Shiga toxin-1 Decreases Endothelial Cell Tissue Factor Pathway Inhibitor Not Co-localized with Tissue Factor on the Cell Membrane

Grabowski, Eríc F.; Liu, Bohan; Gerace, Matthew; Kushak, Rafail I.; Ingelfinger, Julie R.

doi:10.1016/j.thromres.2015.03.018

Cited by 6 publications

(7 citation statements)

References 18 publications

(27 reference statements)

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“…Furthermore, terminal complement components (e.g., C5a and C5b-9) increase tissue factor expression in endothelial cells 49 . Besides complement activation, the MBL/MASPs complex plays a role in coagulation activation via several mechanisms including the cleavage of fibrinogen to fibrin 11,12,50,51 . These series of events may result in glomerular dysfunction and renal tubular injury in STEC HUS.…”

Section: Discussionmentioning

confidence: 99%

“…Stx is then transported to the ribosome where the A subunit cleaves an adenosine at position 4324 from the 5' terminal of the 28 S ribosome and leads to protein synthesis inhibition and cell injury 10 . In a small number of instances, protein synthesis may be enhanced (e.g., tissue factor) 11,12 . Although these intracellular mechanisms have been elucidated, the mechanisms by which ribosomal inactivation induces the peculiar characteristics of STEC HUS are unknown 13 .…”

Section: Introductionmentioning

confidence: 99%

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Human mannose-binding lectin inhibitor prevents Shiga toxin–induced renal injury

Ozaki

Kang

Tan

et al. 2016

Kidney International

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Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC HUS) is a worldwide endemic problem and its pathophysiology is not fully elucidated. Here we tested whether the mannose-binding lectin (MBL2), an initiating factor of lectin complement pathway activation, plays a crucial role in STEC HUS. Using novel human MBL2 expressing mice (MBL2 KI) that lack murine Mbls (MBL2+/+Mbl1−/−Mbl2−/−), a novel STEC HUS model consisted of an intraperitoneal injection with Shiga toxin-2 (Stx-2) with or without anti-MBL2 antibody (3F8, intraperitoneal). Stx-2 induced weight loss, anemia, thrombocytopenia, and increased serum creatinine, free serum hemoglobin, and cystatin C levels, but a significantly decreased glomerular filtration rate all compared to control/sham mice. Immunohistochemical staining revealed renal C3d deposition and fibrin deposition in glomeruli in Stx-2 injected mice. Treatment with 3F8 completely inhibited serum MBL2 levels, and significantly attenuated Stx-2 induced renal injury, free serum hemoglobin levels, renal C3d and fibrin deposition, and preserved the glomerular filtration rate. Thus, MBL2 inhibition significantly protected against complement activation and renal injury induced by Stx-2. This novel mouse model can be used to study the role of complement, particularly lectin pathway-mediated complement activation, in Stx-2 induced renal injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human mannose-binding lectin inhibitor prevents Shiga toxin–induced renal injury

Ozaki

Kang

Tan

et al. 2016

Kidney International

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“…The A subunit then enters the cell, where it injures the eukaryotic ribosome, interfering with protein synthesis in target cells. That action, ultimately, alters the expression of certain proteins, including tissue factor and tissue factor pathway inhibitor [32, 33], and induces apoptosis. Stx-producing infection also contributes to release of inflammatory cytokines and cytokine-mediated events, particularly TNFα [34], platelet activation [35], increased procoagulant tissue factor activity on glomerular endothelial cells [36], and activation of complement [20, 21, 37].…”

