ovarian cancer cells to PARP inhibitors through modulation of RAD51-DEK interaction . Oncogene . 2023 ; 42 ( 37 ): 2725 - 36 .
Ostapoff KT , Awasthi N , Cenik BK , Hinz S , Dredge K , Schwarz RE , et al . PG545, an angiogenesis and heparanase inhibitor, reduces primary tumor growth and metastasis in experimental pancreatic cancer . Mol Cancer Ther . 2013 ; 12 ( 7 ): 1190 - 201 .
Ling J , Lundkvist Å , Guerrini M , Ferro V , Li JP , Li J . A heparan sulfate mimetic RAFT copolymer inhibits SARS-CoV-2 infection and ameliorates viral-induced inflammation . Adv Sci (Weinh) . 2025 ; 12 ( 6 ): e2411737 .
Masola V , Granata S , Bellin G , Gambaro G , Onisto M , Rugiu C , et al . Specific heparanase inhibition reverses glucose-induced mesothelial-to-mesenchymal transition . Nephrol Dial Transplant . 2017 ; 32 ( 7 ): 1145 - 54 .
Aisa-Alvarez A , Soto ME , Guarner-Lans V , Camarena-Alejo G , Franco-Granillo J , Martínez-Rodríguez EA , et al . Usefulness of antioxidants as adjuvant therapy for septic shock: a randomized clinical trial . Medicina (Kaunas) . 2020 ; 56 ( 11 ): 619 .
De Backer WA , Amsel B , Jorens PG , Bossaert L , Hiemstra PS , van Noort P , et al . N-acetylcysteine pretreatment of cardiac surgery patients influences plasma neutrophil elastase and neutrophil influx in bronchoalveolar lavage fluid . Intensive Care Med . 1996 ; 22 ( 9 ): 900 - 8 .
Taher A , Lashgari M , Sedighi L , Rahimi-Bashar F , Poorolajal J , Mehrpooya M . A pilot study on intravenous N-acetylcysteine treatment in patients with mild-to-moderate COVID19-associated acute respiratory distress syndrome . Pharmacol Rep . 2021 ; 73 ( 6 ): 1650 - 9 .
Peng N , Geng Y , Ouyang J , Liu S , Yuan F , Wan Y , et al . Endothelial glycocalyx injury is involved in heatstroke-associated coagulopathy and protected by N-acetylcysteine . Front Immunol . 2023 ; 14 : 1159195 .
Alvarez IA , Lee M , Eshaq RS , Leskova W , Harris NR . High glucose induces oxidative stress that alters glycocalyx proteoglycan levels in primary rat retinal microvascular endothelial cells and in isolated ophthalmic arteries . Pathophysiology . 2024 ; 31 ( 1 ): 89 - 99 .
Aisa-Álvarez A , Pérez-Torres I , Guarner-Lans V , Manzano-Pech L , Cruz-Soto R , Márquez-Velasco R , et al . Randomized clinical trial of antioxidant therapy patients with septic shock and organ dysfunction in the ICU: SOFA score reduction by improvement of the enzymatic and non-enzymatic antioxidant system . Cells . 2023 ; 12 ( 9 ): 1330 .
Spapen HD , Diltoer MW , Nguyen DN , Hendrickx I , Huyghens LP . Effects of N-acetylcysteine on microalbuminuria and organ failure in acute severe sepsis: results of a pilot study . Chest . 2005 ; 127 ( 4 ): 1413 - 9 .
Tsuji F , Oki K , Okahara A , Suhara H , Yamanouchi T , Sasano M , et al . Differential effects between marimastat, a TNF-alpha converting enzyme inhibitor, and anti-TNF-alpha antibody on murine models for sepsis and arthritis . Cytokine . 2002 ; 17 ( 6 ): 294 - 300 .
