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1.
J Thromb Haemost ; 10(8): 1665-71, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22712744

ABSTRACT

BACKGROUND: ADAMTS13 cleaves hyperactive ultra-large von Willebrand factor (ULVWF) multimers into smaller and less active forms. It remains unknown whether VWF-mediated inflammatory processes play a role in the enhanced brain injury due to ADAMTS13 deficiency. OBJECTIVE: We tested the hypothesis that the deleterious effect of ADAMTS13 deficiency on ischemic brain injury is mediated through VWF-dependent enhanced vascular inflammation. METHODS: Transient focal cerebral ischemia was induced by 60 min of occlusion of the right middle cerebral artery. Myeloperoxidase (MPO) activity and inflammatory cytokines in the infarcted region were evaluated 23 h after reperfusion injury. Neutrophil infiltration within the infarct and surrounding areas was quantitated by immunohistochemistry. RESULTS: We report that ADAMTS13-deficient mice exhibited significantly enlarged infarct size, concordant with increased myeloperoxidase (MPO) activity, neutrophil infiltration and expression of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). In contrast, VWF-deficient mice exhibited significantly reduced MPO activity, neutrophil infiltration and inflammatory cytokine induction, demonstrating a role of VWF in these inflammatory processes. Mice deficient for both ADAMTS13 and VWF exhibited an identical reduction of the same inflammatory parameters, demonstrating that the increased inflammation observed in ADAMTS13-deficient mice is VWF dependent. Finally, the increased infarct size observed in ADAMTS13-deficient mice was completely abrogated by prior immunodepletion of neutrophils, demonstrating a causal role for acute inflammation in the enhanced brain injury that occurs in the setting of ADAMTS13 deficiency. CONCLUSION: These findings provide new evidence for ADAMTS13 in reducing VWF-mediated acute cerebral inflammation following ischemic stroke.


Subject(s)
Brain/enzymology , Infarction, Middle Cerebral Artery/enzymology , Metalloendopeptidases/metabolism , Reperfusion Injury/enzymology , Vasculitis, Central Nervous System/prevention & control , von Willebrand Factor/metabolism , ADAMTS13 Protein , Acute Disease , Animals , Brain/blood supply , Brain/immunology , Brain/pathology , Disease Models, Animal , Immunohistochemistry , Infarction, Middle Cerebral Artery/genetics , Infarction, Middle Cerebral Artery/immunology , Infarction, Middle Cerebral Artery/pathology , Inflammation Mediators/metabolism , Interleukin-6/metabolism , Male , Metalloendopeptidases/deficiency , Metalloendopeptidases/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophil Infiltration , Peroxidase/metabolism , Reperfusion Injury/genetics , Reperfusion Injury/immunology , Reperfusion Injury/pathology , Time Factors , Tumor Necrosis Factor-alpha/metabolism , Vasculitis, Central Nervous System/enzymology , Vasculitis, Central Nervous System/genetics , Vasculitis, Central Nervous System/immunology , Vasculitis, Central Nervous System/pathology , von Willebrand Factor/genetics
2.
Eur J Neurol ; 18(8): 1053-9, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21219546

ABSTRACT

BACKGROUND AND PURPOSE: There is increasing evidence that the genetic variation in the genes coding for pro-inflammatory markers and matrix metalloproteinase may play an important role in the pathogenesis of various human diseases including stroke. The aim of this study was to evaluate the association of genetic variants within the genes encoding tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-3 (MMP-3), with stroke. METHODS: Five hundred and twenty-five ischemic stroke patients and 500 age- and sex-matched controls were included in this study. We analyzed +488 G/A polymorphism in TNF-α gene and -1612 5A/6A polymorphism in MMP-3 gene. The genotypes were determined by Amplification Refractory Mutation System PCR. The strength of association between genotypes and stroke was measured by the odds ratio with 95% confidence interval (CI) and chi-squared analysis. RESULTS: Allelic and genotypic frequencies of TNF-α G/A polymorphism differed significantly between patients and healthy controls (P < 0.001). A stepwise logistic regression analysis confirmed these findings (P < 0.001). Further, evaluating the association of this polymorphism with stroke subtypes, we found significant association with intracranial large artery atherosclerosis, extracranial large artery atherosclerosis, and stroke of undetermined etiology. As far as MMP-3-1612 5A/6A polymorphism is concerned, there was no significant difference in genotypic distribution and allelic frequency between the patients and healthy controls (P = 0.5 and 0.9, respectively). We tested the gene-gene interaction between TNF-α and MMP-3 genes using the logistic regression model. However, there was no evidence for a gene-gene interaction between TNF-α and MMP-3. CONCLUSION: TNF-α +488 G/A variant is an important risk factor for ischemic stroke in the South Indians from Andhra Pradesh, whereas MMP-3-1612 5A/6A polymorphism is not associated with stroke in the same population.


