RESUMO
Inflammation in Guillain-Barré syndrome (GBS) is manifested by changes in matrix metalloproteinase (MMP) and pro-inflammatory cytokine expression. We investigated the expression of MMP-2, -9 and TNF-α and correlated it with pathological changes in sciatic nerve tissue from Campylobacter jejuni-induced chicken model for GBS. Campylobacter jejuni and placebo were fed to chickens and assessed for disease symptoms. Sciatic nerves were examined by histopathology and immunohistochemistry. Expressions of MMPs and TNF-α, were determined by real-time PCR, and activities of MMPs by zymography. Diarrhea developed in 73.3% chickens after infection and 60.0% of them developed GBS like neuropathy. Pathology in sciatic nerves showed perinodal and/or patchy demyelination, perivascular focal lymphocytic infiltration and myelin swelling on 10th- 20th post infection day (PID). MMP-2, -9 and TNF-α were up-regulated in progressive phase of the disease. Enhanced MMP-2, -9 and TNF-α production in progressive phase correlated with sciatic nerve pathology in C. jejuni-induced GBS chicken model.
Assuntos
Infecções por Campylobacter/enzimologia , Campylobacter jejuni/fisiologia , Síndrome de Guillain-Barré/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Paralisia/enzimologia , Animais , Infecções por Campylobacter/genética , Infecções por Campylobacter/microbiologia , Infecções por Campylobacter/patologia , Campylobacter jejuni/genética , Galinhas , Modelos Animais de Doenças , Síndrome de Guillain-Barré/genética , Síndrome de Guillain-Barré/microbiologia , Síndrome de Guillain-Barré/patologia , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Paralisia/genética , Paralisia/microbiologia , Nervo Isquiático/enzimologia , Nervo Isquiático/microbiologia , Nervo Isquiático/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Although ischemic stroke is a major cause of death and disability worldwide, only a small fraction of patients benefit from the current thrombolytic therapy due to a risk of cerebral hemorrhage caused by inflammation. Thus, the development of a new strategy to combat inflammation during thrombolysis is an urgent demand. The small molecule thrombolytic SMTP-7 effectively treats ischemic stroke in several animal models with reducing cerebral hemorrhage. Here we revealed that SMTP-7 targeted soluble epoxide hydrolase (sEH) to suppress inflammation. SMTP-7 inhibited both of the two sEH enzyme activities: epoxide hydrolase (which inactivates anti-inflammatory epoxy-fatty acids) and lipid phosphate phosphatase. SMTP-7 suppressed epoxy-fatty acid hydrolysis in HepG2 cells in culture, implicating the sEH inhibition in the anti-inflammatory mechanism. The sEH inhibition by SMTP-7 was independent of its thrombolytic activity. The simultaneous targeting of thrombolysis and sEH by a single molecule is a promising strategy to revolutionize the current stroke therapy.
Assuntos
Anti-Inflamatórios/farmacologia , Benzopiranos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Fibrinolíticos/farmacologia , Pirrolidinonas/farmacologia , Sequência de Aminoácidos , Animais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/enzimologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/enzimologia , Epóxido Hidrolases/sangue , Epóxido Hidrolases/química , Síndrome de Guillain-Barré/tratamento farmacológico , Síndrome de Guillain-Barré/enzimologia , Células Hep G2 , Humanos , Cinética , Masculino , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Plasminogênio/metabolismo , Ratos Endogâmicos LewRESUMO
Benign acute childhood myositis (BACM) is a rare, acute, self-limiting muscle disorder, mainly affecting school-aged boys, with an excellent prognosis, requiring no therapeutic intervention. We report a series of seven previously healthy school-aged children with clinical and laboratory findings suggesting BACM where no specific diagnostic investigations were performed. All of the children were hospitalized without any specific therapeutic intervention and were discharged after two or three days free of symptoms, residual impairment or other complication. This report emphasizes that the correct diagnosis of BACM, by considering the characteristic clinical and laboratory findings of this syndrome and by recognizing more severe pathological conditions, which must be excluded from the diagnosis, can prevent unnecessary diagnostic investigations and reassure both parents and patients of the excellent prognosis.
