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1.
World J Gastroenterol ; 28(30): 4075-4088, 2022 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-36157120

RESUMO

BACKGROUND: Clostridioides difficile (C. difficile) is the most common pathogen causing health care-associated infections. C. difficile TcdA and TcdB have been shown to activate enteric neurons; however, what population of these cells is more profoundly influenced and the mechanism underlying these effects remain unknown. AIM: To characterize a specific population of TcdA-affected myenteric neurons and investigate the role of the P2X7 receptor in TcdA-induced ileal inflammation, cell death, and the changes in the enteric nervous system in mice. METHODS: Swiss mice were used to model TcdA-induced ileitis in ileal loops exposed to TcdA (50 µg/Loop) for 4 h. To investigate the role of the P2X7 receptor, Brilliant Blue G (50 mg/kg, i.p.), which is a nonspecific P2X7 receptor antagonist, or A438079 (0.7 µg/mouse, i.p.), which is a competitive P2X7 receptor antagonist, were injected one hour prior to TcdA challenge. Ileal samples were collected to analyze the expression of the P2X7 receptor (by quantitative real-time polymerase chain reaction and immunohistochemistry), the population of myenteric enteric neurons (immunofluorescence), histological damage, intestinal inflammation, cell death (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling), neuronal loss, and S100B synthesis (immunohistochemistry). RESULTS: TcdA upregulated (P < 0.05) the expression of the P2X7 receptor gene in the ileal tissues, increasing the level of this receptor in myenteric neurons compared to that in control mice. Comparison with the control mice indicated that TcdA promoted (P < 0.05) the loss of myenteric calretinin+ (Calr) and choline acetyltransferase+ neurons and increased the number of nitrergic+ and Calr+ neurons expressing the P2X7 receptor. Blockade of the P2X7 receptor decreased TcdA-induced intestinal damage, cytokine release [interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor-α], cell death, enteric neuron loss, and S100B synthesis in the mouse ileum. CONCLUSION: Our findings demonstrated that TcdA induced the upregulation of the P2X7 receptor, which promoted enteric neuron loss, S100B synthesis, tissue damage, inflammation, and cell death in the mouse ileum. These findings contribute to the future directions in understanding the mechanism involved in intestinal dysfunction reported in patients after C. difficile infection.


Assuntos
Toxinas Bacterianas , Clostridioides difficile , Ileíte , Animais , Apoptose , Biotina/metabolismo , Calbindina 2 , Colina O-Acetiltransferase/metabolismo , DNA Nucleotidilexotransferase/metabolismo , Enterotoxinas , Ileíte/induzido quimicamente , Inflamação/patologia , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Camundongos , Neurônios/patologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7 , Fator de Necrose Tumoral alfa/metabolismo
3.
Life Sci ; 301: 120562, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35487304

RESUMO

AIMS: Anomalies in dopaminergic machinery have been shown in inflammatory bowel disease (IBD) patients and preclinical models of IBD. Thus, we aimed to evaluate the impact of dextran sodium sulfate (DSS)-induced ileitis on enteric dopaminergic pathways. MATERIALS AND METHODS: Male C57/Bl6 mice (10 ± 2 weeks old) received 2% DSS in drinking water for 5 days and were then switched to regular drinking water for 3 days. To measure ileitis severity inflammatory cytokines (IL-1ß, TNFα, IL-6) levels were assessed. Changes in ileal muscle tension were isometrically recorded following: 1) cumulative addition of dopamine on basal tone (0.1-1000 µM); ii) 4-Hz electric field stimulation (EFS) in the presence of 30 µM dopamine with/without 10 µM SCH-23390 (dopamine D1 receptor (D1R) antagonist) or 10 µM sulpiride (D2R antagonist). Immunofluorescence distribution of the neuronal HuC/D protein, glial S100ß marker, D1R, and dopamine transporter (DAT) were determined in longitudinal-muscle-myenteric plexus whole-mounts (LMMPs) by confocal microscopy. D1R and D2R mRNA transcripts were evaluated by qRT-PCR. KEY FINDINGS: DSS caused an inflammatory process in the small intestine associated to dysmotility and altered barrier permeability, as suggested by decreased fecal output and enhanced stool water content. DSS treatment caused a significant increase of DAT and D1R myenteric immunoreactivity as well as of D1R and D2R mRNA levels, accompanied by a significant reduction of dopamine-mediated relaxation, involving primarily D1-like receptors. SIGNIFICANCE: Mouse ileitis affects enteric dopaminergic neurotransmission mainly involving D1R-mediated responses. These findings provide novel information on the participation of dopaminergic pathways in IBD-mediated neuromuscular dysfunction.


