On November 2, 2025, the research group led by Dr. Zeng Ling from Army Medical University systematically elucidated the molecular mechanisms, pathological processes, and latest clinical advances in sepsis-induced endothelial barrier dysfunction from the perspective of vascular endothelial cells. This work provides novel insights for precise intervention in sepsis and septic shock. The findings were published in Research under the title "Sepsis-Induced Endothelial Barrier Dysfunction: Mechanisms, Pathology, and Therapeutic Advances" (Research, 2025, Article ID: 0997, DOI: 10.34133/research.0997).
Background
Sepsis, a life-threatening systemic inflammatory response triggered by infection, has long challenged clinicians with its persistently high mortality (up to 40-50 % in septic shock). At the heart of this syndrome lies the collapse of the vascular endothelial barrier: when the endothelium “falls apart,” plasma leaks, coagulation derails, immune control is lost, and the cascade ends in multi-organ failure. Current therapeutic strategies primarily center on pathogen eradication and organ function support, yet lack a systematic, targeted intervention for endothelial barrier injury.
Research Progress
I. Core mechanisms of endothelial barrier failure in sepsis
First, circulating lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α) and other mediators released during sepsis activate endothelial heparanase, triggering the enzymatic shedding of the endothelial glycocalyx (EG). Loss of this luminal “coat” increases vascular permeability to macromolecules, exposes adhesion molecules such as E-selectin and ICAM-1, and promotes neutrophil adhesion. The ensuing burst of inflammation further damages the glycocalyx, breaching the endothelium’s “first line of defense.” Second, the intense inflammatory and oxidative milieu drives endothelial cells into multiple, simultaneous modes of programmed death-apoptosis, pyroptosis, ferroptosis, and excessive autophagy. The concurrent activation of these death pathways amplifies endothelial attrition and accelerates barrier collapse. Finally, neutrophil elastase and metalloproteinases (ADAM10/17) proteolytically cleave tight-junction and adherens-junction proteins. Accumulation of nitric oxide (NO) and up-regulation of vascular endothelial growth factor (VEGF) further derange vasomotor tone. Together these insults dismantle inter-endothelial junctions, widen paracellular gaps, and produce the clinical hallmark of sepsis-vascular leak.
II. Increased endothelial permeability and sepsis-associated coagulopathy
In sepsis, loss of endothelial anticoagulant and fibrinolytic activity unleashes platelet aggregation and systemic coagulation. Activated endothelial cells up-regulate tissue factor (TF) and externalize phosphatidylserine (PS), triggering the clotting cascade; plasminogen-activator inhibitor-1 (PAI-1) accumulates, suppressing fibrinolysis and promoting microthrombosis; and neutrophil extracellular traps (NETs) supply a pro-coagulant scaffold that activates factor XII, further fueling coagulation chaos.

III. Interaction of endothelial cells with other cells in the immunoinflammatory response
In sepsis, reciprocal activation between endothelial cells and leukocytes amplifies inflammation into a self-sustaining loop. Activated endothelium up-regulates VCAM-1 and ICAM-1, capturing neutrophils and monocytes via leukocyte integrins (LFA-1, VLA-4); the newly recruited cells release TNF-α, IL-1β, and other cytokines that keep the endothelium in an activated state, driving further secretion of chemokines such as CXCL8 and CCL2. Platelets join the circuit by forming P-selectin-mediated platelet-leukocyte aggregates with both endothelial cells and leukocytes, intensifying local inflammation and regional hypoperfusion. In later-stage sepsis, exhausted endothelial cells express PD-L1 and indoleamine 2,3-dioxygenase (IDO), imposing an immunosuppressive milieu that cripples leukocyte function and tips the host toward immune paralysis.
IV. Emerging therapeutic strategies that target the endothelial barrier
1. Glycocalyx protectors-repairing the “first line of defense”
Human serum albumin (HSA) binds to the glycocalyx, preserving oncotic pressure and scavenging free radicals; hydrocortisone and antithrombin suppress TNF-α driven glycocalyx shedding.
2. Barrier stabilizers-reducing vascular leak
Angiopoietin-1 (ANG1) activates Tie2 to tighten inter-endothelial junctions and decrease leakage. HDAC6 inhibitors (e.g., tubastatin A) curb lung endothelial cell death and dampen inflammation. Mesenchymal stromal cells (MSCs) release paracrine factors that up-regulate VE-cadherin and reinforce barrier integrity.
3. Anticoagulant approaches-correcting coagulopathy
Recombinant human soluble thrombomodulin (rhsTM) binds thrombin to generate activated protein C (APC), limiting coagulation amplification; phase III trials show reduced 28-day mortality in patients with sepsis-associated coagulopathy (SAC). Recombinant antithrombin-γ (rAT) neutralizes activated clotting factors to treat sepsis-induced disseminated intravascular coagulation (DIC). ADAMTS13 cleaves ultra-large von Willebrand factor (ULVWF) multimers, curbing microthrombus formation.
4. Complement inhibitors-interrupting the complement-inflammation-thrombosis axis
Anti-C5a monoclonal antibodies (e.g., vilobelimab) block C5a-C5aR1 interaction, suppressing neutrophil chemotaxis and endothelial activation. C3 inhibitors (e.g., Cp40) halt complement activation, protecting the endothelial barrier and decreasing microthrombi.

Future Perspectives
Although the endothelial cell is now recognized as the “central hub” of sepsis, therapies aimed at the endothelial barrier still face major hurdles. Future sepsis research will likely focus on how metabolic reprogramming of endothelial cells uses specific metabolites to modulate inflammation and barrier function, the direct impact of gut microbial translocation on endothelial phenotype, cell heterogeneity and intercellular crosstalk revealed by spatial transcriptomics, dynamic feedback loops between endothelial and immune cells, mechanisms governing endothelial repair and regeneration, and the temporal trajectory of endothelial phenotypic shifts-insights that will open new avenues for precision therapeutics and ultimately improve patient outcomes.

The complete study is accessible via DOI:10.34133/research.0997