Assuntos
Aspartato Aminotransferases/sangue , Creatina Quinase/sangue , L-Lactato Desidrogenase/sangue , Miosite/diagnóstico , Procedimentos Desnecessários , Doença Aguda , Criança , Diagnóstico Diferencial , Feminino , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/enzimologia , Humanos , Isoenzimas/sangue , Masculino , Miosite/enzimologia , Exame Neurológico , Osteomielite/diagnóstico , Osteomielite/enzimologia , Pais , Exame Físico , PrognósticoRESUMO
BACKGROUND: The underlying change of gene network expression of Guillain-Barré syndrome (GBS) remains elusive. We sought to identify GBS-associated gene networks and signaling pathways by analyzing the transcriptional profile of leukocytes in the patients with GBS. METHODS AND FINDINGS: Quantitative global gene expression microarray analysis of peripheral blood leukocytes was performed on 7 patients with GBS and 7 healthy controls. Gene expression profiles were compared between patients and controls after standardization. The set of genes that significantly correlated with GBS was further analyzed by Ingenuity Pathways Analyses. 256 genes and 18 gene networks were significantly associated with GBS (fold change ≥2, P<0.05). FOS, PTGS2, HMGB2 and MMP9 are the top four of 246 significantly up-regulated genes. The most significant disease and altered biological function genes associated with GBS were those involved in inflammatory response, infectious disease, and respiratory disease. Cell death, cellular development and cellular movement were the top significant molecular and cellular functions involved in GBS. Hematological system development and function, immune cell trafficking and organismal survival were the most significant GBS-associated function in physiological development and system category. Several hub genes, such as MMP9, PTGS2 and CREB1 were identified in the associated gene networks. Canonical pathway analysis showed that GnRH, corticotrophin-releasing hormone and ERK/MAPK signaling were the most significant pathways in the up-regulated gene set in GBS. CONCLUSIONS: This study reveals the gene networks and canonical pathways associated with GBS. These data provide not only networks between the genes for understanding the pathogenic properties of GBS but also map significant pathways for the future development of novel therapeutic strategies.
Assuntos
Redes Reguladoras de Genes/genética , Síndrome de Guillain-Barré/genética , Transdução de Sinais/genética , Anexina A3/genética , Anexina A3/metabolismo , Estudos de Casos e Controles , Regulação para Baixo/genética , Feminino , Síndrome de Guillain-Barré/enzimologia , Humanos , Leucócitos/metabolismo , Masculino , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma/genética , Regulação para Cima/genéticaRESUMO
Molecular mimicry between lipooligosaccharides (LOS) of Campylobacter jejuni and gangliosides in peripheral nerves plays a crucial role in the pathogenesis of C. jejuni-related Guillain-Barré syndrome (GBS). We have analyzed the LOS outer core structures of 26 C. jejuni strains associated with GBS and its variant, Miller Fisher syndrome (MFS), by capillary electrophoresis coupled with electrospray ionization mass spectrometry. Sixteen out of 22 (73%) GBS-associated and all 4 (100%) MFS-associated strains expressed LOS with ganglioside mimics. GM1a was the most prevalent ganglioside mimic in GBS-associated strains (10/22, 45%), and in eight of these strains, GM1a was found in combination with GD1a mimics. All seven strains isolated from patients with ophthalmoplegia (GBS or MFS) expressed disialylated (GD3 or GD1c) mimics. Three out of 22 GBS-associated strains (14%) did not express sialylated ganglioside mimics because their LOS locus lacked the genes necessary for sialylation. Three other strains (14%) did not express ganglioside mimics because of frameshift mutations in either the cstII sialyltransferase gene or the cgtB galactosyltransferase gene. It is not possible to determine if these mutations were already present during C. jejuni infection. This is the first report in which mass spectrometry combined with DNA sequence data were used to infer the LOS outer core structures of a large number of neuropathy-associated C. jejuni strains. We conclude that molecular mimicry between gangliosides and C. jejuni LOS is the presumable pathogenic mechanism in most cases of C. jejuni-related GBS. However, our findings suggest that in some cases, other mechanisms may play a role. Further examination of the disease etiology in these patients is mandatory.