Assuntos
Água Potável , Ileíte , Doenças Inflamatórias Intestinais , Animais , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Dopamina , Antagonistas de Dopamina , Humanos , Ileíte/induzido quimicamente , Intestino Delgado/metabolismo , Masculino , Camundongos , RNA Mensageiro/genética , Receptores de Dopamina D1/metabolismo , Transmissão Sináptica/fisiologia
5.
Dig Dis Sci ; 67(10): 4687-4694, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35006492

RESUMO

BACKGROUND AND AIMS: The treatment of chronic pouchitis remains a challenge due to the paucity of high-quality studies. We aimed to provide guidance for clinicians on the appropriateness of medical and surgical treatments in chronic pouchitis. METHODS: Appropriateness of medical and surgical treatments in patients with chronic pouchitis was considered in 16 scenarios incorporating presence/absence of four variables: pouchitis symptoms, response to antibiotics, significant prepouch ileitis, and Crohn's disease (CD)-like complications (i.e., stricture or fistula). Appropriateness of permanent ileostomy in patients refractory to medical treatments was considered in eight additional scenarios. Using the RAND/UCLA appropriateness method, international IBD expert panelists rated appropriateness of treatments in each scenario on a 1-9 scale. RESULTS: Chronic antibiotic therapy was rated appropriate only in asymptomatic antibiotic-dependent patients with no CD-like complications and inappropriate in all other scenarios. Ileal-release budesonide was rated appropriate in 6/16 scenarios including patients with significant prepouch ileitis but no CD-like complications. Probiotics were considered either inappropriate (14/16) or uncertain (2/16). Biologic therapy was considered appropriate in most scenarios (14/16) and uncertain in situations where significant prepouch ileitis or CD-like complications were absent (2/16). In patients who are refractory to all medications, permanent ileostomy was considered appropriate in all scenarios (7/8) except in asymptomatic patients with no CD-like complications. CONCLUSIONS: In the presence of significant prepouch ileitis or CD-like complications, chronic antibiotics and probiotics are inappropriate. Biologics are appropriate in all patients except in asymptomatic patients with no evidence of complications. Permanent ileostomy is appropriate in most medically refractory patients.


Assuntos
Produtos Biológicos , Doença de Crohn , Doença Enxerto-Hospedeiro , Ileíte , Pouchite , Antibacterianos/uso terapêutico , Produtos Biológicos/uso terapêutico , Budesonida/uso terapêutico , Doença de Crohn/tratamento farmacológico , Humanos , Ileíte/etiologia , Pouchite/diagnóstico , Pouchite/tratamento farmacológico
6.
J Crohns Colitis ; 16(6): 978-991, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34893805

RESUMO

BACKGROUND AND AIMS: Crohn's disease is a debilitating chronic inflammatory disorder of the mammalian gastrointestinal tract. Current interventions using anti-tumour necrosis factor [anti-TNF] biologics show long-term benefit in only half of patients. This study focused on the role of the TNF receptor 1 [TNFR1] in pathogenesis in a TNF-driven model of ileitis. METHODS: We studied TNFΔAU-rich element [ARE]/+ [TNFdARE] mice, which develop progressive ileitis similar to Crohn's ileitis. Histopathological analysis and gene expression profiling were used to characterize disease progression from 5 to 16 weeks. Mice with TNFR1 hemizygosity [TNFdARE/R1het] allowed us to assess gene dosage effects. Transcriptional profiling established inflection points in disease progression; inflammatory gene expression increased at 8 weeks with a plateau by 10 weeks, so these were selected as endpoints of treatment using the TNF biologic infliximab and the TNFR1-specific XPro1595. Differences in recruitment of cells in the lamina propria were assessed using flow cytometry. RESULTS: TNFdARE/R1het mice displayed stable long-term protection from disease, associated with decreased recruitment of CD11bhiF4/80lo monocytes and CD11bhiLy6Ghi neutrophils, suggesting an important role of TNFR1 signalling in pathogenesis, and indicating potential benefit from TNFR1-specific intervention. Treatment with infliximab and XPro1595 both showed a similar impact on disease in TNFdARE mice. Importantly, these beneficial effects were greatly surpassed by hemizygosity at the TNFR1 locus. CONCLUSIONS: Treatment with either infliximab or XPro1595 produced moderate protection from ileitis in TNFdARE mice. However, hemizygosity at the TNFR1 locus in TNFdARE mice showed far better protection, implicating TNFR1 signalling as a key mediator of TNF-driven disease.