Jr Fisher CJ , Agosti JM , Opal SM , Lowry SF , Balk RA , Sadoff JC , et al . Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. The soluble TNF receptor sepsis study group . N Engl J Med . 1996 ; 334 ( 26 ): 1697 - 702 .
Gallagher J , Fisher C , Sherman B , Munger M , Meyers B , Ellison T , et al . A multicenter, open-label, prospective, randomized, dose-ranging pharmacokinetic study of the anti-TNF-alpha antibody afelimomab in patients with sepsis syndrome . Intensive Care Med . 2001 ; 27 ( 7 ): 1169 - 78 .
Abraham E , Wunderink R , Silverman H , Perl TM , Nasraway S , Levy H , et al . Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group . JAMA . 1995 ; 273 ( 12 ): 934 - 41 .
Hogwood J , Gray E , Mulloy B . Heparin, heparan sulphate and sepsis: potential new options for treatment . Pharmaceuticals (Basel) . 2023 ; 16 ( 2 ): 271 .
Li JC , Wang LJ , Feng F , Chen TT , Shi WG , Liu LP . Role of heparanase in sepsis-related acute kidney injury (review) . Exp Ther Med . 2023 ; 26 ( 2 ): 379 .
van den Brink DP , Kleinveld DJB , Bongers A , Vos J , Roelofs J , Weber NC , et al . The effects of heparan sulfate infusion on endothelial and organ injury in a rat pneumosepsis model . J Clin Med . 2023 ; 12 ( 20 ): 6438 .
Chiba T , Yamada M , Hashimoto Y , Sato M , Sasabe J , Kita Y , et al . Development of a femtomolar-acting humanin derivative named colivelin by attaching activity-dependent neurotrophic factor to its N terminus: characterization of colivelin-mediated neuroprotection against alzheimer's disease-relevant insults in vitro and in vivo . J Neurosci . 2005 ; 25 ( 44 ): 10252 - 61 .
Urban C , Hayes HV , Piraino G , Wolfe V , Lahni P , O’Connor M , et al . Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice . Front Immunol . 2022 ; 13 : 984298 .
Wang Z , Kawabori M , Houkin K . FTY720 (Fingolimod) ameliorates brain injury through multiple mechanisms and is a strong candidate for stroke treatment . Curr Med Chem . 2020 ; 27 ( 18 ): 2979 - 93 .
Sorenson CM , Farnoodian M , Wang S , Song YS , Darjatmoko SR , Polans AS , et al . Fingolimod (FTY720), a sphinogosine-1-phosphate receptor agonist, mitigates choroidal endothelial proangiogenic properties and choroidal neovascularization . Cells . 2022 ; 11 ( 6 ): 969 .
Hemdan NY , Weigel C , Reimann CM , Gräler MH . Modulating sphingosine 1-phosphate signaling with DOP or FTY720 alleviates vascular and immune defects in mouse sepsis . Eur J Immunol . 2016 ; 46 ( 12 ): 2767 - 77 .
Natarajan V , Dudek SM , Jacobson JR , Moreno-Vinasco L , Huang LS , Abassi T , et al . Sphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury . Am J Respir Cell Mol Biol . 2013 ; 49 ( 1 ): 6 - 17 .
Wang L , Letsiou E , Wang H , Belvitch P , Meliton LN , Brown ME , et al . MRSA-induced endothelial permeability and acute lung injury are attenuated by FTY720 S-phosphonate . Am J Physiol Lung Cell Mol Physiol . 2022 ; 322 ( 1 ): L149 - 61 .
Chen C , Zong S , Wang Z , Yang R , Guo Y , Wang Y , et al . FTY720 attenuates LPS-induced inflammatory bone loss by inhibiting osteoclastogenesis via the NF-κB and HDAC4/ATF pathways . J Immunol Res . 2023 ; 2023 : 8571649 .
Chung HL , Ye Q , Park YJ , Zuo Z , Mok JW , Kanca O , et al . Very-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation . Cell Metab . 2023 ; 35 ( 5 ): 855 - 74.e5 .
