Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.116
Filtrar
1.
Gut ; 69(2): 252-263, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31092589

RESUMO

OBJECTIVE: To study the role of α4ß7 integrin for gut homing of monocytes and to explore the biological consequences of therapeutic α4ß7 inhibition with regard to intestinal wound healing. DESIGN: We studied the expression of homing markers on monocyte subsets in the peripheral blood and on macrophage subsets in the gut of patients with IBD and controls with flow cytometry and immunohistochemistry. Integrin function was addressed with dynamic adhesion assays and in vivo gut homing assays. In vivo wound healing was studied in mice deficient for or depleted of α4ß7 integrin. RESULTS: Classical and non-classical monocytes were clearly dichotomous regarding homing marker expression including relevant expression of α4ß7 integrin on human and mouse non-classical monocytes but not on classical monocytes. Monocyte-expressed α4ß7 integrin was functionally important for dynamic adhesion to mucosal vascular addressin cell adhesion molecule 1 and in vivo gut homing. Impaired α4ß7-dependent gut homing was associated with reduced (effect size about 20%) and delayed wound healing and suppressed perilesional presence of wound healing macrophages. Non-classical monocytes in the peripheral blood were increased in patients with IBD under clinical treatment with vedolizumab. CONCLUSION: In addition to reported effects on lymphocytes, anti-α4ß7 therapy in IBD also targets non-classical monocytes. Impaired gut homing of such monocytes might lead to a reduction of wound healing macrophages and could potentially explain increased rates of postoperative complications in vedolizumab-treated patients, which have been observed in some studies.


Assuntos
Doenças Inflamatórias Intestinais/patologia , Integrinas/fisiologia , Intestinos/patologia , Monócitos/fisiologia , Cicatrização/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Estudos de Casos e Controles , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Quimiotaxia de Leucócito/fisiologia , Feminino , Fármacos Gastrointestinais/farmacologia , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/fisiopatologia , Integrinas/antagonistas & inibidores , Integrinas/sangue , Mucosa Intestinal/metabolismo , Intestinos/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/metabolismo , Cicatrização/efeitos dos fármacos , Adulto Jovem
2.
J Enzyme Inhib Med Chem ; 35(1): 1-20, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31619080

RESUMO

Inflammatory bowel disease (IBD) is a chronic immuno-inflammation in gastrointestinal tract. We have evaluated the activity of the compounds to inhibit the adhesion of monocytes to colon epithelial cells is triggered by a pro-inflammatory cytokine, tumour necrosis factor (TNF)-α. The in vitro activity of the compounds, 13b (an ureido-derivative), 14c, 14j, 14k, 14n (thioureido-), 18c and 18d (sulfonamido-), was in correlation with in vivo anti-colitis activity revealed as significant recovery in body- and colon-weights and colon myeloperoxidase level, a biochemical marker of inflammation reflecting neutrophil infiltration. In vivo, TNBS-induced changes in the expression of inflammatory cytokines (TNF-α, IL-6, IL-1ß, IL-10, and TGF-ß), NLRP3 inflammasome components (NLRP-3, Caspase-1, and IL-18), and epithelial junction molecules (E-cadherin, claudin2/3, and ZO-1) were blocked and recovered by oral administration of the compounds (1 mg/kg). Compound 14n which showed the best efficacy can be a promising lead for orally available therapeutics for pathology of IBD.


Assuntos
Anti-Inflamatórios/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Piridinas/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Células Cultivadas , Colite/induzido quimicamente , Colite/tratamento farmacológico , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Células HT29 , Humanos , Doenças Inflamatórias Intestinais/patologia , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ácido Trinitrobenzenossulfônico , Células U937
3.
Surg Clin North Am ; 99(6): 1063-1082, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31676048

RESUMO

The roles of flexible endoscopy in the setting of inflammatory bowel disease include diagnosis, surveillance, and determining response to treatment and monitoring for the development of recurrence, dysplasia, or malignancy. Advanced techniques, such as chromoendoscopy and narrow band imaging, can be useful adjuncts when performing endoscopy in patients with inflammatory bowel disease. There are several roles for therapeutic endoscopy in the setting of inflammatory bowel disease, including endoscopic balloon dilation and endoscopic stricturotomy.