Assuntos
Doença de Crohn , Ileíte , Animais , Doença de Crohn/complicações , Progressão da Doença , Ileíte/tratamento farmacológico , Ileíte/etiologia , Ileíte/prevenção & controle , Infliximab/farmacologia , Infliximab/uso terapêutico , Mamíferos/metabolismo , Camundongos , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/metabolismo
7.
Dig Dis Sci ; 67(5): 1783-1793, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34350516

RESUMO

BACKGROUND: Clinical observations indicate that mechanical factors contribute to the expression or recurrence of Crohn's disease. We investigated whether the creation of an intestinal stenosis could alter the severity of the expected Crohn-like ileitis, in a Crohn's disease animal model, the TNFΔare/+ mouse. METHODS: Thirty-six, 6-weeks-old TNFΔare/+ mice, were divided into 3 intervention groups: triple suture, single suture and sham. In the terminal ileum, in the first group, a triple suture stenosis was created, whereas, in the second, a loose suture was placed. Same triple-suture stenosis was performed on twelve wild type mice. All animals were sacrificed at 6 weeks post-operatively and the ileum parts were evaluated histopathologically. A summative total ileitis score was applied in each sample using a bespoke semiquantitative histological scoring system for the Crohn-like changes. RESULTS: The triple suture stenosis induced significant muscular hypertrophy proximal to interventional site which was more prominent in TNFΔare/+ than wild type mice. In triple suture group, the total ileitis score was significantly increased proximal to the intervention as compared to the single suture (P: 0.004) and the sham groups (P: 0.013). The total ileitis score distally, was unaffected, regardless of the experimental intervention. Intestinal stenosis did not induce intestinal inflammation in wild type mice. CONCLUSION: The creation of a stenosis in the terminal ileum of TNFΔare/+ mice alters Crohn-like inflammation. We assume that mechanical forces, such as intraluminal pressure, may contribute as important co-factors to the pathophysiology of Crohn's disease in genetically predisposed subjects.


Assuntos
Doença de Crohn , Ileíte , Obstrução Intestinal , Animais , Constrição Patológica , Doença de Crohn/patologia , Humanos , Ileíte/patologia , Inflamação , Obstrução Intestinal/etiologia , Camundongos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
8.
Mucosal Immunol ; 15(1): 10-26, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34316007

RESUMO

Crohn's disease (CD) and ulcerative colitis (UC) are both characterized by chronic inflammation and severe dysfunction of the gastrointestinal tract. These two forms of inflammatory bowel disease (IBD) represent distinct clinical disorders with diverse driving mechanisms; however, this divergence is not reflected in currently approved therapeutics that commonly target general proinflammatory pathways. A compelling need therefore remains to understand factors that differentiate the topology and the distinct clinical manifestations of CD versus UC, in order to develop more effective and specialized therapies. Animal models provide valuable platforms for studying IBD heterogeneity and deciphering disease-specific mechanisms. Both the established and the newly developed ileitis mouse models are characterized by various disease initiating mechanisms and diverse phenotypic outcomes that reflect the complexity of human CD-ileitis. Microbial dysbiosis, destruction of epithelial barrier integrity, immune cell deregulation, as well as the recently described genome instability and stromal cell activation have all been proposed as the triggering factors for the development of ileitis-associated pathology. In this review, we aim to critically evaluate the mechanistic underpinnings of murine models of CD-ileitis, discuss their phenotypic similarities to human disease, and envisage their further exploitation for the development of novel targeted and personalized therapeutics.


Assuntos
Doença de Crohn/fisiopatologia , Disbiose/fisiopatologia , Ileíte/fisiopatologia , Animais , Doença de Crohn/terapia , Modelos Animais de Doenças , Disbiose/terapia , Humanos , Ileíte/terapia , Inflamação , Camundongos , Fenótipo
9.
Gut ; 71(3): 487-496, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-33963042