Liu J , Zhang L , Liu L , Wu T , Wang L , Han Q . The potential capacities of FTY720: novel therapeutic functions, targets, and mechanisms against diseases . Eur J Med Chem . 2025 ; 290 : 117508 .
Geraghty JR , Rangasamy SB , Xu H , Loeb JA , Testai FD . Fingolimod reduces blood-brain barrier damage, inflammation, and neuronal death in experimental subarachnoid hemorrhage . Exp Neurol . 2026 ; 396 : 115554 .
Camp SM , Chiang ET , Sun C , Usatyuk PV , Bittman R , Natarajan V , et al . “Pulmonary endothelial cell barrier enhancement by novel FTY720 analogs: methoxy-FTY720, fluoro-FTY720, and β-glucuronide-FTY720” . Chem Phys Lipids . 2016 ; 194 : 85 - 93 .
Tasat DR , Yakisich JS . Rationale for the use of sphingosine analogues in COVID-19 patients . Clin Med (Lond) . 2021 ; 21 ( 1 ): e84 - 7 .
Abedi F , Zarei B , Elyasi S . Albumin: a comprehensive review and practical guideline for clinical use . Eur J Clin Pharmacol . 2024 ; 80 ( 8 ): 1151 - 69 .
Caironi P , Tognoni G , Masson S , Fumagalli R , Pesenti A , Romero M , et al . Albumin replacement in patients with severe sepsis or septic shock . N Engl J Med . 2014 ; 370 ( 15 ): 1412 - 21 .
Siddall EC , Radhakrishnan J . The pathophysiology of edema formation in the nephrotic syndrome . Kidney Int . 2012 ; 82 ( 6 ): 635 - 42 .
Bruegger D , Schwartz L , Chappell D , Jacob M , Rehm M , Vogeser M , et al . Release of atrial natriuretic peptide precedes shedding of the endothelial glycocalyx equally in patients undergoing on-and off-pump coronary artery bypass surgery . Basic Res Cardiol . 2011 ; 106 ( 6 ): 1111 - 21 .
Chappell D , Bruegger D , Potzel J , Jacob M , Brettner F , Vogeser M , et al . Hypervolemia increases release of atrial natriuretic peptide and shedding of the endothelial glycocalyx . Crit Care . 2014 ; 18 ( 5 ): 538 .
Gimblet CJ , Donato AJ , Jalal DI , Pierce GL . Sex differences in endothelial glycocalyx thickness and the response to glycocalyx-targeted therapy among older adults . Physiol Rep . 2025 ; 13 ( 12 ): e70428 .
Pavlidis G , Kountouri A , Katogiannis K , Thymis J , Nikolaou PE , Chania C , et al . Effects of 4-month treatment with glycocalyx dietary supplement on endothelial glycocalyx and vascular function after COVID-19 infection . Eur J Clin Invest . 2025 ; 55 ( 7 ): e70058 .
Smart L , Hughes D . The effects of resuscitative fluid therapy on the endothelial surface layer . Front Vet Sci . 2021 ; 8 : 661660 .
Zampieri FG , Bagshaw SM , Semler MW . Fluid therapy for critically ill adults with sepsis: a review . JAMA . 2023 ; 329 ( 22 ): 1967 - 80 .
Haase N , Perner A , Hennings LI , Siegemund M , Lauridsen B , Wetterslev M , et al . Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis . BMJ . 2013 ; 346 : f839 .
Perner A , Haase N , Guttormsen AB , Tenhunen J , Klemenzson G , Åneman A , et al . Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis . N Engl J Med . 2012 ; 367 ( 2 ): 124 - 34 .
Garnacho-Montero J , Fernández-Mondéjar E , Ferrer-Roca R , Herrera-Gutiérrez ME , Lorente JA , Ruiz-Santana S , et al . Crystalloids and colloids in critical patient resuscitation . Med Intensiva . 2015 ; 39 ( 5 ): 303 - 15 .
