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1.
J Clin Invest ; 125(7): 2609-25, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26011640

RESUMO

Subarachnoid hemorrhage (SAH) carries a 50% mortality rate. The extravasated erythrocytes that surround the brain contain heme, which, when released from damaged red blood cells, functions as a potent danger molecule that induces sterile tissue injury and organ dysfunction. Free heme is metabolized by heme oxygenase (HO), resulting in the generation of carbon monoxide (CO), a bioactive gas with potent immunomodulatory capabilities. Here, using a murine model of SAH, we demonstrated that expression of the inducible HO isoform (HO-1, encoded by Hmox1) in microglia is necessary to attenuate neuronal cell death, vasospasm, impaired cognitive function, and clearance of cerebral blood burden. Initiation of CO inhalation after SAH rescued the absence of microglial HO-1 and reduced injury by enhancing erythrophagocytosis. Evaluation of correlative human data revealed that patients with SAH have markedly higher HO-1 activity in cerebrospinal fluid (CSF) compared with that in patients with unruptured cerebral aneurysms. Furthermore, cisternal hematoma volume correlated with HO-1 activity and cytokine expression in the CSF of these patients. Collectively, we found that microglial HO-1 and the generation of CO are essential for effective elimination of blood and heme after SAH that otherwise leads to neuronal injury and cognitive dysfunction. Administration of CO may have potential as a therapeutic modality in patients with ruptured cerebral aneurysms.


Assuntos
Heme Oxigenase-1/fisiologia , Proteínas de Membrana/fisiologia , Microglia/enzimologia , Hemorragia Subaracnóidea/sangue , Hemorragia Subaracnóidea/enzimologia , Reação de Fase Aguda/líquido cefalorraquidiano , Animais , Apoptose , Monóxido de Carbono/administração & dosagem , Monóxido de Carbono/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Eritrócitos/patologia , Feminino , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/líquido cefalorraquidiano , Heme Oxigenase-1/deficiência , Humanos , Aneurisma Intracraniano/líquido cefalorraquidiano , Aneurisma Intracraniano/enzimologia , Masculino , Aprendizagem em Labirinto/fisiologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/deficiência , Metaloporfirinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/patologia , Fagocitose/fisiologia , Protoporfirinas/farmacologia , Hemorragia Subaracnóidea/patologia
2.
J Neurosurg ; 121(6): 1388-93, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25280089

RESUMO

OBJECT: Experimental studies have demonstrated the crucial role of posthemorrhagic erythrocyte catabolism in the pathogenesis of subarachnoid hemorrhage (SAH). The authors of this study aimed to investigate the prognostic value of a series of CSF biomarkers linked to heme metabolism in SAH patients. METHODS: Patients with Fisher Grade III aneurysmal SAH undergoing early aneurysm obliteration were enrolled. The levels of heme oxygenase-1 (HO-1), oxyhemoglobin, ferritin, and bilirubin in intrathecal CSF were measured on the 7th day posthemorrhage. The associations of functional outcome with clinical and CSF parameters were analyzed. RESULTS: The study included 41 patients (mean age 59 ± 14 years; 16 male, 25 female), 17 (41.5%) of whom had an unfavorable outcome (Glasgow Outcome Scale score ≤ 3) 3 months after SAH. In terms of the clinical data, age > 60 years, admission World Federation of Neurosurgical Societies Grade ≥ III, and the presence of acute hydrocephalus were independent factors associated with an unfavorable outcome. After adjusting for clinical parameters, a higher level of HO-1 appeared to be the most significant CSF parameter related to an unfavorable outcome among all tested CSF molecules (OR 0.934, 95% CI 0.883-0.989, p = 0.018). Further analysis using a generalized additive model identified a cutoff HO-1 value of 81.2 µM, with higher values predicting unfavorable outcome (82.4% accuracy). CONCLUSIONS: The authors propose that the level of intrathecal CSF HO-1 at Day 7 post-SAH can be an effective outcome indicator in patients with Fisher Grade III aneurysmal SAH.