RESUMO

OBJECTIVE: Although immunoglobulin A (IgA) is abundantly expressed in the gut and known to be an important component of mucosal barriers against luminal pathogens, its precise function remains unclear. Therefore, we tried to elucidate the effect of IgA on gut homeostasis maintenance and its mechanism. DESIGN: We generated various IgA mutant mouse lines using the CRISPR/Cas9 genome editing system. Then, we evaluated the effect on the small intestinal homeostasis, pathology, intestinal microbiota, cytokine production, and immune cell activation using intravital imaging. RESULTS: We obtained two lines, with one that contained a <50 base pair deletion in the cytoplasmic region of the IgA allele (IgA tail-mutant; IgAtm/tm) and the other that lacked the most constant region of the IgH α chain, which resulted in the deficiency of IgA production (IgA-/-). IgA-/- exhibited spontaneous inflammation in the ileum but not the other parts of the gastrointestinal tract. Associated with this, there were significantly increased lamina propria CD4+ T cells, elevated productions of IFN-γ and IL-17, increased ileal segmented filamentous bacteria and skewed intestinal microflora composition. Intravital imaging using Ca2+ biosensor showed that IgA-/- had elevated Ca2+ signalling in Peyer's patch B cells. On the other hand, IgAtm/tm seemed to be normal, suggesting that the IgA cytoplasmic tail is dispensable for the prevention of the intestinal disorder. CONCLUSION: IgA plays an important role in the mucosal homeostasis associated with the regulation of intestinal microbiota and protection against mucosal inflammation especially in the ileum.


Assuntos
Ileíte/etiologia , Íleo/patologia , Imunoglobulina A/fisiologia , Animais , Linfócitos B/fisiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Microbioma Gastrointestinal , Homeostase , Ileíte/metabolismo , Ileíte/patologia , Íleo/metabolismo , Íleo/ultraestrutura , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Microscopia Intravital , Masculino , Camundongos , Camundongos Mutantes , Linfócitos T/fisiologia
10.
Clin Gastroenterol Hepatol ; 20(5): e964-e973, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-33549866

RESUMO

BACKGROUND & AIMS: Patients with primary sclerosing cholangitis (PSC) commonly undergo ileal pouch-anal anastomosis (IPAA) for medically-refractory ulcerative colitis (UC) or colorectal dysplasia. Pouchitis develops more frequently in patients with PSC, potentially leading to increased morbidity. We aimed to assess clinical characteristics and treatment outcomes for pouchitis in patients with PSC compared to a matched, non-PSC cohort. METHODS: All patients with PSC who underwent IPAA and were diagnosed with pouchitis (PSC-pouchitis) were identified. A matched cohort composed of non-PSC patients who underwent IPAA for UC and subsequently developed pouchitis (UC-pouchitis) was developed. Relevant demographic, clinical, endoscopic, histologic, and treatment data were collected and compared between groups. RESULTS: Of those with PSC-pouchitis (n=182), 53.9% and 46.1% underwent IPAA for medically-refractory disease and dysplasia, respectively, compared to 88.7% and 11.3% in the UC-pouchitis group (P < .001). Patients with PSC-pouchitis were more likely to develop chronic pouchitis (68.1% vs 34.1%; P < .001), have moderate-to-severe pouch inflammation (54.9% vs 32.4%; P < .001), and prepouch ileitis (34.1% vs 11.5%; P < .001) compared to UC-pouchitis. Of those with PSC-pouchitis, 50.6% and 17.6% developed chronic antibiotic-dependent or antibiotic-refractory pouchitis, respectively, compared to 25.8% and 7.7% with UC-pouchitis. There was no difference in treatment response between the two groups with use of thiopurines, anti-tumor necrosis factor agents, and newer biologics. CONCLUSIONS: PSC-associated pouchitis presents with a unique clinical phenotype, characterized by increased risk of chronic pouchitis, moderate-to-severe pouch inflammation, prepouch ileitis, and less response to conventional antimicrobial therapy.


Assuntos
Colangite Esclerosante , Colite Ulcerativa , Bolsas Cólicas , Ileíte , Pouchite , Proctocolectomia Restauradora , Antibacterianos , Colangite Esclerosante/complicações , Colangite Esclerosante/cirurgia , Colite Ulcerativa/complicações , Colite Ulcerativa/cirurgia , Bolsas Cólicas/efeitos adversos , Humanos , Ileíte/complicações , Inflamação/etiologia , Fenótipo , Pouchite/tratamento farmacológico , Pouchite/etiologia , Proctocolectomia Restauradora/efeitos adversos
11.
Immunity ; 54(12): 2795-2811.e9, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34788601

RESUMO

Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their impact on disease progression. Whole-mount and intravital imaging of the ileum and ileum-draining collecting lymphatic vessels (CLVs) draining to mesenteric lymph nodes from TNFΔARE mice, a model of ileitis, revealed TLO formation at valves of CLVs. TLOs obstructed cellular and molecular outflow from the gut and were sites of lymph leakage and backflow. Tumor necrosis factor (TNF) neutralization begun at early stages of TLO formation restored lymph transport. However, robustly developed, chronic TLOs resisted regression and restoration of flow after TNF neutralization. TNF stimulation of cultured lymphatic endothelial cells reprogrammed responses to oscillatory shear stress, preventing the induction of valve-associated genes. Disrupted transport of immune cells, driven by loss of valve integrity and TLO formation, may contribute to the pathology of Crohn's disease.


