Endotoxin increases both protein and fluid microvascular permeability in cat skeletal muscle

Holbeck, Staffan; Grände, Per‐Olof

doi:10.1097/01.ccm.0000048620.88344.70

Cited by 19 publications

(13 citation statements)

References 34 publications

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“…This disruption is mediated by activation of PP2A [12]. Because endothelial barrier dysfunction contributes to morbidity in sepsis [2–5], there is an urgent need to identify the molecular mechanisms of this pathology and potential treatments. The present study discovered that intracellular ascorbate protects endothelial barrier function during septic insult and that this protection is associated with inhibition of oxidant production, PP2A activation, and occludin dephosphorylation and redistribution.…”

Section: Discussionmentioning

confidence: 99%

“…Endothelial barrier dysfunction occurs in systemic capillaries and venules of patients with sepsis. This dysfunction increases the microvessels’ permeability to macromolecules, such as albumin, and frequently leads to plasma extravasation, edema, organ failure and septic shock [2–5]. Since no effective pharmacological therapy is available to prevent the increase in permeability, there is a pressing need to identify the molecular mechanisms of this pathology and potential treatments.…”

Section: Introductionmentioning

confidence: 99%

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Ascorbate protects endothelial barrier function during septic insult: Role of protein phosphatase type 2A

Han

Pendem

Teh

et al. 2010

Free Radical Biology and Medicine

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Endothelial barrier dysfunction contributes to morbidity in sepsis. We tested the hypothesis that raising the intracellular ascorbate concentration protects the endothelial barrier from septic insult by inhibiting protein phosphatase type 2A. Monolayer cultures of microvascular endothelial cells were incubated with ascorbate, dehydroascorbic acid (DHAA), NADPH oxidase inhibitors apocynin and diphenyliodonium, or PP2A inhibitor okadaic acid, and then were exposed to septic insult (lipopolysaccharide and interferon-γ). Under standard culture conditions that depleted intracellular ascorbate, septic insult stimulated oxidant production and PP2A activity, dephosphorylated phosphoserine and phosphothreonine residues in the tight junction-associated protein occludin, decreased the abundance of occludin at cell borders, and increased monolayer permeability to albumin. NADPH oxidase inhibitors prevented PP2A activation and monolayer leak, showing that these changes required reactive oxygen species. Okadaic acid, at a concentration that inhibited PP2A activity and monolayer leak, prevented occludin dephosphorylation and redistribution, implicating PP2A in the responses of occludin to septic insult. Incubation with ascorbate or DHAA raised intracellular ascorbate concentrations and mitigated the effects of septic insult. In conclusion, ascorbate acts within microvascular endothelial cells to inhibit septic stimulation of oxidant production by NADPH oxidase and thereby prevents PP2A activation, PP2A-dependent dephosphorylation and redistribution of occludin, and disruption of the endothelial barrier.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ascorbate protects endothelial barrier function during septic insult: Role of protein phosphatase type 2A

Han

Pendem

Teh

et al. 2010

Free Radical Biology and Medicine

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“…Endotoxin is known to stimulate the immune system in a dose-dependent manner [25]. Indeed, a marked increase in permeability in vivo has previously been shown in, for example, cats after intravenous administration of 1 mg/kg endotoxin [10]. On one occasion, an autointoxication with 1 mg of Salmonella endotoxin resulted in profound vasodilatory shock and a 15 l cumulative fluid balance over 72 hours in a laboratory worker [34].…”

Section: Discussionmentioning

confidence: 99%

Untitled

et al. 2005

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Introduction Septic shock is associated with increased microvascular permeability. As a model for study of the pathophysiology of sepsis, endotoxin administration to humans has facilitated research into inflammation, coagulation and cardiovascular effects. The present study was undertaken to determine whether endotoxin administration to human volunteers can be used as a model to study the sepsisassociated increase in microvascular permeability.Methods In an open intervention study conducted in a university medical centre, 16 healthy volunteers were evaluated in the research unit of the intensive care unit. Eight were administered endotoxin intravenously (2 ng/kg Escherichia coli O113) and eight served as control individuals. Microvascular permeability was assessed before and 5 hours after the administration of endotoxin (n = 8) or placebo (n = 8) by three different methods: transcapillary escape rate of I 125 -albumin; venous occlusion straingauge plethysmography to determine the filtration capacity; and bioelectrical impedance analysis to determine the extracellular and total body water. Results Administration of endotoxin resulted in the expected increases in proinflammatory cytokines, temperature, flu-like symptoms and cardiovascular changes. All changes were significantly different from those in the control group. In the endotoxin group all microvascular permeability parameters remained unchanged from baseline: transcapillary escape rate of I 125 -albumin changed from 7.2 ± 0.6 to 7.7 ± 0.9%/hour; filtration capacity changed from 5.0 ± 0.3 to 4.2 ± 0.4 ml/min per 100 ml mmHg × 10 -3 ; and extracellular/total body water changed from 0.42 ± 0.01 to 0.40 ± 0.01 l/l (all differences not significant). Conclusion Although experimental human endotoxaemia is frequently used as a model to study sepsisassociated pathophysiology, an endotoxin-induced increase in microvascular permeability in vivo could not be detected using three different methods. Endotoxin administration to human volunteers is not suitable as a model in which to study changes in microvascular permeability.

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“…These models have revealed that the microvasculature is exquisitely sensitive to the deleterious effects of sepsis [6] , [7] . The microvascular responses to sepsis or endotoxemia include impaired endothelium‐dependent vasodilatation [8] , oxidative stress [48] , increased endothelial cell adhesion molecule expression [6] , [7] , increased vascular permeability [23] , and the adhesion of leukocytes and platelets in postcapillary venules [12] , [22] . While one or more of these responses to sepsis have been demonstrated in the microvasculature of the mesentery, gut wall, and lung [12] , [22] , [30] , it remains unclear whether the cerebral microvasculature exhibits similar phenotypic changes during sepsis.…”

Section: Introductionmentioning

confidence: 99%

Obesity Exacerbates Sepsis‐Induced Inflammation and Microvascular Dysfunction in Mouse Brain

Russell²,

et al. 2005

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Endotoxin increases both protein and fluid microvascular permeability in cat skeletal muscle

Abstract: Endotoxin causes a significant increase in both protein and fluid microvascular wall permeability. These effects may explain the marked leakage of plasma to the interstitium that is often seen in critically ill patients with sepsis and systemic inflammatory response syndrome.

Cited by 19 publications

References 34 publications

Ascorbate protects endothelial barrier function during septic insult: Role of protein phosphatase type 2A

Ascorbate protects endothelial barrier function during septic insult: Role of protein phosphatase type 2A

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Obesity Exacerbates Sepsis‐Induced Inflammation and Microvascular Dysfunction in Mouse Brain

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