Assuntos
Colonoscopia/métodos , Neoplasias Colorretais/diagnóstico , Progressão da Doença , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/terapia , Biópsia por Agulha , Neoplasias Colorretais/patologia , Feminino , Humanos , Imuno-Histoquímica , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/patologia , Masculino , Imagem de Banda Estreita/métodos , Sensibilidade e Especificidade , Índice de Gravidade de Doença
4.
Surg Clin North Am ; 99(6): 1111-1121, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31676051

RESUMO

Patients with inflammatory bowel disease are at an increased risk of cancer secondary to long-standing intestinal inflammation. Surgical options must take into account the significant risk of synchronous disease at other colonic sites. Ileal pouch anal anastomosis is a viable option for patients with ulcerative colitis, but this should be restricted to early cancers that are unlikely to require preoperative or postoperative radiation treatment.


Assuntos
Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/cirurgia , Lesões Pré-Cancerosas/patologia , Anastomose Cirúrgica , Colectomia/métodos , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/patologia , Colite Ulcerativa/cirurgia , Neoplasias Colorretais/cirurgia , Comorbidade , Doença de Crohn/epidemiologia , Doença de Crohn/patologia , Doença de Crohn/cirurgia , Feminino , Humanos , Incidência , Doenças Inflamatórias Intestinais/patologia , Masculino , Lesões Pré-Cancerosas/epidemiologia , Prognóstico , Medição de Risco , Estomas Cirúrgicos , Análise de Sobrevida
5.
Surg Clin North Am ; 99(6): 1209-1221, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31676059

RESUMO

Short bowel syndrome / intestinal failure (SBS/IF) is a rare and debilitating disease process that mandates a multidisciplinary approach in its management. Inflammatory bowel disease (IBD), in particular Crohn's disease (CD), predisposes patients to development of SBS/IF. This review discusses SBS/IF from the perspective of IBD, with an emphasis on prevention and treatment in the setting of CD. The aims of this review are to emphasize the unique treatment goals of the newly diagnosed SBS/IF patient, and highlight the role of both medical and surgical therapies in the management of IBD-related SBS/IF, including intestinal transplantation.


Assuntos
Doenças Inflamatórias Intestinais/cirurgia , Intestinos/transplante , Síndrome do Intestino Curto/etiologia , Síndrome do Intestino Curto/terapia , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/cirurgia , Tratamento Conservador/métodos , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/cirurgia , Feminino , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/patologia , Masculino , Prognóstico , Recuperação de Função Fisiológica , Reoperação/métodos , Medição de Risco , Síndrome do Intestino Curto/fisiopatologia
6.
Postepy Biochem ; 65(3): 227-230, 2019 10 01.
Artigo em Polonês | MEDLINE | ID: mdl-31643171

RESUMO

Inflammatory bowel diseases (IBD) are a group of diseases which concern an increasing number of patients and are more and more often recognized at a young age. Because of unknown etiology, IBD treatment involves mainly non-specific suppression of inflammatory condition and is based among others on steroids. Glucocorticosteroids display anti-inflammatory action by affecting the course of immune responses, but they also possess several side effects which manifest predominantly during a long-term therapy. These concern, among others the eye and manifest by impaired vision; if left untreated, can lead to blindness. The glucocorticosteroid induced cataract is one of the most common complications of treatment with glucocorticosteroids. In the absence of pharmacological options which have a protective effect, the glucocor­ticosteroid induced cataract is a major problem not only for patients but also clinicians and needs immediate solutions.


Assuntos
Catarata/induzido quimicamente , Catarata/complicações , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Catarata/prevenção & controle , Glucocorticoides/administração & dosagem , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia
7.
Nat Commun ; 10(1): 4614, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601814

RESUMO

Autophagy is a central component of integrated stress responses that influences many inflammatory diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). While the core machinery is known, the molecular basis of the epigenetic regulation of autophagy and its role in colon inflammation remain largely undefined. Here, we report that BRG1, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is required for the homeostatic maintenance of intestinal epithelial cells (IECs) to prevent the inflammation and tumorigenesis. BRG1 emerges as a key regulator that directly governs the transcription of Atg16l1, Ambra1, Atg7 and Wipi2, which are important for autophagosome biogenesis. Defective autophagy in BRG1-deficient IECs results in excess reactive oxygen species (ROS), which leads to the defects in barrier integrity. Together, our results establish that BRG1 may represent an autophagy checkpoint that is pathogenetically linked to colitis and is therefore likely a potential therapeutic target for disease intervention.