Assuntos
Doença de Crohn/imunologia , Células Endoteliais/imunologia , Íleo/imunologia , Linfa/metabolismo , Vasos Linfáticos/imunologia , Mesentério/imunologia , Estruturas Linfoides Terciárias/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Movimento Celular , Células Cultivadas , Modelos Animais de Doenças , Humanos , Ileíte , Linfangite , Camundongos , Camundongos Knockout , Estresse Mecânico
12.
Brain Behav Immun ; 98: 245-250, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34403735

RESUMO

Patients with inflammatory bowel disease (IBD) are particularly susceptible to behavioral diagnoses, and the microbiome has been repeatedly implicated in the pathogenesis of IBD. The intestinal microbiome's ability to affect behavior has become increasingly recognized and studied. The so-called 'psychobiome' has been linked to a plethora of neurological and psychological diagnoses, including autism and Parkinson's disease. Despite the ability of many bacterial species within the human intestinal microbiome to synthesize neurotransmitters, it has never been previously reported that a single bacterial species is sufficient to induce depression. Here, we demonstrate that our mouse model of Crohn's disease (CD)-like ileitis, the SAMP1/YitFc (SAMP1), does not exhibit baseline behavioral abnormalities. By comparison, SAMP6 mice develop depressive-like behavior that is associated with a rise in the GABA-producing bacterial genus Parabacteroides. We finally demonstrate that administration of Parabacteroides distasonis into our SAMP1 mice induces depressive-like behavior. Colonization with P. distasonis was not associated with increased intestinal inflammation or alterations in other measures of behavior. The intestinal environment of CD may be particularly conducive to colonization with P. distasonis and subsequent induction of depressive-like behavior. To our knowledge, this is the first report of a bacterial species specifically inducing depressive-like behavior.


Assuntos
Doença de Crohn , Ileíte , Animais , Bacteroidetes , Modelos Animais de Doenças , Humanos , Camundongos
13.
Arq Gastroenterol ; 58(2): 145-149, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34231660

RESUMO

BACKGROUND: Ileitis is defined as an inflammation of the ileum, which is evaluated during colonoscopy. Biopsies should be performed on altered ileus, aiding to the diagnosis. OBJECTIVE: Evaluate the correlation of anatomopathological findings on ileitis between pathologists and endoscopists. METHODS: A retrospective, cross-sectional study, between 2013 and 2017. Examination report, indications for colonoscopy, and medical records were evaluated to identify whether the colonoscopic findings were clinically significant. Anatomopathological samples were reviewed by a pathologist expert in gastrointestinal tract. Patients over 18 years of age who had undergone ileoscopy were included, whereas patients below 18 years of age and those with previous intestinal resections were excluded. The correlation was assessed using the kappa coefficient index. RESULTS: A total of 5833 colonoscopies were conducted in the study period and 3880 cases were included. Ileal alterations were observed in 206 cases, with 2.94% being clinically significant. A hundred and sixty three biopsies were evaluated using the kappa index, resulting in agreement among pathologists of 0.067 and among pathologist and endoscopist of 0.141. CONCLUSION: It was observed that despite the low concordance between pathologists and endoscopists, there was no change in patient outcomes. This study confirms the importance of knowledge of the main anatomopathological changes related to ileitis by pathologists and endoscopists, making the best diagnosis and follow-up.


Assuntos
Ileíte , Patologistas , Adolescente , Adulto , Colonoscopia , Estudos Transversais , Humanos , Idioma , Estudos Retrospectivos
15.
Drug Dev Res ; 82(8): 1235-1246, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34075610