Assuntos
Campylobacter jejuni/química , Síndrome de Guillain-Barré/metabolismo , Síndrome de Guillain-Barré/microbiologia , Lipopolissacarídeos/química , Síndrome de Miller Fisher/metabolismo , Síndrome de Miller Fisher/microbiologia , Sequência de Aminoácidos , Campylobacter jejuni/genética , Campylobacter jejuni/metabolismo , Sequência de Carboidratos , Síndrome de Guillain-Barré/enzimologia , Humanos , Lipopolissacarídeos/metabolismo , Síndrome de Miller Fisher/enzimologia , Mimetismo Molecular , Dados de Sequência Molecular , Sialiltransferases/química , Sialiltransferases/genéticaRESUMO
Pro and active-matrix metalloproteinase-9 (MMP-9) was measured in sera from patients with amyotrophic lateral sclerosis (ALS), Guillain-Barre syndome (GBS), and healthy subjects. Both forms of MMP-9 were elevated in sera of ALS and GBS patients, compared with healthy controls. It has been postulated that elevated MMP-9 reflects damage to peripheral nerve and muscle. This possibility was investigated in sera, and tissue extracts of sciatic nerves and muscle from mice 5 and 12 days after axotomy of the sciatic nerve. Pro-MMP-9 was elevated in sera and extracts of damaged nerve and muscle, suggesting such damage may be followed by elevated pro-MM9-9 in sera. Active MMP-9 was only elevated in the sera. However, in situ activation of MMP-9 is tightly regulated and localised, and probably difficult to demonstrate by ELISA, resulting in a short half-life active MMP-9, implying any active MMP-9 in the serum may have a more immediate origin than injured muscle or nerve, for example circulating blood cells.
Assuntos
Esclerose Lateral Amiotrófica/enzimologia , Precursores Enzimáticos/biossíntese , Precursores Enzimáticos/sangue , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/patologia , Animais , Western Blotting , Ativação Enzimática , Precursores Enzimáticos/isolamento & purificação , Ensaio de Imunoadsorção Enzimática , Feminino , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/enzimologia , Humanos , Masculino , Metaloproteinase 9 da Matriz/isolamento & purificação , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Músculo Esquelético/enzimologia , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Compressão Nervosa , Nervo Isquiático/enzimologia , Nervo Isquiático/patologia , Regulação para CimaRESUMO
BACKGROUND: Increased levels of lactic dehydrogenase (LDH) in the cerebrospinal fluid (CSF) have been reported in association with several intracranial pathologies. No studies have been performed on patients with Guillain-Barré syndrome (GBS). AIMS: To study LDH isoenzymes in CSF of children with GBS. METHODS: CSF samples collected from nine patients with GBS were analysed for total LDH isoenzymes activity, and compared to samples from 15 patients with normal results. RESULTS: Mean total LDH activity was 33.33 (6.63) U/l. All patients had significantly increased LDH-3 isoenzyme compared to controls. LDH-3 was the predominant fraction, accounting for more than 50% of total LDH activity and present in more than twice the percentage of LDH-1 or LDH-2. By contrast, in the control group, there were high percentages of mainly LDH-1 and LDH-2. CONCLUSIONS: GBS is apparently associated with a distinct LDH isoenzyme pattern in the CSF. More studies are needed to confirm the rise in LDH-3, as serial CSF analyses are unavailable, and to determine the optimum time of analysis when this finding first becomes detectable.
Assuntos
Síndrome de Guillain-Barré/líquido cefalorraquidiano , L-Lactato Desidrogenase/líquido cefalorraquidiano , Criança , Pré-Escolar , Feminino , Síndrome de Guillain-Barré/enzimologia , Humanos , Lactente , Isoenzimas/líquido cefalorraquidiano , MasculinoRESUMO
Members of the family of matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of inflammatory demyelination. MMPs apparently mediate important steps in the genesis of inflammatory demyelination, such as cell migration, blood-brain/nerve barrier breakdown, demyelination, and cytokine activation. This review will highlight in vitro as well as in vivo findings, which support the importance of this group of proteases in the pathogenesis of inflammatory demyelinating disorders of the central and peripheral nervous system.
Assuntos
Síndrome de Guillain-Barré/enzimologia , Síndrome de Guillain-Barré/imunologia , Metaloproteinases da Matriz/imunologia , Esclerose Múltipla/enzimologia , Esclerose Múltipla/imunologia , Humanos , Metaloproteinases da Matriz/metabolismoRESUMO
We describe a patient with Guillain-Barré syndrome (GBS) following Campylobacter jejuni enteritis, accompanied with severe cramping pain and a marked increase in serum creatine kinase (CK) levels. Both conditions became evident three weeks after the onset of GBS and continued for longer than one month. In this patient, it is possible that rapid extensive denervation due to severe axonal degeneration of motor nerve terminals might have caused hyperexcitability in regional muscles, leading to recurrent muscle cramps and persistent release of muscular CK.