Assuntos
Autofagia/fisiologia , Colite/etiologia , Neoplasias Colorretais/etiologia , DNA Helicases/genética , Doenças Inflamatórias Intestinais/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Animais , Estudos de Casos e Controles , Colite/complicações , Colite/patologia , Neoplasias Colorretais/genética , DNA Helicases/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica , Humanos , Doenças Inflamatórias Intestinais/patologia , Camundongos Knockout , Proteínas Nucleares/metabolismo , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/metabolismo
8.
Zhonghua Er Ke Za Zhi ; 57(9): 694-699, 2019 Sep 02.
Artigo em Chinês | MEDLINE | ID: mdl-31530355

RESUMO

Objective: To investigate the incidence and risk factors of extraintestinal manifestations (EIMs) in children with inflammatory bowel disease (IBD). Methods: The clinical data of 161 children with IBD was collected from the electronic medical records in the Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine from January 2012 to December 2017. These patients were divided into Crohn's disease (CD) group and ulcerative colitis (UC) group, accounting for 82.0% (132 cases) and 18.0%(29 cases), respectively. The incidence of EIMs in each group was analyzed. The potential risk factors of EIMs including the IBD phenotype, gender, age, location of the CD lesion, disease activity of CD, and the presence of perianal lesion were analyzed with logistic regression model. Results: Eighty-eight patients (54.7%) had EIMs. The main EIMs were immune-mediated EIMs and growth retardation, accounting for 41.0% (66/161) and 24.2% (39/161), respectively. Aphthous ulcer (39/161, 23.0%) was the most common symptom among immune-mediated EIMs, followed by arthropathy (20/161, 12.4%) and skin lesions (19/161, 11.8%). Forty-three patients (26.7%) had EIMs before being diagnosed as IBD. Fifty-eight (65.9%) patients had only one EIM during the whole course of IBD. By logistic regression analysis, CD (OR=5.536, 95%CI:1.825-16.788) and perianal disease (OR=1.969, 95%CI:1.035-3.746) were the risk factors of immune-mediated EIMs. Meanwhile, CD (OR=11.319, 95%CI: 1.487-86.179), younger than six-year-old at diagnosis (OR=8.556, 95%CI: 3.109-23.545), moderate to severe activity of CD (OR=3.447, 95%CI: 1.196-9.934) and perianal disease (OR=3.361, 95%CI: 1.720-7.793) increased the risk of growth retardation. Conclusions: The children with IBD have a high incidence of EIMs, which were more common in CD than in UC. The risk factors of developing EIMs include CD, perianal diseases, younger than six-year-old at diagnosis and moderate to severe activity of CD.


Assuntos
Colite Ulcerativa/epidemiologia , Doença de Crohn/epidemiologia , Doenças Inflamatórias Intestinais/epidemiologia , Criança , China/epidemiologia , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/patologia , Doença de Crohn/diagnóstico , Doença de Crohn/patologia , Humanos , Incidência , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/patologia , Fatores de Risco
9.
J Vet Intern Med ; 33(5): 1995-2004, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31496004

RESUMO

BACKGROUND: The cause of low serum vitamin D concentrations in dogs with chronic inflammatory enteropathy (CIE) is not well understood. OBJECTIVE: Improve understanding of pathogenesis of low serum vitamin D concentrations in dogs with CIE by comparing several clinical, clinicopathologic, and histologic variables between CIE dogs with low and normal serum 25-hydroxyvitamin D concentrations (25[OH]D). ANIMALS: Fifteen dogs with CIE and low serum 25[OH]D concentrations; 15 dogs with CIE and normal serum 25(OH)D concentrations. METHODS: Prospective cohort study. Clinical and clinicopathologic variables were compared between groups. Correlations between serum 25(OH)D concentration and histopathologic variables were assessed. RESULTS: Dogs with CIE and low serum 25(OH)D concentrations had higher canine chronic enteropathy clinical activity index scores (P = .003), lower serum α-tocopherol (P < .001), cholesterol (P < .001), and albumin (P < .001) concentrations and higher serum C-reactive protein (P = .004) concentrations compared to CIE dogs with normal serum 25(OH)D concentrations. Serum concentrations of vitamin D-binding protein (VDBP) were not different between groups (P = .91). Duodenal morphologic and inflammatory histopathological scores (P = .002 and P = .004, respectively) and total histopathological scores in duodenum and combined duodenum and ileum negatively correlated with serum 25(OH)D concentration. CONCLUSIONS AND CLINICAL IMPORTANCE: The pathogenesis of low serum vitamin D concentrations in dogs with CIE is likely multifactorial. Fat malabsorption deserves further study in dogs with low serum vitamin D concentration and CIE. Loss of VDBP does not appear to be an important cause of low serum vitamin D concentration in dogs with CIE.