Section: Discussionmentioning

confidence: 99%

Platelet thrombus formation in eHUS is prevented by anti-MBL2

et al. 2019

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E. coli associated Hemolytic Uremic Syndrome (epidemic hemolytic uremic syndrome, eHUS) caused by Shiga toxin-producing bacteria is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury that cause acute renal failure in up to 65% of affected patients. We hypothesized that the mannose-binding lectin (MBL) pathway of complement activation plays an important role in human eHUS, as we previously demonstrated that injection of Shiga Toxin-2 (Stx-2) led to fibrin deposition in mouse glomeruli that was blocked by co-injection of the anti-MBL-2 antibody 3F8. However, the markers of platelet thrombosis in affected mouse glomeruli were not delineated. To investigate the effect of 3F8 on markers of platelet thrombosis, we used kidney sections from our mouse model (MBL-2+/+ Mbl-A/C-/-; MBL2 KI mouse). Mice in the control group received PBS, while mice in a second group received Stx-2, and those in a third group received 3F8 and Stx-2. Using double immunofluorescence (IF) followed by digital image analysis, kidney sections were stained for fibrin(ogen) and CD41 (marker for platelets), von-Willebrand factor (marker for endothelial cells and platelets), and podocin (marker for podocytes). Electron microscopy (EM) was performed on ultrathin sections from mice and human with HUS. Injection of Stx-2 resulted in an increase of both fibrin and platelets in glomeruli, while administration of 3F8 with Stx-2 reduced both platelet and fibrin to control levels. EM studies confirmed that CD41-positive objects observed by IF were platelets. The increases in platelet number and fibrin levels by injection of Stx-2 are consistent with the generation of platelet-fibrin thrombi that were prevented by 3F8.

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“…The A subunit then enters the cell, where it injures the eukaryotic ribosome, interfering with protein synthesis in target cells. That action, ultimately, alters the expression of certain proteins, including tissue factor and tissue factor pathway inhibitor [30,31], and induces apoptosis. Stx-producing infection also contributes to release of inflammatory cytokines and cytokine-mediated events, particularly TNFα [32], platelet activation [33], increased procoagulant tissue factor activity on glomerular endothelial cells [34], and activation of complement [19,20,35].…”

Section: Discussionmentioning

confidence: 99%

Platelet Thrombus Formation in eHUS is Prevented by Anti-MBL2

Kushak

Boyle

Rosales

et al. 2019

Preprint

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Epidemic Hemolytic Uremic Syndrome (eHUS) caused by Shiga toxin-producing bacteria is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury that cause acute renal failure in up to 65% of affected patients. We hypothesized that the mannose-binding lectin (MBL) pathway of complement activation plays an important role in human eHUS, as we previously demonstrated that injection of Shiga Toxin-2 (Stx-2) led to fibrin deposition in mouse glomeruli that was blocked by co-injection of the anti-MBL-2 antibody 3F8.However, the markers of platelet thrombosis in affected mouse glomeruli were not delineated.To investigate the effect of 3F8 on markers of platelet thrombosis, we used kidney sections from our mouse model (MBL-2+/+ Mbl-A/C-/-; MBL2 KI mouse). Mice in the control group received PBS, while mice in a second group received Stx-2, and those in a third group received 3F8 and Stx-2. Using double immunofluorescence (IF) followed by digital image analysis, kidney sections were stained for fibrin(ogen) and CD41 (marker for platelets), von-Willebrand factor (marker for endothelial cells and platelets), and podocin (marker for podocytes). Electron microscopy (EM) was performed on ultrathin sections from mice and human with HUS.Injection of Stx-2 resulted in an increase of both fibrin and platelets in glomeruli, while administration of 3F8 with Stx-2 reduced both platelet and fibrin to control levels. EM studies confirmed that CD41-positive objects observed by IF were platelets. The increases in platelet number and fibrin levels by injection of Stx-2 are consistent with the generation of platelet-fibrin thrombi that were prevented by 3F8.

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Shiga toxin-1 Decreases Endothelial Cell Tissue Factor Pathway Inhibitor Not Co-localized with Tissue Factor on the Cell Membrane

Cited by 6 publications

References 18 publications

Human mannose-binding lectin inhibitor prevents Shiga toxin–induced renal injury

Human mannose-binding lectin inhibitor prevents Shiga toxin–induced renal injury

Platelet thrombus formation in eHUS is prevented by anti-MBL2

Platelet Thrombus Formation in eHUS is Prevented by Anti-MBL2

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