Perner A , Junttila E , Haney M , Hreinsson K , Kvåle R , Vandvik PO , et al . Scandinavian clinical practice guideline on choice of fluid in resuscitation of critically ill patients with acute circulatory failure . Acta Anaesthesiol Scand . 2015 ; 59 ( 3 ): 274 - 85 .
Hölschermann H , Schuster D , Parviz B , Haberbosch W , Tillmanns H , Muth H . Statins prevent NF-kappaB transactivation independently of the IKK-pathway in human endothelial cells . Atherosclerosis . 2006 ; 185 ( 2 ): 240 - 5 .
Lyu F , Long W , Ma L . Atherosclerosis-induced arterial erectile dysfunction: pathogenesis, diagnosis, and therapeutic strategies . Transl Androl Urol . 2025 ; 14 ( 9 ): 2732 - 53 .
Hasan IH , Shaheen SY , Alhusaini AM , Mahmoud AM . Simvastatin mitigates diabetic nephropathy by upregulating farnesoid X receptor and Nrf2/HO-1 signaling and attenuating oxidative stress and inflammation in rats . Life Sci . 2024 ; 340 : 122445 .
Kapustová A , Macášek P , Baďurová B , Melegová J , Rimpelová S , Kubovčiak J , et al . In vitro investigation of statin effects on genes associated with severe COVID-19 in cancerous and non-cancerous cells . Biomedicines . 2025 ; 13 ( 7 ): 1714 .
Mylonas KS , Peroulis M , Kapetanakis EI , Kapelouzou A . Myocardial expression of pluripotency, longevity, and proinflammatory genes in the context of hypercholesterolemia and statin treatment . J Clin Med . 2024 ; 13 ( 7 ): 1994 .
Laufs U , Fata VL , Liao JK . Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase . J Biol Chem . 1997 ; 272 ( 50 ): 31725 - 9 .
Zheng X , Zhang W , Wang Z . Simvastatin preparations promote PDGF-BB secretion to repair LPS-induced endothelial injury through the PDGFRβ/PI3K/Akt/IQGAP1 signalling pathway . J Cell Mol Med . 2019 ; 23 ( 12 ): 8314 - 27 .
Liao Y , Chen X , Miller-Little W , Wang H , Willard B , Bulek K , et al . The Ras GTPase-activating-like protein IQGAP1 bridges Gasdermin D to the ESCRT system to promote IL-1β release via exosomes . EMBO J. EMB J . 2023 ; 42 ( 1 ): e110780 .
Zheng X , Hu X , Zhang W . The phenotype of vascular smooth muscle cells co-cultured with endothelial cells is modulated by PDGFR-β/IQGAP1 signaling in LPS-induced intravascular injury . Int J Med Sci . 2019 ; 16 ( 8 ): 1149 - 56 .
Olivella-Gomez J , Sanabria-Herrera N , Garcia-Gallo E , Duque S , Luna D , Oliveros H , et al . Impact of statins on short and long term mortality in severe community acquired pneumonia in the intensive care unit . Sci Rep . 2025 ; 15 ( 1 ): 41212 .
Philippou C , Tsioutis C , Tsiappari M , Spernovasilis N , Papadopoulos D , Agouridis AP . The impact of statin use on sepsis mortality: a systematic review and meta-analysis . Medicina (Kaunas) . 2025 ; 61 ( 9 ): 1563 .
Yu L , Zou S , Zheng S , Deng J , Zhou Q , Jin J . Pre-ICU statin therapy reduces 28-day mortality in sepsis-associated brain dysfunction: a propensity-matched analysis of potential neuroprotective mechanisms . Front Pharmacol . 2025 ; 16 : 1586372 .
