Sepsis and Endothelial Permeability

Lee, Warren L.; Slutsky, Arthur S.

doi:10.1056/nejmcibr1007320

Cited by 428 publications

(382 citation statements)

References 5 publications

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“…Previous studies suggested that the endothelium plays a critical role in the pathogenesis of the vascular leak, ultimately leading to shock and thereby contributing to the unacceptably high mortality among patients with sepsis [10] [2]. A better understanding of the function of the endothelium in sepsis, and of the influence of diabetes and other comorbidities on endothelium activation may one day lead to new life-saving therapies [2].…”

Section: Discussionmentioning

confidence: 99%

“…Despite significant advances in medical diagnosis and treatment, the overall survival in sepsis has not improved substantially over time [2,3]. This can partly be explained by the fact that sepsis is not a disease, but a syndrome comprising heterogeneous pathophysiological entities.…”

Section: Introductionmentioning

confidence: 99%

“…Previous work has suggested that the endothelium is critical to the vascular leak and the subsequent shock state that contributes to mortality among patients with sepsis [2,10]. In addition, the endothelium participates in the inflammatory response during sepsis through signalling molecules, such as E-selectin, which adheres to the circulating white blood cells to facilitate cell rolling, and soluble vascular cell adhesion molecule 1 (VCAM-1) and soluble intercellular adhesion molecule 1 (ICAM-1), which solidify cellular bonds for transmigration [11].…”

Section: Introductionmentioning

confidence: 99%

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Influence of diabetes on endothelial cell response during sepsis

et al. 2011

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Aims/hypothesis Several endothelial pathways of cell adhesion, coagulation and vascular endothelial growth factor (VEGF) signalling are activated during sepsis. The objective of this analysis was to investigate the influence of diabetes on biomarkers of endothelial cell activation in sepsis. Methods This was a prospective observational cohort study of a convenience sample of adult patients (age ≥18 years) for whom infection was clinically suspected and who presented to an urban tertiary care emergency department between Results A total of 207 patients (34% with sepsis, 32% with severe sepsis and 34% with septic shock) were studied, including 63 (30%) with diabetes. Compared with patients without diabetes, patients with diabetes had significantly increased E-selectin and sFLT-1 levels overall; this was most pronounced during septic shock in the stratified analysis. Multivariate models including age, sex, sepsis severity and other variables as potential covariates confirmed the association of diabetes with elevated circulating plasma levels of E-selectin (standardised β 0.24, p<0.001) and sFLT-1 (standardised β 0.19, p<0.01), but there was no significant association with VCAM-1, ICAM-1 or PAI-1. Conclusions/interpretation During septic shock, patients with diabetes had higher levels of circulating biomarkers of endothelial cell adhesion (E-selectin) and VEGF signalling (sFLT-1). Future studies should address whether enhanced activation of the endothelium places patients with diabetes at increased risk for the development of sepsis and worsening morbidity and mortality.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of diabetes on endothelial cell response during sepsis

et al. 2011

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“…The progression from infection to organ failure is precipitated by excessive accumulation of interstitial fluid (edema) and increased heterogeneity (maldistribution) of capillary blood flow, both of which lengthen the diffusion distance for oxygen and allow tissues to become hypoxic (23,34). The edema and blood flow maldistribution are consequences of capillary leakage and plugging, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Also contributing to the risk of shock in these patients is endothelial barrier dysfunction that increases the permeability of the capillary wall to macromolecules and thereby accelerates plasma protein extravasation (i.e., capillary leakage) and loss of circulating blood volume (34).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Wilson

2013

Antioxidants & Redox Signaling

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Significance: Evidence is emerging that parenteral administration of high-dose vitamin C may warrant development as an adjuvant therapy for patients with sepsis. Recent Advances: Sepsis increases risk of death and disability, but its treatment consists only of supportive therapies because no specific therapy is available. The characteristics of severe sepsis include ascorbate (reduced vitamin C) depletion, excessive protein nitration in microvascular endothelial cells, and microvascular dysfunction composed of refractive vasodilation, endothelial barrier dysfunction, and disseminated intravascular coagulation. Parenteral administration of ascorbate prevents or even reverses these pathological changes and thereby decreases hypotension, edema, multiorgan failure, and death in animal models of sepsis. Critical Issues: Dehydroascorbic acid appears to be as effective as ascorbate for protection against microvascular dysfunction, organ failure, and death when injected in sepsis models, but information about pharmacodynamics and safety in human subjects is only available for ascorbate. Although the plasma ascorbate concentration in critically ill and septic patients is normalized by repletion protocols that use high doses of parenteral ascorbate, and such doses are tolerated well by most healthy subjects, whether such large amounts of the vitamin trigger adverse effects in patients is uncertain. Future Directions: Further study of sepsis models may determine if high concentrations of ascorbate in interstitial fluid have pro-oxidant and bacteriostatic actions that also modify disease progression. However, the ascorbate depletion observed in septic patients receiving standard care and the therapeutic mechanisms established in models are sufficient evidence to support clinical trials of parenteral ascorbate as an adjuvant therapy for sepsis.

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Overexpression of interleukin‐10 in engineered macrophages protects endothelial cells against LPS‐induced injury in vitro

Weng

Nie

et al. 2022

FEBS Open Bio

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Endothelial dysfunction is a primary pathophysiological change in sepsis. Macrophages are known to interact with vascular endothelial cells during the development of sepsis. Recently, drug delivery based on engineered macrophages was reported as an alternative approach for the management of diseases. Interleukin‐10 (IL10) is a well‐known anti‐inflammatory cytokine, which reduces inflammation and inhibits dysfunction of endothelial cells caused by sepsis. It is currently poorly understood whether genetically modified macrophages with overexpression of IL10 are able to restore endothelial integrity and function at the cellular level. In this study, we used lentiviral vectors to construct RAW264.7 macrophages engineered to overexpress IL10 (IL10‐eM) and investigated the effects of the IL10‐eM supernatant on LPS‐induced endothelial dysfunction using a noncontact coculture system. We found that cotreatment with IL10‐eM supernatant significantly attenuates the effects of LPS‐induced dysfunction of endothelial cells, including endothelial inflammatory response, endothelial permeability, and apoptosis. In addition, we discovered that LPS‐induced downregulation of VE‐cadherin and high production of reactive oxygen species were significantly attenuated upon IL10‐eM exposure. Furthermore, upregulation of IL6, TNFα, and Bax was decreased after treatment of cells with IL10‐eM supernatant. These results demonstrated that supernatant from engineered macrophages genetically modified with IL10 can effectively protect endothelial cells against LPS‐induced dysfunction in vitro, suggesting that exosomes from such engineered macrophages may have therapeutic effects against sepsis.

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Sepsis and Endothelial Permeability

Cited by 428 publications

References 5 publications

Influence of diabetes on endothelial cell response during sepsis

Influence of diabetes on endothelial cell response during sepsis

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Overexpression of interleukin‐10 in engineered macrophages protects endothelial cells against LPS‐induced injury in vitro

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