Subject(s)
Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Matrix Metalloproteinase 3/genetics , Stroke/genetics , Tumor Necrosis Factor-alpha/genetics , Comorbidity , Female , Gene Frequency/genetics , Genetic Association Studies/methods , Genetic Predisposition to Disease/epidemiology , Humans , India/epidemiology , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Risk Factors , Stroke/enzymology , Stroke/metabolism , Vasculitis, Central Nervous System/enzymology , Vasculitis, Central Nervous System/genetics , Vasculitis, Central Nervous System/metabolism
3.
Microcirculation ; 18(1): 12-23, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21166922

ABSTRACT

OBJECTIVE: The aim of this study was to assess the ability of Gpx1 to regulate leukocyte-endothelial cell interactions in the cerebral microcirculation under inflammatory conditions associated with oxidative stress. METHODS: To induce cerebral inflammation, wild-type and Gpx1(-/-) mice underwent systemic treatment with TNF or transient focal cerebral ischemia via MCAO. Leukocyte rolling and adhesion in cerebral postcapillary venules were assessed by intravital microscopy. RESULTS: Absence of Gpx1(-/-) resulted in increased cerebral oxidant production in response to TNF. Under these conditions, leukocyte rolling in cerebral venules was significantly elevated in Gpx1(-/-) mice, whereas leukocyte adhesion was lower than that in wild-type mice. Despite this, expression of key adhesion molecules did not differ between the strains. Following MCAO, Gpx1(-/-) mice displayed significant reductions in rolling and adhesion associated with severe blood flow restriction. In contrast, following treatment with the anti-oxidant ebselen to equalize postischemic cerebral blood flow in wild-type and Gpx1(-/-) mice, absence of Gpx1 was associated with significant elevations in leukocyte interactions. CONCLUSIONS: These data show that under some inflammatory conditions, Gpx1 regulates leukocyte-endothelial cell interactions in the cerebral microvasculature, but that this is affected by the nature of the inflammatory insult.


Subject(s)
Brain/blood supply , Cell Communication , Endothelial Cells/enzymology , Glutathione Peroxidase/metabolism , Leukocyte Rolling , Leukocytes/enzymology , Vasculitis, Central Nervous System/enzymology , Animals , Brain/enzymology , Brain/pathology , Cerebrovascular Circulation , Endothelial Cells/pathology , Glutathione Peroxidase/genetics , Inflammation/enzymology , Inflammation/genetics , Inflammation/pathology , Leukocytes/pathology , Mice , Mice, Knockout , Microcirculation , Vasculitis, Central Nervous System/genetics , Vasculitis, Central Nervous System/pathology , Glutathione Peroxidase GPX1
4.
J Neurochem ; 107(1): 241-52, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18691391