Kruger P , Fitzsimmons K , Cook D , Jones M , Nimmo G . Statin therapy is associated with fewer deaths in patients with bacteraemia . Intensive Care Med . 2006 ; 32 ( 1 ): 75 - 9 .
Cinezan C , Magureanu DC , Hiceag ML , Rus CB , Ilias IT , Bogdan ID , et al . Shared risk factors and molecular mechanisms between aortic stenosis and atherosclerosis: a rationale for therapeutic repositioning . Int J Mol Sci . 2025 ; 26 ( 17 ): 8163 .
Seidah NG , Abifadel M , Prost S , Boileau C , Prat A . The proprotein convertases in hypercholesterolemia and cardiovascular diseases: emphasis on proprotein convertase Subtilisin/Kexin 9 . Pharmacol Rev . 2017 ; 69 ( 1 ): 33 - 52 .
Huang L , Li Y , Cheng Z , Lv Z , Luo S , Xia Y . PCSK9 promotes endothelial dysfunction during sepsis via the TLR4/MyD88/NF-κB and NLRP3 pathways . Inflammation . 2023 ; 46 ( 1 ): 115 - 28 .
Dwivedi DJ , Grin PM , Khan M , Prat A , Zhou J , Fox-Robichaud AE , et al . Differential expression of PCSK9 modulates infection, inflammation, and coagulation in a murine model of sepsis . Shock . 2016 ; 46 ( 6 ): 672 - 80 .
Navarese EP , Podhajski P , Gurbel PA , Grzelakowska K , Ruscio E , Tantry U , et al . PCSK9 inhibition during the inflammatory stage of SARS-CoV-2 infection . J Am Coll Cardiol . 2023 ; 81 ( 3 ): 224 - 34 .
Chislock EM , Pendergast AM . Abl family kinases regulate endothelial barrier function in vitro and in mice . PLoS One . 2013 ; 8 ( 12 ): e85231 .
Li R , Liu Y , Liu Q , Guo Z , Wang B , Huang S , et al . CMTM3 promotes colitis-associated carcinogenesis via CLTC stabilization and modulation of VE-cadherin . Cell Mol Gastroenterol Hepatol . 2025 ; 19 ( 8 ): 101528 .
Xin Y , Cereda M , Yehya N , Humayun S , Delvecchio P , Thompson JM , et al . Imatinib alleviates lung injury and prolongs survival in ventilated rats . Am J Physiol Lung Cell Mol Physiol . 2022 ; 322 ( 6 ): L866 - L72 .
Aman J , Duijvelaar E , Botros L , Kianzad A , Schippers JR , Smeele PJ , et al . Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial . Lancet Respir Med . 2021 ; 9 ( 9 ): 957 - 68 .
Brell B , Temmesfeld-Wollbrück B , Altzschner I , Frisch E , Schmeck B , Hocke AC , et al . Adrenomedullin reduces staphylococcus aureus alpha-toxin-induced rat ileum microcirculatory damage . Crit Care Med . 2005 ; 33 ( 4 ): 819 - 26 .
Marino R , Struck J , Maisel AS , Magrini L , Bergmann A , Di Somma S . Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis . Crit Care . 2014 ; 18 ( 1 ): R34 .
Temmesfeld-Wollbrück B , Brell B , Dávid I , Dorenberg M , Adolphs J , Schmeck B , et al . Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock . Intensive Care Med . 2007 ; 33 ( 4 ): 703 - 10 .
Geven C , Peters E , Schroedter M , Struck J , Bergmann A , McCook O , et al . Effects of the humanized anti-adrenomedullin antibody adrecizumab (HAM8101) on vascular barrier function and survival in rodent models of systemic inflammation and sepsis . Shock . 2018 ; 50 ( 6 ): 648 - 54 .
Laterre PF , Pickkers P , Marx G , Wittebole X , Meziani F , Dugernier T , et al . Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial . Intensive Care Med . 2021 ; 47 ( 11 ): 1284 - 94 .