Assuntos
Heme Oxigenase-1/líquido cefalorraquidiano , Hidrocefalia , Índice de Gravidade de Doença , Hemorragia Subaracnóidea , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bilirrubina/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Feminino , Ferritinas/líquido cefalorraquidiano , Humanos , Hidrocefalia/líquido cefalorraquidiano , Hidrocefalia/diagnóstico , Hidrocefalia/enzimologia , Masculino , Pessoa de Meia-Idade , Oxiemoglobinas/líquido cefalorraquidiano , Prognóstico , Hemorragia Subaracnóidea/líquido cefalorraquidiano , Hemorragia Subaracnóidea/diagnóstico , Hemorragia Subaracnóidea/enzimologia , Adulto Jovem
3.
New Microbiol ; 34(4): 345-50, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22143807

RESUMO

A transmissible cytotoxic agent thought to be associated with one or more misfolded protein(s) was found in several cerebrospinal fluid (CSF) samples from neurological patients. Since some experiments carried out to identify this unusual infectious factor showed the block of its propagation by rabbit gammaglobulins (IgGs), the search for such an activity by human IgGs was programmed. Neutralizing assays carried out using human sera as IgGs source showed a blocking property displayed by: twenty serum samples from as many patients with a diagnosis of acute infection, two of ten sera from healthy subjects and four serum samples from patients with lupus erythematous (SLE). When neutralizing sera were tested on cell cultures in immunofluorescence assays for the serum ability to label specific protein( s), similar fluorescent pictures resulted in treated and control cells. On the other hand, the SLE serum samples disclosed a granulosity of the nuclear material of cytotoxic cells in accordance with the DNA apoptotic laddering reported in previous papers. Oxidative disorders, as suggested by the immunoblotting analysis of the antioxidant enzymes Mn-superoxide dismutase (SOD2) and heme-oxygenase 1 (HO-1), point to an alteration of the oxidative pathway among the causes of the DNA damage induced by the cytotoxic transmissible agent under study.


Assuntos
Isquemia Encefálica/líquido cefalorraquidiano , Isquemia Encefálica/imunologia , Proteínas do Líquido Cefalorraquidiano/imunologia , Testes de Neutralização/métodos , Deficiências na Proteostase/líquido cefalorraquidiano , Deficiências na Proteostase/imunologia , Animais , Isquemia Encefálica/sangue , Células Cultivadas , Proteínas do Líquido Cefalorraquidiano/sangue , Proteínas do Líquido Cefalorraquidiano/líquido cefalorraquidiano , Citotoxinas/sangue , Citotoxinas/líquido cefalorraquidiano , Citotoxinas/imunologia , Fibroblastos/citologia , Fibroblastos/imunologia , Heme Oxigenase-1/sangue , Heme Oxigenase-1/líquido cefalorraquidiano , Humanos , Imunoglobulina G/farmacologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/líquido cefalorraquidiano , Lúpus Eritematoso Sistêmico/imunologia , Neuroglia/citologia , Neuroglia/imunologia , Estresse Oxidativo/fisiologia , Deficiências na Proteostase/sangue , Coelhos , Superóxido Dismutase/sangue , Superóxido Dismutase/líquido cefalorraquidiano
4.
Dev Neurosci ; 28(4-5): 342-7, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16943657

RESUMO

Heme oxygenase 1 (HO-1) is an enzyme important in the catabolism of heme that is induced under conditions of oxidative stress. HO-1 degradation of heme yields biliverdin, bilirubin, carbon monoxide and iron. HO-1 is thought to serve a protective antioxidant function, and upregulation of HO-1 has been demonstrated in experimental models of neurodegeneration, subarachnoid hemorrhage, cerebral ischemia and traumatic brain injury (TBI). We measured HO-1 concentration in cerebral spinal fluid samples from 48 infants and children following TBI and 7 control patients by ELISA. Increased HO-1 was seen in TBI versus control patients--mean 2.75+/-0.63, peak 4.17+/-0.96 ng/ml versus control (<0.078 ng/ml, not detectable) (p<0.001). Increased HO-1 concentration was associated with increased injury severity and unfavorable neurological outcome (both p<0.05). Increased HO-1 concentration was independently associated with younger age; however, statistical analysis could not rule out the possibility that the effect of age was related to inflicted TBI from child abuse. HO-1 increases after TBI and appears to be more prominent in infants compared with older children after injury.


Assuntos
Lesões Encefálicas/líquido cefalorraquidiano , Lesões Encefálicas/enzimologia , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Heme Oxigenase-1/líquido cefalorraquidiano , Fatores Etários , Envelhecimento/fisiologia , Biomarcadores/análise , Biomarcadores/líquido cefalorraquidiano , Lesões Encefálicas/diagnóstico , Isquemia Encefálica/líquido cefalorraquidiano , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/enzimologia , Criança , Pré-Escolar , Avaliação da Deficiência , Progressão da Doença , Feminino , Heme/metabolismo , Heme Oxigenase-1/análise , Humanos , Lactente , Masculino , Degeneração Neural/líquido cefalorraquidiano , Degeneração Neural/diagnóstico , Degeneração Neural/enzimologia , Estresse Oxidativo/fisiologia , Valor Preditivo dos Testes , Prognóstico , Regulação para Cima/fisiologia
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