ABSTRACT

Mice deficient in the anti-oxidant enzyme glutathione peroxidase-1 (Gpx1) have a greater susceptibility to cerebral injury following a localized ischemic event. Much of the response to ischemia-reperfusion is caused by aberrant responses within the microvasculature, including inflammation, diminished endothelial barrier function (increased vascular permeability), endothelial activation, and reduced microvascular perfusion. However, the role of Gpx1 in regulating these responses has not been investigated. Wild-type and Gpx1-/- mice underwent focal cerebral ischemia via mid-cerebral artery occlusion followed by measurement of cerebral perfusion via laser Doppler and intravital microscopy. Post-ischemic brains in wild-type mice displayed significant deficit in microvascular perfusion. However, in Gpx1-/- mice, the deficit in cerebral blood flow was significantly greater than that in wild-type mice, and this was associated with significant increase in infarct size and increased vascular permeability. Ischemia-reperfusion also resulted in expression of matrix metalloproteinase-9 (MMP-9) in endothelial cells. The absence of Gpx1 was associated with marked increase in pro-MMP-9 expression as well as potentiated MMP-9 activity. Pre-treatment of Gpx1-/- mice with the anti-oxidant ebselen restored microvascular perfusion, limited the induction and activation of MMP-9, and attenuated the increases in infarct size and vascular permeability. These findings demonstrate that the anti-oxidant function of Gpx1 plays a critical role in protecting the cerebral microvasculature against ischemia-reperfusion injury by preserving microvascular perfusion and inhibiting MMP-9 expression.


Subject(s)
Brain Ischemia/enzymology , Cerebral Arteries/enzymology , Cerebrovascular Circulation/genetics , Glutathione Peroxidase/genetics , Microcirculation/enzymology , Reperfusion Injury/enzymology , Animals , Antioxidants/pharmacology , Azoles/pharmacology , Brain Ischemia/genetics , Brain Ischemia/physiopathology , Cerebral Arteries/diagnostic imaging , Cerebral Arteries/physiopathology , Disease Models, Animal , Endothelial Cells/metabolism , Infarction, Middle Cerebral Artery/enzymology , Infarction, Middle Cerebral Artery/genetics , Infarction, Middle Cerebral Artery/physiopathology , Isoindoles , Laser-Doppler Flowmetry , Male , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Microcirculation/diagnostic imaging , Microcirculation/physiopathology , Organoselenium Compounds/pharmacology , Oxidative Stress/genetics , Reperfusion Injury/genetics , Reperfusion Injury/physiopathology , Ultrasonography , Vasculitis, Central Nervous System/enzymology , Vasculitis, Central Nervous System/genetics , Glutathione Peroxidase GPX1
5.
Neurocrit Care ; 4(3): 237-40, 2006.
Article in English | MEDLINE | ID: mdl-16757830

ABSTRACT

INTRODUCTION: Bacterial meningitis is associated with a high mortality and a high incidence of neurological sequelae. Parainfectious vasculitis leading to ischemic brain damage is a known complication of bacterial meningitis but its treatment is uncertain. METHODS AND RESULTS: We report the case of a 53-year-old man with pneumococcal meningitis who developed numerous ischemic lesions in the brainstem and basal ganglia caused by parainfectious vasculitis. Clinical and radiological improvement was observed after delayed corticosteroid initiation. Symptomatic vasculitis relapsed after steroid withdrawal and stabilized after reintroduction of the immunosuppressive therapy. Although the cerebrospinal fluid (CSF) contained high levels of MMP-9 at the time of symptomatic vasculitis, a significant decrease of the enzyme accompanied the introduction of corticotherapy and the regression of vasculitic symptoms. No relation between the level of MMP-9 and the white blood cell count in CSF could be found. CONCLUSION: Parainfectious vasculitis may respond to late corticosteroid treatment. MMP-9 level in CSF may be a marker of vasculitic complication in bacterial meningitis.


Subject(s)
Meningitis, Pneumococcal/pathology , Vasculitis, Central Nervous System/microbiology , Cyclophosphamide/therapeutic use , Glucocorticoids/therapeutic use , Humans , Immunosuppressive Agents/therapeutic use , Male , Matrix Metalloproteinases/metabolism , Meningitis, Pneumococcal/drug therapy , Meningitis, Pneumococcal/enzymology , Middle Aged , Prednisolone/therapeutic use , Vasculitis, Central Nervous System/drug therapy , Vasculitis, Central Nervous System/enzymology
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