Assuntos
Doenças do Cão/patologia , Doenças Inflamatórias Intestinais/veterinária , Vitamina D/análogos & derivados , Animais , Proteína C-Reativa/análise , Colesterol/sangue , Estudos de Coortes , Doenças do Cão/sangue , Cães , Feminino , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/patologia , Masculino , Estudos Prospectivos , Albumina Sérica/análise , Tocoferóis/sangue , Vitamina D/sangue , Proteína de Ligação a Vitamina D/sangue
11.
J Korean Med Sci ; 34(32): e204, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31432649

RESUMO

BACKGROUND: It has been known that vitamin D level (serum 25[OH]D) has correlation with inflammatory bowel disease (IBD). The purpose of this study is to investigate changes of serum 25[OH]D in pediatric IBD patients according to the disease activity. METHODS: A total of 96 children and adolescent with IBD were enrolled in this retrospective study. Serologic inflammatory markers and clinical disease activity scores of the patients were collected, and their correlations with serum 25[OH]D were analyzed. Seasonal variations of serum 25[OH]D were also investigated both in active disease state and remission state. RESULTS: Of the 96 patients, 41 (43%) were women and patients with a vitamin D deficiency (< 20 ng/mL) at diagnosis were 77 (80.2%). There was no significant difference between Crohn's disease and ulcerative colitis for serum 25[OH]D. Serum 25[OH]D was higher in remission group than in active disease group (12.4 [8.8-29] ng/mL vs. 17.9 [12.3-34.4] ng/mL; P < 0.001) and the difference was more significant than other micronutrients. There was no significant difference in serum 25[OH]D concentration between patients with ileal involvement and patients without ileal involvement. There were seasonal variations in the active phase, but there was no significant difference by season in the remission phase. CONCLUSION: Serum 25[OH]D is inversely correlated with disease activity in IBD. Monitoring and supplementation is required especially for active disease status and in winter and spring season.


Assuntos
Calcifediol/sangue , Doenças Inflamatórias Intestinais/diagnóstico , Adolescente , Biomarcadores/sangue , Criança , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/patologia , Doença de Crohn/diagnóstico , Doença de Crohn/patologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/patologia , Masculino , Micronutrientes/sangue , Estudos Retrospectivos , Estações do Ano , Índice de Gravidade de Doença , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/diagnóstico
12.
Surgery ; 166(4): 670-677, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31420214

RESUMO

BACKGROUND: The aim of this study was to assess the association of the mode of surgery on female fertility after restorative proctocolectomy with ileal pouch-anal anastomosis. METHODS: All female patients aged 18 to 44 years who underwent restorative proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis, familial adenomatous polyposis, or Crohn's disease at the Cleveland Clinic Ohio or the Cleveland Clinic Florida from 1983 to 2012 were sent a standardized fertility questionnaire. Infertility was defined as lack of pregnancy after 1 year of unprotected sexual intercourse. Patients who had attempted to conceive after restorative proctocolectomy with ileal pouch-anal anastomosis were compared based on the surgical approach: laparoscopic ileal pouch-anal anastomosis versus open ileal pouch-anal anastomosis. RESULTS: A total of 890 female patients were surveyed, of which 519 (58.3%) responded. Of these, 161 (31%) had attempted pregnancy after surgery: 18 (12%) had laparoscopic ileal pouch-anal anastomosis and 143 (88%) had open ileal pouch-anal anastomosis. There were no significant differences regarding demographics between groups. There was no difference in reported infertility rates (61.1% vs 65%, respectively, P = 0.69) between the laparoscopic ileal pouch-anal anastomosis and open ileal pouch-anal anastomosis groups. The median time to pregnancy (3.5 months vs 9 months, respectively, log-rank P = 0.01) was reduced in patients who underwent laparoscopic ileal pouch-anal anastomosis compared with those who underwent open ileal pouch-anal anastomosis. CONCLUSION: Postoperative infertility rates were higher after ileal pouch-anal anastomosis regardless of mode of surgery. However, laparoscopy was associated with a significantly reduced time to conceive compared with the open approach.


