Neutrophil-Mediated Endothelial Injury in Haemolytic Uraemic Syndrome

Forsyth, Kevin; Fitzpatrick, Mark; Simpson, Anna; Barratt, T. M.; Levinsky, Roland J.

doi:10.1016/s0140-6736(89)90591-6

Cited by 140 publications

(98 citation statements)

References 29 publications

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“…There is considerable evidence that neutrophils and monocytes play an active role in the pathogenesis of Stx-associated HUS, and that their interactions with activated endothelial cells serve to amplify microvascular injury in the kidney (15). During the acute phase of D+HUS, neutrophils are activated, become more adhesive, and damage the endothelium by producing a1-antitrypsin-complexed elastase (39,40). Kidney biopsies from D+HUS children showed mononuclear and PMNs within the glomeruli, along the zone of microvascular injury (41,42).…”

Section: Discussionmentioning

confidence: 99%

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Zoja

Locatelli

Pagani

et al. 2012

The Journal of Immunology

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Shiga toxin (Stx)-producing Escherichia coli is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The pathophysiology of renal microvascular thrombosis in Stx-HUS is still ill-defined. Based on evidence that abnormalities in thrombomodulin (TM), an anticoagulant endothelial glycoprotein that modulates complement and inflammation, predispose to atypical HUS, we assessed whether impaired TM function may adversely affect evolution of Stx-HUS. Disease was induced by coinjection of Stx2/LPS in wild-type mice (TMwt/wt) and mice that lack the lectin-like domain of TM (TMLeD/LeD), which is critical for its anti-inflammatory and cytoprotective properties. After Stx2/LPS, TMLeD/LeD mice exhibited more severe thrombocytopenia and renal dysfunction than TMwt/wt mice. Lack of lectin-like domain of TM resulted in a stronger inflammatory reaction after Stx2/LPS with more neutrophils and monocytes/macrophages infiltrating the kidney, associated with PECAM-1 and chemokine upregulation. After Stx2/LPS, intraglomerular fibrin(ogen) deposits were detected earlier in TMLeD/LeD than in TMwt/wt mice. More abundant fibrin(ogen) deposits were also found in brain and lungs. Under basal conditions, TMLeD/LeD mice exhibited excess glomerular C3 deposits, indicating impaired complement regulation in the kidney that could lead to local accumulation of proinflammatory products. TMLeD/LeD mice with HUS had a higher mortality rate than TMwt/wt mice. If applicable to humans, these findings raise the possibility that genetic or acquired TM defects might have an impact on the severity of microangiopathic lesions after exposure to Stx-producing E. coli infections and raise the potential for using soluble TM in the treatment of Stx-HUS.

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Section: Discussionmentioning

confidence: 99%

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Zoja

Locatelli

Pagani

et al. 2012

The Journal of Immunology

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“…Increased elastase levels are found in the blood of HUS patients (121,124,125), indicating neutrophil activation. Circulating polymorphonuclear leukocytes are activated (121)(122)(123). Although the underlying mechanisms leading to circulating leukocytosis remain unclear, increased circulating levels of granulocyte colony-stimulating factor (126) and IL-8 (124) have been reported in children with HUS.…”

Section: Host Responsementioning

confidence: 99%

“…Neutrophils from patients with HUS have a higher capacity to adhere to cultured human endothelium and to induce endothelial injury by degradation of endothelial fibronectin (122). The latter may be blocked by anti-CD18 MAb (122).…”

Section: Host Responsementioning

confidence: 99%

Pathogenesis of Shiga Toxin-Associated Hemolytic Uremic Syndrome

2001

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“…After STEC ingestion, Stx is transported in the circulation to the capillary bed of target organs, including the kidney (5,6). Glomerular endothelium that expresses the receptor globotriaosyl ceramide (Gb3)/CD77 (10,11) is the main target of the toxic effects of Stx1 and 2 (12), which activate a cascade of signals contributing to vascular dysfunction, leukocyte recruitment, and thrombus formation (13)(14)(15)(16)(17)(18)(19). We previously reported that Stx promoted von Willebrand factor (VWF)-dependent thrombus growth on microvascular endothelium under flow via upregulation of P-selectin (17).…”

mentioning

confidence: 99%

Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis

Morigi

Galbusera

Gastoldi

et al. 2011

The Journal of Immunology

214

201

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Shiga toxin (Stx)-producing E.coli O157:H7 has become a global threat to public health; it is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure with thrombi occluding renal microcirculation. In this study, we explored whether Stx triggers complement-dependent microvascular thrombosis in in vitro and in vivo experimental settings of HUS. Stx induced on human microvascular endothelial cell surface the expression of P-selectin, which bound and activated C3 via the alternative pathway, leading to thrombus formation under flow. In the search for mechanisms linking complement activation and thrombosis, we found that exuberant complement activation in response to Stx generated an increased amount of C3a that caused further endothelial P-selectin expression, thrombomodulin (TM) loss, and thrombus formation. In a murine model of HUS obtained by coinjection of Stx2 and LPS and characterized by thrombocytopenia and renal dysfunction, upregulation of glomerular endothelial P-selectin was associated with C3 and fibrin(ogen) deposits, platelet clumps, and reduced TM expression. Treatment with anti–P-selectin Ab limited glomerular C3 accumulation. Factor B-deficient mice after Stx2/LPS exhibited less thrombocytopenia and were protected against glomerular abnormalities and renal function impairment, indicating the involvement of complement activation via the alternative pathway in the glomerular thrombotic process in HUS mice. The functional role of C3a was documented by data showing that glomerular fibrin(ogen), platelet clumps, and TM loss were markedly decreased in HUS mice receiving C3aR antagonist. These results identify Stx-induced complement activation, via P-selectin, as a key mechanism of C3a-dependent microvascular thrombosis in diarrhea-associated HUS.

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Neutrophil-Mediated Endothelial Injury in Haemolytic Uraemic Syndrome

Cited by 140 publications

References 29 publications

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Pathogenesis of Shiga Toxin-Associated Hemolytic Uremic Syndrome

Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis

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