Endothelial Cell Inflammatory Responses in Sepsis

In sepsis, the vascular endothelium becomes both target and amplifier of the systemic inflammatory response. Endothelial cells detect pathogen-associated and damage-associated molecular patterns through surface receptors, triggering intracellular signalling cascades that culminate in the activation of transcription factors such as NF-κB and the release of pro-inflammatory cytokines. Concurrent upregulation of adhesion molecules and chemokines promotes leukocyte adhesion and transmigration, while cytoskeletal reorganisation and intercellular junction disruption lead to increased vascular permeability. The resultant capillary leak, microthrombosis and impaired tissue perfusion are central to organ dysfunction. Late mediators such as high-mobility group box 1 (HMGB1) exacerbate endothelial injury, often through necroptotic cell death pathways. Recent advances have emphasised the dual role of endothelial cells as both initiators and perpetuators of inflammation in sepsis, revealing potential interventions that range from blockade of receptor-mediated signalling to reinforcement of barrier integrity. Biomarker discovery and targeted modulation of endothelial responses hold promise for reducing the high global burden of sepsis-related morbidity and mortality.

Research from Nature Portfolio

Investigation into circulating HMGB1 levels in patients and experimental models has clarified its role in endothelial dysfunction and necroptosis. Elevated plasma HMGB1 correlates with markers of programmed cell necrosis, receptor-interacting kinase 3 and mixed lineage kinase domain-like protein, and predicts disease severity and outcome, suggesting a feed-forward loop in vascular injury. In parallel, small-molecule alkaloids derived from traditional sources have been shown to inhibit thrombin generation and platelet aggregation, attenuating microthrombotic events that compound endothelial inflammation and barrier disruption in septic contexts.

Endothelial Cell Inflammatory Responses in Sepsis publication trend

The graph below shows the total number of articles in endothelial cell inflammatory responses in sepsis across all publications each year (not limited to Nature Index journals).

Technical terms

Endothelial cell: A specialised cell lining the interior surface of blood vessels that regulates vascular tone, permeability and immune cell trafficking.

Cytokine: A small secreted protein that mediates intercellular communication during immune and inflammatory responses.

High-mobility group box 1 (HMGB1): A nuclear protein released by stressed or dying cells that acts as a late pro-inflammatory mediator in sepsis.

Necroptosis: A regulated form of necrotic cell death driven by receptor-interacting kinases and associated with inflammatory cytokine release.

Vascular permeability: The property of blood vessels that allows fluids, solutes and cells to pass through the endothelium into surrounding tissue.

Toll-like receptor 4 (TLR4): A pattern-recognition receptor on endothelial and immune cells that recognises lipopolysaccharide and initiates innate inflammatory signalling.

References

1. Association of plasma level of high-mobility group box-1 with necroptosis and sepsis outcomes. Scientific Reports (2021).
2. Antithrombotic and antiplatelet activities of small-molecule alkaloids from Scolopendra subspinipes mutilans. Scientific Reports (2016).
3. Anti-Septic Functions of Cornuside against HMGB1-Mediated Severe Inflammatory Responses. International Journal of Molecular Sciences (2022).
4. Inhibitory Activities of Rare Ginsenoside Rg4 on Cecal Ligation and Puncture-Induced Sepsis. International Journal of Molecular Sciences (2022).
5. Moesin Is a Novel Biomarker of Endothelial Injury in Sepsis. Journal of Immunology Research (2021).