RESUMO

Inhibitors of bromodomain and extra-terminal motif (BET) proteins are emerging epigenetic therapeutics that suppress gene expressions that drive cancer and inflammation. The present study examined anti-inflammatory effects of a quinazoline-based BET inhibitor, CN210, in a murine ileitis model. CN210 was given orally 30 min before and 24 h after a subcutaneous administration of indomethacin. Macroscopic and histological evidences of ileitis, mucosal myeloperoxidase (MPO) activity and cytokine expressions were evaluated 48 h after the indomethacin administration. To further characterize the anti-inflammatory pathways modulated by CN210, its effects on RAW264 cells treated with lipopolysaccharide (LPS) were investigated. Competitive ligand binding and docking studies of CN210 to CREB-binding protein (CBP) and p300 were also performed. Oral administration of CN210 significantly reduced the severity of ileitis, normalized both proinflammatory MPO activity and concomitant cytokine expressions induced by indomethacin administration. Furthermore, CN210 attenuated the expression of cytokines and reversed the activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPK) induced by LPS. Competitive ligand binding assays showed that CN210 bound to the bromodomains of two paralogous histone acetyltransferases, CBP and p300, in addition to the bromodomains of BET proteins. Docking studies of CN210 to the bromodomains of CBP and p300 showed a similarity to the binding mode of SGC-CBP30, a specific CBP/p300 inhibitor. CN210 ameliorates indomethacin-induced ileitis by inhibiting the expression of inflammatory cytokines through the attenuation of NF-κB and MAPK pathways. CN210 thus represents a new mode of therapy for non-steroidal anti-inflammatory drug-induced ileitis and inflammatory bowel disease.


Assuntos
Anti-Inflamatórios/farmacologia , Citocinas/antagonistas & inibidores , Ileíte/tratamento farmacológico , Indometacina/efeitos adversos , Proteínas/antagonistas & inibidores , Animais , Citocinas/biossíntese , Proteína p300 Associada a E1A/metabolismo , Ileíte/induzido quimicamente , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/fisiologia , Peroxidase/metabolismo , Fosfoproteínas/metabolismo , Quinazolinas/farmacologia , Células RAW 264.7
16.
Arq. gastroenterol ; 58(2): 145-149, Apr.-June 2021. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1285314

RESUMO

ABSTRACT BACKGROUND: Ileitis is defined as an inflammation of the ileum, which is evaluated during colonoscopy. Biopsies should be performed on altered ileus, aiding to the diagnosis. OBJECTIVE: Evaluate the correlation of anatomopathological findings on ileitis between pathologists and endoscopists. METHODS: A retrospective, cross-sectional study, between 2013 and 2017. Examination report, indications for colonoscopy, and medical records were evaluated to identify whether the colonoscopic findings were clinically significant. Anatomopathological samples were reviewed by a pathologist expert in gastrointestinal tract. Patients over 18 years of age who had undergone ileoscopy were included, whereas patients below 18 years of age and those with previous intestinal resections were excluded. The correlation was assessed using the kappa coefficient index. RESULTS: A total of 5833 colonoscopies were conducted in the study period and 3880 cases were included. Ileal alterations were observed in 206 cases, with 2.94% being clinically significant. A hundred and sixty three biopsies were evaluated using the kappa index, resulting in agreement among pathologists of 0.067 and among pathologist and endoscopist of 0.141. CONCLUSION: It was observed that despite the low concordance between pathologists and endoscopists, there was no change in patient outcomes. This study confirms the importance of knowledge of the main anatomopathological changes related to ileitis by pathologists and endoscopists, making the best diagnosis and follow-up.


RESUMO CONTEXTO: Ileíte é definida como uma inflamação ileal, que pode ser avaliada durante a colonoscopia. Biópsias devem ser realizadas em íleos alterados, acrescentando na definição diagnóstica. OBJETIVO: Avaliar a correlação de achados anatomopatológicos das ileítes entre patologistas e endoscopistas. MÉTODOS: Estudo retrospectivo, transversal, entre os anos de 2013 e 2017. Foram avaliados laudos de exames, indicações e prontuários para identificar quando os achados colonoscópicos foram significativos. As amostras de anatomopatologia foram revisadas por um patologista especialista em trato gastrointestinal. Foram incluídos pacientes acima de 18 anos, com ileoscopia, e excluídos pacientes menores de 18 anos e os com ressecções intestinais prévias. A correlação foi avaliada utilizando-se o coeficiente kappa. RESULTADOS: Durante o período do estudo foram realizadas 5833 colonoscopias, das quais 3880 foram incluídas. Alterações ileais foram observadas em 206 casos, com 2,94% sendo clinicamente significativo. Cento e sessenta e três biópsias foram avaliadas, resultando em coeficiente kappa entre patologistas de 0,067 e entre patologista e endoscopista de 0,141. CONCLUSÃO: Foi observado que a despeito da baixa concordância entre patologistas e endoscopistas, não houve mudança no desfecho clínico do paciente. Esse estudo confirma a importância do conhecimento dos achados anatomopatológicos principais das ileítes entre patologistas e endoscopias, fazendo o melhor diagnóstico e seguimento.


