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

Han, Min; Pendem, Suresh; Teh, Suet Ling; Sukumaran, Dinesh K.; Wu, Feng; Wilson, John X.

doi:10.1016/j.freeradbiomed.2009.10.034

Cited by 62 publications

(62 citation statements)

References 55 publications

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“…Immunoblot analysis of freshly harvested endothelial cells of the septic skeletal muscles reveals dephosphorylation of serine and threonine in occludin (68), similar to the observation made in microvascular endothelial cell cultures exposed to LPS + IFNc (24). Moreover, the systemic inflammatory response of mice to CLP is associated with a very reproducible extravasation of fluorescent dextran (average molecular mass 70 kDa) in cremaster muscle and Evans blue-conjugated albumin in hindlimb skeletal muscles within 12 h, at which time survival is 100% (64,68) (Fig.…”

Section: Vitamin C Therapy For Sepsissupporting

confidence: 74%

“…The tyrosine nitration of PP2Ac increases the phosphatase activity of PP2A, which dephosphorylates serine and threonine residues in occludin (24,41). This dephosphorylation causes a redistribution of occludin away from tight junctions and consequently increases paracellular permeability to albumin (24,62,66) (Fig. 4).…”

Section: Extravasation Of Plasma Proteins and Fluidmentioning

confidence: 99%

“…This septic insult increases the expression of NADPH oxidase 1 (Nox1) and iNOS proteins, the nitration of other proteins by peroxynitrite (assessed as 3-nitrotyrosine immunoreactivity), and the paracellular permeability to albumin (24,62,66) (Fig. 4).…”

Section: Extravasation Of Plasma Proteins and Fluidmentioning

confidence: 99%

“…Tyrosine residues in the catalytic subunit of PP2A (PP2Ac) become nitrated in microvascular endothelial cells exposed to LPS + IFNc, because this insult increases NADPH oxidase synthesis of superoxide, iNOS synthesis of NO, and consequently the production of peroxynitrite from superoxide and NO (62,65). The tyrosine nitration of PP2Ac increases the phosphatase activity of PP2A, which dephosphorylates serine and threonine residues in occludin (24,41). This dephosphorylation causes a redistribution of occludin away from tight junctions and consequently increases paracellular permeability to albumin (24,62,66) (Fig.…”

Section: Extravasation Of Plasma Proteins and Fluidmentioning

confidence: 99%

“…This concentration is equal to the plasma ascorbate concentration achieved by an ascorbate infusion protocol that lessens edema formation in burn patients (57). For the ascorbate and DHAA treatments in cell cultures, the protection of the endothelial barrier is associated with increased intracellular ascorbate concentration and it depends on inhibition of both peroxynitrite formation and PP2A nitration/ activation (24). Administration of ascorbate prevents the induction by septic insult of NAPDH oxidase, and consequently blocks induction of iNOS, in microvascular endothelial cells (65).…”

Section: Vitamin C Therapy For Sepsismentioning

confidence: 99%

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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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Section: Vitamin C Therapy For Sepsissupporting

confidence: 74%

Section: Extravasation Of Plasma Proteins and Fluidmentioning

confidence: 99%

Section: Extravasation Of Plasma Proteins and Fluidmentioning

confidence: 99%

Section: Extravasation Of Plasma Proteins and Fluidmentioning

confidence: 99%

Section: Vitamin C Therapy For Sepsismentioning

confidence: 99%

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Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Wilson

2013

Antioxidants & Redox Signaling

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Claudins and Other Tight Junction Proteins

Günzel¹,

Fromm²

2012

Comprehensive Physiology

337

292

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Epithelial transport relies on the proper function and regulation of the tight junction (TJ), other-wise uncontrolled paracellular leakage of solutes and water would occur. They also act as a fence against mixing of membrane proteins of the apical and basolateral side. The proteins determining paracellular transport consist of four transmembrane regions, intracellular N and C terminals, one intracellular and two extracellular loops (ECLs). The ECLs interact laterally and with counterparts of the neighboring cell and by this achieve a general sealing function. Two TJ protein families can be distinguished, claudins, comprising 27 members in mammals, and TJ-associated MARVEL proteins (TAMP), comprising occludin, tricellulin, and MarvelD3. They are linked to a multitude of TJ-associated regulatory and scaffolding proteins. The major TJ proteins are classified according to the physiological role they play in enabling or preventing paracellular transport. Many TJ proteins have sealing functions (claudins 1, 3, 5, 11, 14, 19, and tricellulin). In contrast, a significant number of claudins form channels across TJs which feature selectivity for cations (claudins 2, 10b, and 15), anions (claudin-10a and -17), or are permeable to water (claudin-2). For several TJ proteins, function is yet unclear as their effects on epithelial barriers are inconsistent (claudins 4, 7, 8, 16, and occludin). TJs undergo physiological and pathophysiological regulation by altering protein composition or abundance. Major pathophysiological conditions which involve changes in TJ protein composition are (1) effects of pathogens binding to TJ proteins, (2) altered TJ protein composition during inflammation and infection, and (3) altered TJ protein expression in cancers.

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Antioxidants in Sepsis

Wilson

2014

Systems Biology of Free Radicals and Antioxidants

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

Cited by 62 publications

References 55 publications

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Claudins and Other Tight Junction Proteins

Antioxidants in Sepsis

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