Assuntos
Infecções por Campylobacter/complicações , Campylobacter jejuni/isolamento & purificação , Creatina Quinase/sangue , Enterite/complicações , Síndrome de Guillain-Barré/diagnóstico , Dor/etiologia , Adulto , Infecções por Campylobacter/diagnóstico , Síndrome de Guillain-Barré/enzimologia , Síndrome de Guillain-Barré/etiologia , Síndrome de Guillain-Barré/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Plasmaferese , Rabdomiólise/complicações , Rabdomiólise/diagnósticoRESUMO
Free radicals are molecules that contain at least one unpaired electron and by nature are highly reactive and potentially destructive. Free radical damage can play an important role of demyelination. Glutathione peroxidase, which plays a role in free radical defenses, and myeloperoxidase and lactoferrin, which are considered to reflect the strength of oxidative stress, were examined by monoclonal antibody-based enzyme immunoassay on serum samples taken from patients with neuroimmunological disorders, namely, 35 multiple sclerosis(MS), and 2 Baló disease, 10 Guillain-Barré syndrome(GBS), and 25 human T-lymphotropic virus type-1 associated myelopathy (HAM). The levels of glutathione peroxidase in active phase of MS (8.37 +/- 5.59 micrograms/ml: p < 0.05) were increased rather than in inactive phase (5.05 +/- 2.44 micrograms/ml) and control (5.41 +/- 1.40 micrograms/ml), the levels of myeloperoxidase in HAM (95.5 +/- 89.1 ng/ml: p < 0.05) were increased rather than in controls (21.5 +/- 4.1 ng/ml), and the levels of lactoferrin were not significantly increased than in other disease and control. Moreover the levels of myeloperoxidase and lactoferrin are increased in Baló disease (myeloperoxidase 487, 762 ng/ml; not significant, lactoferrin 2.58, 2.77 ng/ml; not significant) than in control (myeloperoxidase 21.5 +/- 4.1 ng/ml, lactoferrin 0.69 +/- 0.32 ng/ml). In conclusion, we have here first demonstrated that the levels of these enzyme were not paralleled in MS and Baló diseases. In GBS the levels of all these enzyme were not increased. Thus, these findings suggest that these enzyme may play an important role of the disease activity of Baló, and may reflect the activity of the defense of MS.
Assuntos
Esclerose Cerebral Difusa de Schilder/enzimologia , Glutationa Peroxidase/sangue , Síndrome de Guillain-Barré/enzimologia , Lactoferrina/sangue , Esclerose Múltipla/enzimologia , Paraparesia Espástica Tropical/enzimologia , Peroxidase/sangue , Adulto , Radicais Livres , Humanos , Pessoa de Meia-Idade , Estresse OxidativoRESUMO
OBJECTIVE: To study the expression and activity of matrix metalloproteinases (MMPs) MMP-2 (72-kd type IV collagenase, gelatinase A), MMP-3 (58-kd stromelysin-1), and MMP-9 (92-kd type IV collagenase, gelatinase B) and tissue inhibitors of MPs (TIMP) in patients with Guillain-Barre syndrome (GBS). BACKGROUND: MMPs are able to proteolysis of basement membranes and other matrix components, promoting transmigration of inflammatory cells from circulation to nerve tissue. METHODS: Twenty-five patients with GBS were analyzed according to the phase of the disease, i.e., progression, plateau, early recovery, and late recovery. Determinations of MMP-2, MMP-3, MMP-9, and TIMP-1 were performed using ELISA, zymography, and immunocytochemistry in circulation or peripheral nerve. RESULTS: MMP-9 plasma levels were increased in 67% of patients on admission and decreased from progression to late recovery (p < 0.002). During the course of GBS, MMP-9 was progressively balanced by its inhibitor TIMP-1, as assessed by the MMP-9/TIMP-1 ratio. MMP-9 and TIMP-1 plasma levels and the MMP-9/TIMP-1 ratio correlated positively with disability. MMP-2 expression was similar to controls. MMP-3 activity was not detected, and plasma levels were not different from those in controls. Positive MMP-9 immunolabeling was 51 +/- 11% of circulating lymphocytes. It was observed in some endothelial cells and mononuclear cells adherent to the endothelium and close to myelinated fibers. CONCLUSIONS: Circulating matrix metalloproteinases (MMP-9) correlates with disease severity in Guillain-Barré syndrome (GBS). MMP-9 likely represents an important molecule in the pathogenesis of GBS and therefore could represent an interesting therapeutic target.