Assuntos
Infertilidade Feminina/etiologia , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/cirurgia , Laparoscopia/efeitos adversos , Laparotomia/efeitos adversos , Proctocolectomia Restauradora/métodos , Centros Médicos Acadêmicos , Adolescente , Adulto , Estudos de Coortes , Colectomia/métodos , Colite Ulcerativa/patologia , Colite Ulcerativa/cirurgia , Doença de Crohn/patologia , Doença de Crohn/cirurgia , Feminino , Seguimentos , Humanos , Incidência , Infertilidade Feminina/epidemiologia , Laparoscopia/métodos , Laparotomia/métodos , Proctocolectomia Restauradora/efeitos adversos , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto Jovem
13.
EBioMedicine ; 46: 522-531, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31327693

RESUMO

The gastrointestinal mucosa is critical for maintaining the integrity and functions of the gut. Disruption of this barrier is a hallmark and a risk factor for many intestinal and chronic inflammatory diseases. Inflammatory bowel disease (IBD) and HIV infection are characterized by microbial translocation and systemic inflammation. Despite the clinical overlaps between HIV and IBD, significant differences exist such as the severity of gut damage and mechanisms of immune cell homeostasis. Studies have supported the role of metabolic activation of immune cells in promoting chronic inflammation in HIV and IBD. This inflammatory response persists in HIV+ persons even after long-term virologic suppression by antiretroviral therapy (ART). Here, we review gut dysfunction and microbiota changes during HIV infection and IBD, and discuss how this may induce metabolic reprogramming of monocytes, macrophages and T cells to impact disease outcomes. Drawing from parallels with IBD, we highlight how factors such as lipopolysaccharides, residual viral replication, and extracellular vesicles activate biochemical pathways that regulate immunometabolic processes essential for HIV persistence and non-AIDS metabolic comorbidities. This review highlights new mechanisms and support for the use of immunometabolic-based therapeutics towards HIV remission/cure, and treatment of metabolic diseases.


Assuntos
Gastroenteropatias/etiologia , Gastroenteropatias/fisiopatologia , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , HIV/imunologia , Animais , Permeabilidade da Membrana Celular , Comorbidade , Disbiose , Metabolismo Energético , Ácidos Graxos/metabolismo , Microbioma Gastrointestinal/imunologia , Infecções por HIV/complicações , Infecções por HIV/virologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo
14.
Blood ; 134(9): 765-775, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31262781

RESUMO

Platelets are specialized cells essential for hemostasis that also function as crucial effectors capable of mediating inflammatory and immune responses. These sentinels continually survey their environment and discriminate between homeostatic and danger signals such as modified components of the extracellular matrix. The glycosaminoglycan hyaluronan (HA) is a major extracellular matrix component that coats the vascular lumen and, under normal conditions, restricts access of inflammatory cells. In response to tissue damage, the endothelial HA matrix enhances leukocyte recruitment and regulates the early stages of the inflammatory response. We have shown that platelets can degrade HA from the surface of activated endothelial cells via the enzyme hyaluronidase-2 (HYAL2) and that HYAL2 is deficient in platelets isolated from patients with inflammatory bowel disease (IBD). Platelets are known to be involved in the pathogenesis of several chronic disease states, including IBD, but they have been largely overlooked in the context of intestinal inflammation. We therefore wanted to define the mechanism by which platelet HYAL2 regulates the inflammatory response during colitis. In this study, we provide evidence that HA catabolism is disrupted in human intestinal microvascular endothelial cells isolated from patients with IBD. Furthermore, mice deficient in HYAL2 are more susceptible to an acute model of colitis, and this increased susceptibility is abrogated by transfusion of HYAL2-competent platelets. Finally, we show that platelets, via HYAL2-dependent degradation of endothelial HA, regulate the early stages of inflammation in colitis by limiting leukocyte extravasation.


Assuntos
Plaquetas/imunologia , Colite/imunologia , Hialuronoglucosaminidase/imunologia , Animais , Plaquetas/patologia , Células Cultivadas , Colite/patologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Proteínas Ligadas por GPI/imunologia , Humanos , Ácido Hialurônico/imunologia , Inflamação/imunologia , Inflamação/patologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Camundongos , Camundongos Knockout
15.
Gastroenterology ; 157(4): 1093-1108.e11, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31325428