Rehberg S , Yamamoto Y , Sousse L , Bartha E , Jonkam C , Hasselbach AK , et al . Selective V(1a) agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis . Am J Physiol Heart Circ Physiol . 2012 ; 303 ( 10 ): H1245 - 54 .
Laterre PF , Berry SM , Blemings A , Carlsen JE , François B , Graves T , et al . Effect of selepressin vs placebo on ventilator- and vasopressor-free days in patients with septic shock: the sepsis-act randomized clinical trial . JAMA . 2019 ; 322 ( 15 ): 1476 - 85 .
Ranieri VM , Thompson BT , Barie PS , Dhainaut JF , Douglas IS , Finfer S , et al . Drotrecogin alfa (activated) in adults with septic shock . N Engl J Med . 2012 ; 366 ( 22 ): 2055 - 64 .
Bernard GR , Ely EW , Wright TJ , Fraiz J , Jr Stasek JE, ., Russell JA , et al . Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis . Crit Care Med . 2001 ; 29 ( 11 ): 2051 - 9 .
Liu KD , Levitt J , Zhuo H , Kallet RH , Brady S , Steingrub J , et al . Randomized clinical trial of activated protein C for the treatment of acute lung injury . Am J Respir Crit Care Med . 2008 ; 178 ( 6 ): 618 - 23 .
Lipowsky HH , Lescanic A . The effect of doxycycline on shedding of the glycocalyx due to reactive oxygen species . Microvasc Res . 2013 ; 90 : 80 - 5 .
de Oliveira J , Miranda CH . Doxycycline protects against sepsis-induced endothelial glycocalyx shedding . Sci Rep . 2024 ; 14 ( 1 ): 10477 .
Cui N , Wang H , Long Y , Su L , Liu D . Dexamethasone suppressed LPS-induced matrix metalloproteinase and its effect on endothelial glycocalyx shedding . Mediators Inflamm . 2015 ; 2015 : 912726 .
Garrido-Mesa J , Adams K , Galvez J , Garrido-Mesa N . Repurposing tetracyclines for acute respiratory distress syndrome (ARDS) and severe COVID-19: a critical discussion of recent publications . Expert Opin Investig Drugs . 2022 ; 31 ( 5 ): 475 - 82 .
Guan XG , Zhou SX , Zhang AR , Lu QB , Zhou ZW , Chen JJ , et al . Clinical outcomes of doxycycline, azithromycin and chloramphenicol for the treatment of patients with severe scrub typhus . Int J Antimicrob Agents . 2022 ; 60 ( 4 ): 106647 .
Zhou G , Kamenos G , Pendem S , Wilson JX , Wu F . Ascorbate protects against vascular leakage in cecal ligation and puncture-induced septic peritonitis . Am J Physiol Regul Integr Comp Physiol . 2012 ; 302 ( 4 ): R409 - 16 .
Sevransky JE , Rothman RE , Hager DN , Bernard GR , Brown SM , Buchman TG , et al . Effect of vitamin C, thiamine, and hydrocortisone on ventilator- and vasopressor-free days in patients with sepsis: the victas randomized clinical trial . JAMA . 2021 ; 325 ( 8 ): 742 - 50 .
Gonzalez-Cabrera PJ , Brown S , Studer SM , Rosen H . S1P signaling: new therapies and opportunities . F1000Prime Rep . 2014 ; 6 : 109 .
Chaudhry BZ , Cohen JA , Conway DS . Sphingosine 1-phosphate receptor modulators for the treatment of multiple sclerosis . Neurotherapeutics . 2017 ; 14 ( 4 ): 859 - 73 .
Van Nynatten LR , Bokhary D , Wong MYS , Wang J , Fero H , McChesney C , et al . Predictive enrichment using biomarkers in studies of critically-ill patients with sepsis: a systematic review . Crit Care . 2025 ; 29 ( 1 ): 504 .
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