Assuntos
Humanos , Adolescente , Adulto , Patologistas , Ileíte , Estudos Transversais , Estudos Retrospectivos , Colonoscopia , Idioma
17.
Turk J Gastroenterol ; 32(2): 123-132, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33960935

RESUMO

BACKGROUND: In Turkey, cytomegalovirus (CMV) seropositivity has been reported to be high, between 85 and 100%. CMV has been responsible for disease exacerbation in inflammatory bowel disease (IBD). We aimed to evaluate the presence of CMV in intestinal tissue by immunohistochemical staining in IBD and non-IBD patient groups, in a country with high CMV seroprevalence. METHODS: In this prospective cross-sectional study, the presence of intestinal CMV was investigated with tissue immunohistochemistry (IHC) staining, which is accepted as the gold standard method, and with polymerase chain reaction (PCR) in tissue and blood. Patients (≥18 years old, n = 189) who had a colonoscopic biopsy between January and May 2017 were included in the study at our hospital. Clinical, laboratory, endoscopic, and histopathological data of patients were assessed by dividing them into IBD (n = 34) and non-IBD (n = 155) groups. RESULTS: In this study, 567 colonic biopsy samples from 189 patients were evaluated. Tissue IHC staining was positive for 3 (1.58%) non-IBD patients. One of them was diagnosed as CMV ileitis. CMV DNA was also detected in 14 plasma (7.40%, <80-469 copies/mL) and 20 tissue samples (10.69%, 7-15 289 copies/mL). Tissue IHC staining is accepted as the gold standard for CMV ileitis, and the sensitivity and specificity of tissue PCR was 33% and 89.67%, while the sensitivity and specificity of plasma PCR was 66.66% and 93.54%, respectively. CONCLUSION: Although CMV seroprevalence is high in Turkey, CMV ileitis was diagnosed in only one non-IBD patient (0.53%). Compared to tissue IHC staining, the sensitivity of tissue and blood CMV PCR was low while their specificity was higher.


Assuntos
Colite , Infecções por Citomegalovirus , Ileíte , Doenças Inflamatórias Intestinais , Adolescente , Estudos Transversais , Citomegalovirus/genética , Infecções por Citomegalovirus/epidemiologia , DNA Viral , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Estudos Prospectivos , Estudos Soroepidemiológicos
18.
Proc Natl Acad Sci U S A ; 118(20)2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33972436

RESUMO

Metabolic changes associated with tissue inflammation result in significant extracellular acidosis (EA). Within mucosal tissues, intestinal epithelial cells (IEC) have evolved adaptive strategies to cope with EA through the up-regulation of SLC26A3 to promote pH homeostasis. We hypothesized that EA significantly alters IEC gene expression as an adaptive mechanism to counteract inflammation. Using an unbiased RNA sequencing approach, we defined the impact of EA on IEC gene expression to define molecular mechanisms by which IEC respond to EA. This approach identified a unique gene signature enriched in cyclic AMP response element-binding protein (CREB)-regulated gene targets. Utilizing loss- and gain-of-function approaches in cultured epithelia and murine colonoids, we demonstrate that EA elicits prominent CREB phosphorylation through cyclic AMP-independent mechanisms that requires elements of the mitogen-activated protein kinase signaling pathway. Further analysis revealed that EA signals through the G protein-coupled receptor GPR31 to promote induction of FosB, NR4A1, and DUSP1. These studies were extended to an in vivo murine model in conjunction with colonization of a pH reporter Escherichia coli strain that demonstrated significant mucosal acidification in the TNFΔARE model of murine ileitis. Herein, we observed a strong correlation between the expression of acidosis-associated genes with bacterial reporter sfGFP intensity in the distal ileum. Finally, the expression of this unique EA-associated gene signature was increased during active inflammation in patients with Crohn's disease but not in the patient control samples. These findings establish a mechanism for EA-induced signals during inflammation-associated acidosis in both murine and human ileitis.