RESUMO

BACKGROUND & AIMS: Inflammation, injury, and infection up-regulate expression of the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in the intestinal epithelium. We studied the effects of cell-specific IDO1 expression in the epithelium at baseline and during intestinal inflammation in mice. METHODS: We generated transgenic mice that overexpress fluorescence-tagged IDO1 in the intestinal epithelium under control of the villin promoter (IDO1-TG). We generated intestinal epithelial spheroids from mice with full-length Ido1 (controls), disruption of Ido1 (knockout mice), and IDO1-TG and analyzed them for stem cell and differentiation markers by real-time polymerase chain reaction, immunoblotting, and immunofluorescence. Some mice were gavaged with enteropathogenic Escherichia coli (E2348/69) to induce infectious ileitis, and ileum contents were quantified by polymerase chain reaction. Separate sets of mice were given dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid to induce colitis; intestinal tissues were analyzed by histology. We utilized published data sets GSE75214 and GDS2642 of RNA expression data from ilea of healthy individuals undergoing screening colonoscopies (controls) and patients with Crohn's disease. RESULTS: Histologic analysis of small intestine tissues from IDO1-TG mice revealed increases in secretory cells. Enteroids derived from IDO1-TG intestine had increased markers of stem, goblet, Paneth, enteroendocrine, and tuft cells, compared with control enteroids, with a concomitant decrease in markers of absorptive cells. IDO1 interacted non-enzymatically with the aryl hydrocarbon receptor to inhibit activation of NOTCH1. Intestinal mucus layers from IDO1-TG mice were 2-fold thicker than mucus layers from control mice, with increased proportions of Akkermansia muciniphila and Mucispirillum schaedleri. Compared to controls, IDO1-TG mice demonstrated an 85% reduction in ileal bacteria (P = .03) when challenged with enteropathogenic E coli, and were protected from immune infiltration, crypt dropout, and ulcers following administration of dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid. In ilea of Crohn's disease patients, increased expression of IDO1 correlated with increased levels of MUC2, LYZ1, and aryl hydrocarbon receptor, but reduced levels of SLC2A5. CONCLUSIONS: In mice, expression of IDO1 in the intestinal epithelial promotes secretory cell differentiation and mucus production; levels of IDO1 are positively correlated with secretory cell markers in ilea of healthy individuals and Crohn's disease patients. We propose that IDO1 contributes to intestinal homeostasis.


Assuntos
Bactérias/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular , Microbioma Gastrointestinal , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Doenças Inflamatórias Intestinais/enzimologia , Doenças Inflamatórias Intestinais/microbiologia , Mucosa Intestinal/enzimologia , Mucosa Intestinal/microbiologia , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Notch/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Estudos de Casos e Controles , Linhagem Celular , Linhagem da Célula , Modelos Animais de Doenças , Células Epiteliais/enzimologia , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Genótipo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/deficiência , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/patologia , Camundongos Knockout , Fenótipo , Receptores de Hidrocarboneto Arílico/genética , Receptores Notch/genética , Via Secretória , Transdução de Sinais , Células-Tronco/enzimologia , Células-Tronco/microbiologia , Células-Tronco/patologia
16.
EBioMedicine ; 45: 495-510, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31253515

RESUMO

BACKGROUND: Ulcerative Colitis (UC) is an Inflammatory Bowel Disease (IBD) characterized by uncontrolled immune response, diarrhoea, weight loss and bloody stools, where sustained remission is not currently achievable. Dextran Sulphate Sodium (DSS)-induced colitis is an animal model that closely mimics human UC. Ultrasound (US) has been shown to prevent experimental acute kidney injury through vagus nerve (VN) stimulation and activation of the cholinergic anti-inflammatory pathway (CAIP). Since IBD patients may present dysfunctional VN activity, our aim was to determine the effects of therapeutic ultrasound (TUS) in DSS-induced colitis. METHODS: Acute colitis was induced by 2% DSS in drinking water for 7 days and TUS was administered to the abdominal area for 7 min/day from days 4-10. Clinical symptoms were analysed, and biological samples were collected for proteomics, macroscopic and microscopic analysis, flow cytometry and immunohistochemistry. FINDINGS: TUS attenuated colitis by reducing clinical scores, colon shortening and histological damage, inducing proteomic tolerogenic response in the gut during the injury phase and early recovery of experimental colitis. TUS did not improve clinical and pathological outcomes in splenectomised mice, while α7nAChR (α7 nicotinic acetylcholine receptor - indicator of CAIP involvement) knockout animals presented with disease worsening. Increased levels of colonic F4/80+α7nAChR+ macrophages in wild type mice suggest CAIP activation. INTERPRETATION: These results indicate TUS improved DSS-induced colitis through stimulation of the splenic nerve along with possible contribution by VN with CAIP activation. FUND: Intramural Research Programs of the Clinical Centre, the National Institute of Biomedical Imaging and Bioengineering at the NIH and CAPES/Brazil.


