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1.
J Gastrointestin Liver Dis ; 25(1): 39-48, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27014752

RESUMO

BACKGROUND AND AIMS: Angiotensin II (AII) is a powerful splanchnic vasoconstrictor with pro-inflammatory and pro-fibrotic properties. Angiotensin converting enzyme (ACE) inhibitors and AII Receptor Antagonists (ARBs) are therapeutic in animal models of colitis. The aim of this case-control study is to determine the expression of angiotensinogen and related genes in human ileal Crohn's disease. METHODS: Using quantitative real-time polymerase chain reaction (RT-PCR), we measured mRNA expression levels of angiotensinogen (AGT), hypoxia inducible factor (HIF)1α and melanoma cell adhesion molecule (MCAM; CD146) in 101 human samples (69 biopsy, 12 resection) from affected ileum (inflamed CD cases, n=36) and unaffected ileum (non-inflamed CD cases, n=45 and controls, n=20). Immunohistochemistry for angiotensinogen was also performed. The study was of case-control design in a tertiary care setting. RESULTS: Ileal expression of AGT was lower in CD cases compared to controls (p<0.0001), in inflamed CD samples (p=0.017) and current smokers (p=0.02). HIF1α expression was lower in non-inflamed CD biopsy samples than controls (p=0.006). The presence of disease-associated NOD2 variants was associated with increased expression of markers of angiogenesis (HIF1α p=0.009; MCAM p=0.007) in inflamed CD samples. Angiotensinogen immunohistochemical staining supported the quantitative RT-PCR expression findings. CONCLUSIONS: Angiotensinogen expression is down regulated in human ileal CD, particularly in the presence of inflammation and current cigarette smoking, implicating the mesenteric vasculature and mucosal hypoxia as co-factors in ileal CD pathogenesis. A novel reduction in HIF1α expression in non-inflamed ileal mucosa in CD patients was also demonstrated.


Assuntos
Proteínas Angiogênicas/análise , Angiotensinogênio/análise , Doença de Crohn/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Íleo/química , Neovascularização Patológica , Adulto , Idoso , Proteínas Angiogênicas/genética , Angiotensinogênio/genética , Antígeno CD146/genética , Estudos de Casos e Controles , Doença de Crohn/genética , Doença de Crohn/patologia , Feminino , Regulação da Expressão Gênica , Genótipo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Íleo/patologia , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Proteína Adaptadora de Sinalização NOD2/genética , Fenótipo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Fumar/efeitos adversos , Adulto Jovem
2.
J Gastrointestin Liver Dis ; 21(4): 349-55, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23256116

RESUMO

BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor (PPAR) γ is a transcription factor, highly expressed in colonic epithelial cells, adipose tissue and macrophages, with an important role in the regulation of inflammatory pathways. The common PPARγ variants C161T and Pro12Ala have recently been associated with Ulcerative Colitis (UC) and an extensive UC phenotype respectively, in a Chinese population. PPARγ Pro12Ala variant homozygotes appear to be protected from the development of Crohn's disease (CD) in European Caucasians. METHODS: A case-control study was performed for both variants (CD n=575, UC n=306, Controls n=360) using a polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis in an Australian IBD cohort. A transmission disequilibrium test was also performed using CD trios for the PPARγ C161T variant. Genotype-phenotype analyses were also undertaken. RESULTS: There was no significant difference in genotype distribution data or allele frequency between CD and UC patients and controls. There was no difference in allele transmission for the C161T variant. No significant relationship between the variants and disease location was observed. CONCLUSIONS: We were unable to replicate in a Caucasian cohort the recent association between PPARγ C161T and UC or between PPARγ Pro12Ala and an extensive UC phenotype in a Chinese population. There are significant ethnic differences in genetic susceptibility to IBD and its phenotypic expression.


Assuntos
Doenças Inflamatórias Intestinais/genética , PPAR gama/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Estudos de Coortes , Colite Ulcerativa/genética , Doença de Crohn/genética , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Projeto HapMap , Humanos , Fenótipo
3.
Expert Rev Gastroenterol Hepatol ; 2(5): 645-51, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19072342

RESUMO

An increasing repertoire of therapeutic indications for the angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists has followed an explosion of research exploring the role of the proinflammatory and profibrotic renin-angiotensin-aldosterone system in numerous organ systems. This evidence also implicates the renin-angiotensin-aldosterone system in the pathogenesis of other chronic inflammatory and fibrotic disorders, such as Crohn's disease. While the research to date supports this hypothesis, further investigation of the renin-angiotensin-aldosterone system in human Crohn's disease is required before these agents can realistically be investigated in human trials.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doença de Crohn/tratamento farmacológico , Angiotensina II/fisiologia , Animais , Doença de Crohn/fisiopatologia , Modelos Animais de Doenças , Trato Gastrointestinal/fisiopatologia , Humanos , Camundongos , Sistema Renina-Angiotensina/fisiologia
4.
Inflamm Bowel Dis ; 14(5): 585-90, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18213697

RESUMO

BACKGROUND: The first major Crohn's disease (CD) susceptibility gene, NOD2, implicates the innate intestinal immune system and other pattern recognition receptors in the pathogenesis of this chronic, debilitating disorder. These include the Toll-like receptors, specifically TLR4 and TLR5. A variant in the TLR4 gene (A299G) has demonstrated variable association with CD. We aimed to investigate the relationship between TLR4 A299G and TLR5 N392ST, and an Australian inflammatory bowel disease cohort, and to explore the strength of association between TLR4 A299G and CD using global meta-analysis. METHODS: Cases (CD = 619, ulcerative colitis = 300) and controls (n = 360) were genotyped for TLR4 A299G, TLR5 N392ST, and the 4 major NOD2 mutations. Data were interrogated for case-control analysis prior to and after stratification by NOD2 genotype. Genotype-phenotype relationships were also sought. Meta-analysis was conducted via RevMan. RESULTS: The TLR4 A299G variant allele showed a significant association with CD compared to controls (P = 0.04) and a novel NOD2 haplotype was identified which strengthened this (P = 0.003). Furthermore, we identified that TLR4 A299G was associated with CD limited to the colon (P = 0.02). In the presence of the novel NOD2 haplotype, TLR4 A299G was more strongly associated with colonic disease (P < 0.001) and nonstricturing disease (P = 0.009). A meta-analysis of 11 CD cohorts identified a 1.5-fold increase in risk for the variant TLR4 A299G allele (P < 0.00001). CONCLUSIONS: TLR 4 A299G appears to be a significant risk factor for CD, in particular colonic, nonstricturing disease. Furthermore, we identified a novel NOD2 haplotype that strengthens the relationship between TLR4 A299G and these phenotypes.


Assuntos
Doença de Crohn/genética , DNA/genética , Mutação , Proteína Adaptadora de Sinalização NOD2/genética , Receptor 4 Toll-Like/genética , Adolescente , Adulto , Doença de Crohn/epidemiologia , Feminino , Frequência do Gene , Haplótipos , Humanos , Incidência , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Estudos Prospectivos , Queensland/epidemiologia
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