Assuntos
Acidose/genética , Antiporters/genética , Doença de Crohn/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Ileíte/genética , Receptores Acoplados a Proteínas G/genética , Transportadores de Sulfato/genética , Acidose/metabolismo , Acidose/patologia , Animais , Antiporters/metabolismo , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Fosfatase 1 de Especificidade Dupla/genética , Fosfatase 1 de Especificidade Dupla/metabolismo , Regulação da Expressão Gênica , Humanos , Ileíte/metabolismo , Ileíte/patologia , Íleo/metabolismo , Íleo/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Organoides/metabolismo , Organoides/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Análise de Sequência de RNA , Transdução de Sinais , Transportadores de Sulfato/metabolismo
19.
Nature ; 593(7857): 147-151, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33828301

RESUMO

Bile acids are lipid-emulsifying metabolites synthesized in hepatocytes and maintained in vivo through enterohepatic circulation between the liver and small intestine1. As detergents, bile acids can cause toxicity and inflammation in enterohepatic tissues2. Nuclear receptors maintain bile acid homeostasis in hepatocytes and enterocytes3, but it is unclear how mucosal immune cells tolerate high concentrations of bile acids in the small intestine lamina propria (siLP). CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter MDR1 (encoded by Abcb1a) in the siLP to prevent bile acid toxicity and suppress Crohn's disease-like small bowel inflammation4. Here we identify the nuclear xenobiotic receptor CAR (encoded by Nr1i3) as a regulator of MDR1 expression in T cells that can safeguard against bile acid toxicity and inflammation in the mouse small intestine. Activation of CAR induced large-scale transcriptional reprogramming in Teff cells that infiltrated the siLP, but not the colon. CAR induced the expression of not only detoxifying enzymes and transporters in siLP Teff cells, as in hepatocytes, but also the key anti-inflammatory cytokine IL-10. Accordingly, CAR deficiency in T cells exacerbated bile acid-driven ileitis in T cell-reconstituted Rag1-/- or Rag2-/- mice, whereas pharmacological activation of CAR suppressed it. These data suggest that CAR acts locally in T cells that infiltrate the small intestine to detoxify bile acids and resolve inflammation. Activation of this program offers an unexpected strategy to treat small bowel Crohn's disease and defines lymphocyte sub-specialization in the small intestine.


Assuntos
Ácidos e Sais Biliares/metabolismo , Regulação da Expressão Gênica , Intestino Delgado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Linfócitos T/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Linfócitos T CD4-Positivos/metabolismo , Receptor Constitutivo de Androstano , Doença de Crohn/metabolismo , Feminino , Ileíte/metabolismo , Inflamação/metabolismo , Interleucina-10/biossíntese , Interleucina-10/genética , Intestino Delgado/citologia , Camundongos
20.
Int J Mol Sci ; 22(8)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920650

RESUMO

Electrolytes (NaCl) and fluid malabsorption cause diarrhea in inflammatory bowel disease (IBD). Coupled NaCl absorption, mediated by Na+/H+ and Cl-/HCO3- exchanges on the intestinal villus cells brush border membrane (BBM), is inhibited in IBD. Arachidonic acid metabolites (AAMs) formed via cyclooxygenase (COX) or lipoxygenase (LOX) pathways are elevated in IBD. However, their effects on NaCl absorption are not known. We treated SAMP1/YitFc (SAMP1) mice, a model of spontaneous ileitis resembling human IBD, with Arachidonyl Trifluoro Methylketone (ATMK, AAM inhibitor), or with piroxicam or MK-886, to inhibit COX or LOX pathways, respectively. Cl-/HCO3- exchange, measured as DIDS-sensitive 36Cl uptake, was significantly inhibited in villus cells and BBM vesicles of SAMP1 mice compared to AKR/J controls, an effect reversed by ATMK. Piroxicam, but not MK-886, also reversed the inhibition. Kinetic studies showed that inhibition was secondary to altered Km with no effects on Vmax. Whole cell or BBM protein levels of Down-Regulated in Adenoma (SLC26A3) and putative anion transporter-1 (SLC26A6), the two key BBM Cl-/HCO3- exchangers, were unaltered. Thus, inhibition of villus cell Cl-/HCO3- exchange by COX pathway AAMs, such as prostaglandins, via reducing the affinity of the exchanger for Cl-, and thereby causing NaCl malabsorption, could significantly contribute to IBD-associated diarrhea.


Assuntos
Ácidos Araquidônicos/metabolismo , Antiportadores de Cloreto-Bicarbonato/metabolismo , Enterócitos/metabolismo , Ileíte/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Ácido 4,4'-Di-Isotiocianoestilbeno-2,2'-Dissulfônico/farmacologia , Animais , Ácidos Araquidônicos/farmacologia , Células Cultivadas , Antiportadores de Cloreto-Bicarbonato/antagonistas & inibidores , Inibidores de Ciclo-Oxigenase/farmacologia , Enterócitos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Ileíte/genética , Indóis/farmacologia , Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/farmacologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/genética , Piroxicam/farmacologia
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