Assuntos
Colite/terapia , Inflamação/terapia , Doenças Inflamatórias Intestinais/terapia , Terapia por Ultrassom , Animais , Colite/induzido quimicamente , Colite/patologia , Citocinas/genética , Citocinas/efeitos da radiação , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Macrófagos/efeitos da radiação , Camundongos , Camundongos Knockout , Peroxidase/química , Proteômica , Receptor Nicotínico de Acetilcolina alfa7/genética
17.
J Vet Intern Med ; 33(4): 1669-1676, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31169948

RESUMO

BACKGROUND: Lymphatic endothelial cell (LEC) immunohistochemical markers have identified intestinal lymphatic vasculature abnormalities in humans with inflammatory bowel disease, but have not been used to evaluate intestinal lymphatic vasculature in a group of dogs with chronic inflammatory enteropathy (CIE). OBJECTIVES: To utilize LEC markers to identify and measure intestinal lymphatic vasculature in endoscopic biopsy samples of CIE dogs. To evaluate whether measured lymphatic vasculature variables correlate with serum albumin concentrations. ANIMALS: Twenty-four dogs with CIE; n = 13, serum albumin concentration <2.5 g/dL (CIE-protein-losing enteropathy [PLE]), n = 11, serum albumin concentration ≥2.5 g/dL (CIE-N). METHODS: Prospective study. Lymphatic endothelial cell immunolabeling with Prox-1 and LYVE-1 performed on endoscopic biopsy samples from 24 dogs with CIE. Duodenal and ileal villous lacteal width (VLW) and proprial mucosal lacteal width (MLW) were determined for each case and analyzed for correlation with serum albumin concentration. Lacteal dilatation scores using routine H&E histopathology were assessed for correlation with immunohistochemistry (IHC)-calculated VLW and MLW. RESULTS: Lower serum albumin concentrations were correlated with increased VLW (rho = -.4644; P = .02) and MLW (rho = -.6514; P < .001) in the ileum. Lymphatic endothelial cell IHC identified presumptive proprial mucosal lymphangiectasia in some dogs that was not recognized with routine H&E staining. Lacteal dilatation scores were correlated with VLW in duodenum (rho = .4634; P = .02) and ileum (rho = .5292; P = .008), but did not correlate with MLW. CONCLUSIONS AND CLINICAL IMPORTANCE: Lymphatic endothelial cell immunolabeling identified presumptive proprial mucosal lymphangiectasia in CIE dogs, particularly in the ileum of hypoalbuminemic dogs. Routine evaluation of villous lacteals likely underestimates abnormalities of the lymphatic vasculature in dogs with CIE.


Assuntos
Doenças do Cão/patologia , Doenças Inflamatórias Intestinais/veterinária , Enteropatias Perdedoras de Proteínas/veterinária , Animais , Biomarcadores/análise , Biópsia , Cães , Células Endoteliais/citologia , Feminino , Imuno-Histoquímica , Doenças Inflamatórias Intestinais/patologia , Linfangiectasia Intestinal/veterinária , Sistema Linfático/irrigação sanguínea , Masculino , Estudos Prospectivos , Enteropatias Perdedoras de Proteínas/patologia , Albumina Sérica/análise
18.
DNA Cell Biol ; 38(8): 747-753, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31188020

RESUMO

Aberrant neutrophil (PMN) infiltration of the intestinal mucosa is a hallmark of inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. While the genotoxic function of PMNs and its implications in carcinogenesis have been primarily associated with oxidative stress, recent work by Butin-Israeli and colleagues has defined a novel mechanism where PMN-derived microparticles through the delivery and activity of specific miRNAs promoted formation of double-strand breaks (DSBs), and in parallel, suppressed DSB repair through the downregulation of lamin B1 and Rad51. Respective downregulation of these two proteins compromised the nuclear envelope and high-fidelity repair by homologous recombination, increasing DSB accumulation and aneuploidy. This discovery defined a novel mode of action where PMN-mediated suppression of DSB repair leading to genomic instability in the injured mucosa may facilitate progression toward colorectal cancer.


Assuntos
Instabilidade Genômica , Doenças Inflamatórias Intestinais/tratamento farmacológico , Neutrófilos/patologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Quebras de DNA de Cadeia Dupla , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Lamina Tipo B/genética , Lamina Tipo B/metabolismo , MicroRNAs/metabolismo , Neutrófilos/fisiologia , Estresse Oxidativo/genética , Espécies Reativas de Oxigênio/metabolismo
19.
Med Sci Monit ; 25: 4457-4468, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31201771

RESUMO

BACKGROUND The treatment of inflammatory bowel disease (IBD) is still not satisfactory and novel technologies are clinically needed. This study aimed to examine the effect of mesenchymal stromal cells (MSCs) coated with the anti-vascular cell adhesion molecule 1 (VCAM 1) antibody on experimental colitis. MATERIAL AND METHODS The antibody was coated onto the MSCs isolated from male BALB/C mice to generate anti-VCAM 1 antibody-coated MSC (V-MSC). The Transwell assay was used to detect migration rate. 2,4,6-trinitrobenzenesulfonic acid (TNBS) was used to generate experimental colitis. MSCs were injected intravenously into experimental models. Weight changes, disease activity index, and histological changes were evaluated. The SRY gene were used for cell tracking. Expression of Ki67 and claudin 1 was used to measure local repair using immunohistochemistry. T helper (Th)1, Th2, Th17, and T regulatory cells were counted. RESULTS V-MSCs were successfully generated through coating MSCs with VCAM1 antibody. Analysis showed that the V-MSCs had similar surface types and differentiation as uncoated MSCs. Transwell assays showed that V-MSCs had higher migration rate than MSCs. After injection of V-MSCs, the expression of the SRY gene was enhanced in diseased colon and all indices (including weight changes, DAI score, histological changes, and the expressions of Ki67 and claudin 1) recovered rapidly. The ratio of proinflammatory Th1 and Th17 cells decreased, but the ratio of anti-inflammatory Th2 and Treg cells increased after the treatment. CONCLUSIONS V-MSCs enhance homing and modulating immune balance in the experimental colitis, suggesting that they are potentially useful for treating inflammatory bowel disease or other immune diseases.


Assuntos
Colite/patologia , Células-Tronco Mesenquimais/imunologia , Molécula 1 de Adesão de Célula Vascular/imunologia , Animais , Diferenciação Celular , Proliferação de Células , Colite/imunologia , Colo/patologia , Modelos Animais de Doenças , Imunomodulação/imunologia , Doenças Inflamatórias Intestinais/patologia , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia
20.
Life Sci ; 231: 116571, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31207308

RESUMO

AIMS: The role of long non-coding RNA's (lncRNA) in the biology of ulcerative colitis (UC) is not well understood. We have previously detected changes in lncRNA's associated with UC. This study aims to characterize one specific lncRNA, CDKN2B-AS1 whose expression was downregulated in UC patients. MAIN METHODS: UC biopsies were used to determine the levels of linear and circular CDKN2B-AS1 relative to healthy controls. In situ hybridization was used to determine the localization of CKDN2B-AS1 in the colon. The intestinal epithelial cell line, Caco-2, was used to study the effects of shRNA mediated loss of CDKN2B-AS1. Transepithelial electrical resistance was used to measure barrier function. An RT-PCR array, immunoblots and immunohistochemistry were used to determine tight junction proteins that CDKN2B-AS1 regulates. KEY FINDINGS: CDKN2B-AS1 is transcribed into not only linear transcripts but also as circular RNA through back-splicing and both forms are decreased in IBD. CDKN2B-AS1 is expressed mainly in colonic epithelial cells. Cells with down-regulated CDKN2B-AS1 exhibited increased proliferation and no alterations in apoptosis. Targeting both the linear and circular transcripts of CDKN2B-AS1 with short hairpin RNAs enhanced barrier function. We subsequently determined that Claudin-2, a "leaky Claudin" known to decrease barrier function, was decreased in CDKN2B-AS1 knockdown cells. SIGNIFICANCE: This study identifies a novel lncRNA with both linear and circular transcripts affecting UC biology.


Assuntos
Doenças Inflamatórias Intestinais/genética , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , Adulto , Apoptose/genética , Células CACO-2 , Proliferação de Células/genética , Claudina-2/genética , Claudina-2/metabolismo , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Inibidor de Quinase Dependente de Ciclina p15/biossíntese , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , DNA Circular/genética , Células Epiteliais/metabolismo , Feminino , Humanos , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , RNA/genética , RNA Longo não Codificante/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA