RESUMO
BACKGROUND: Colorectal cancer (CRC) is one of the leading malignancies worldwide, therefore cheap noninvasive screening methods are of great importance. Matrix-metalloproteinase-9 (MMP-9) has a role in the progression of CRC, and its level is elevated in tumour biopsies. Faecal MMP-9 levels are increased in active ulcerative colitis patients, but in CRC patients, they have never been measured. We aimed to assess the faecal MMP-9 levels in patients undergoing total colonoscopy according to endoscopic and histological diagnosis. METHODS: One hundred and nine patients provided faecal samples for MMP-9 analysis. A total colonoscopy was performed; suspicious lesions were evaluated by histology. Faecal MMP-9 levels were measured by ELISA. RESULTS: The number of patients allocated to different groups were: negative/diverticulosis: 34 (referred to as controls); hyperplastic polyps: 15; adenomas: 32 (22 at high risk); and CRC: 28. Faecal MMP-9 was significantly increased in CRC compared with all other groups (P<0.001). Faecal MMP-9 was suitable to distinguish CRC patients from controls (sensitivity: 89.3%; specificity: 91.2%). By means of a lower cutoff level, faecal MMP-9 identified high-risk adenomas besides CRC (sensitivity: 76%; specificity: 85.3%). This lower cutoff level screened 59% of high-risk adenomas. CONCLUSIONS: Faecal MMP-9 may be a promising new noninvasive marker in CRC.
Assuntos
Adenoma/diagnóstico , Neoplasias Colorretais/diagnóstico , Fezes/enzimologia , Metaloproteinase 9 da Matriz/metabolismo , Adenoma/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Colonoscopia , Neoplasias Colorretais/enzimologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Prognóstico , Curva ROCRESUMO
The natural hormone uroguanylin regulates intestinal fluid homeostasis and bowel function through activation of guanylate cyclase-C (GC-C), resulting in increased intracellular cyclic guanosine-3',5'-monophosphate (cGMP). We report the effects of uroguanylin-mediated activation of the GC-C/cGMP pathway in vitro on extracellular cGMP transport and in vivo in rat models of inflammation- and stress-induced visceral hypersensitivity. In vitro exposure of intestinal Caco-2 cells to uroguanylin stimulated bidirectional, active extracellular transport of cGMP into luminal and basolateral spaces. cGMP transport was significantly and concentration dependently decreased by probenecid, an inhibitor of cGMP efflux pumps. In ex vivo Ussing chamber assays, uroguanylin stimulated cGMP secretion from the basolateral side of rat colonic epithelium into the submucosal space. In a rat model of trinitrobenzene sulfonic acid (TNBS)-induced visceral hypersensitivity, orally administered uroguanylin increased colonic thresholds required to elicit abdominal contractions in response to colorectal distension (CRD). Oral administration of cGMP mimicked the antihyperalgesic effects of uroguanylin, significantly decreasing TNBS- and restraint stress-induced visceromotor response to graded CRD in rats. The antihyperalgesic effects of cGMP were not associated with increased colonic spasmolytic activity, but were linked to significantly decreased firing rates of TNBS-sensitized colonic afferents in rats in response to mechanical stimuli. In conclusion, these data suggest that the continuous activation of the GC-C/cGMP pathway along the intestinal tract by the endogenous hormones guanylin and uroguanylin results in significant reduction of gastrointestinal pain. Extracellular cGMP produced on activation of GC-C is the primary mediator in this process via modulation of sensory afferent activity.
Assuntos
Guanilato Ciclase/metabolismo , Peptídeos Natriuréticos/metabolismo , Transdução de Sinais/fisiologia , Dor Visceral/metabolismo , Acetilcolina/farmacologia , Acetilglucosamina/análogos & derivados , Acetilglucosamina/farmacologia , Adenocarcinoma/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Colite/induzido quimicamente , Colite/complicações , Colo/efeitos dos fármacos , Colo/metabolismo , Neoplasias Colorretais/patologia , GMP Cíclico/análogos & derivados , GMP Cíclico/metabolismo , GMP Cíclico/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Estimulação Elétrica , Feminino , Gastroenteropatias/complicações , Gastroenteropatias/etiologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperalgesia/fisiopatologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/fisiologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Morfina/uso terapêutico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Peptídeos Natriuréticos/uso terapêutico , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Peroxidase/metabolismo , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Restrição Física , Ácido Trinitrobenzenossulfônico/toxicidade , Dor Visceral/tratamento farmacológico , Dor Visceral/etiologiaRESUMO
OBJECTIVES: Luminal serine-proteases lead to increased colonic paracellular permeability and visceral hypersensitivity in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Other proteases, namely cysteine-proteases (CPs), increase airway permeability by digesting epithelial tight junction proteins. In this study, we focused on constipation-predominant IBS (IBS-C) and we aimed to (i) evaluate CP levels in two cohorts of IBS patients, (ii) test if IBS-C fecal supernatant (FSN) affects permeability, and visceral sensitivity after repeated administrations in mice, and (iii) evaluate occludin expression in IBS-C colonic biopsies. METHODS: Fecal CP activity was determined using selective substrate and inhibitor (E64). The effect of papain, as positive control, and IBS-C FSN administrations were evaluated on colonic paracellular permeability and mucosal occludin levels in mice and T84 monolayers. Occludin protein levels were evaluated in IBS-C colonic biopsies. Sensitivity to colorectal distension (CRD) was measured after repeated administrations of IBS-C FSN. RESULTS: We found in a subset of IBS-C patients an enhanced fecal CP activity, in comparison with healthy controls and IBS-D patients. CP activity levels positively correlated with disease severity and abdominal pain scoring. This association was confirmed by receiver operating characteristic curve analysis. In mice, repeated application of IBS-C FSN into colon triggered increased permeability, linked to the enzymatic degradation of occludin, and was associated with enhanced visceral sensitivity to CRD. Finally, occludin levels were found decreased in colonic biopsies from IBS-C patients, and IBS-C FSNs were able to degrade recombinant human occludin in vitro. All these effects were abolished by preincubation of IBS-C FSN with a CP inhibitor, E64. CONCLUSIONS: These data suggest that luminal CPs may represent a new factor contributing to the genesis of symptoms in IBS.
Assuntos
Cisteína Proteases/metabolismo , Síndrome do Intestino Irritável/enzimologia , Síndrome do Intestino Irritável/patologia , Junções Íntimas/enzimologia , Junções Íntimas/patologia , Dor Abdominal/enzimologia , Dor Abdominal/patologia , Adulto , Análise de Variância , Animais , Biópsia , Western Blotting , Estudos de Casos e Controles , Células Cultivadas , Constipação Intestinal/enzimologia , Constipação Intestinal/patologia , Eletromiografia , Fezes/enzimologia , Feminino , Humanos , Absorção Intestinal , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Ocludina/metabolismo , Medição da Dor , Reação em Cadeia da Polimerase , Curva ROC , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Ulcerative colitis (UC) is characterized by frequent relapses, with the presence of colorectal inflammation and mucosal lesions. Matrix-metalloprotease 9 (MMP-9) is elevated in colonic biopsies, urine, and blood plasma of UC patients. MMP-9 has been suggested as a predictor of UC in the urine of children; however, 20% of the controls tested positive. So far, fecal MMP-9 levels have never been measured. Our aims were: 1) to compare fecal MMP-9 levels in UC patients to control subjects and a functional gastrointestinal disorder characterized by diarrhea (IBS-D); 2) to test the correlation between UC disease activity and fecal levels of MMP-9; and 3) to correlate fecal MMP-9 levels with a known fecal marker of UC activity, calprotectin. METHODS: UC (n = 47), IBS-D (n = 23) patients, and control subjects (n = 24) provided fecal samples for MMP-9 analysis. In UC patients, disease severity was evaluated by the Mayo score. Fecal MMP-9 and calprotectin levels were measured by enzyme-linked immunosorbent assay and lateral flow assay, respectively. RESULTS: MMP-9 was undetectable or ≤0.22 ng/mL in the feces of all controls and IBS-D patients. In UC patients, fecal MMP-9 levels significantly correlated with the overall Mayo score (P < 0.001), the endoscopic score (P < 0.001), and the serum C-reactive protein levels (P = 0.002). Additionally, in UC patients fecal MMP-9 levels showed a significant correlation with a known disease activity marker, fecal calprotectin (P = 0.014). CONCLUSIONS: These results highlight fecal MMP-9 as a useful tool in the differential diagnosis of diarrheic disorders and in the noninvasive evaluation of disease activity and mucosal healing in UC.
Assuntos
Colite Ulcerativa/metabolismo , Fezes/química , Metaloproteinase 9 da Matriz/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/patologia , Colonoscopia , Diagnóstico Diferencial , Diarreia/etiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/diagnóstico , Síndrome do Intestino Irritável/metabolismo , Complexo Antígeno L1 Leucocitário/metabolismo , Masculino , Pessoa de Meia-Idade , Curva ROC , Índice de Gravidade de DoençaRESUMO
Vasopressin and its receptors modulate several gut functions, but their role in intestinal inflammation is unknown. Our aims were to determine 1) the localization of V1b receptors in human and rodent colon, 2) the role of vasopressin and V1b receptors in experimental colitis using two approaches: V1bâ»(/)â» mice and a selective V1b receptor antagonist, SSR149415, and 3) the mechanisms involved. V1b receptors were localized in normal and inflamed colon from humans and rats. Experimental colitis was induced in rats and mice and some groups were treated before or after colitis induction with oral SSR149415 (3-30 mg/kg). Other groups of mice were submitted to dehydration to increase vasopressin plasma levels, prior to colitis induction. Body weight, damage scores, MPO, and TNF-α tissue levels were determined. Finally, colonic segments of wild-type (WT) and V1bâ»(/)â» mice were mounted in Ussing chambers and paracellular permeability in response to vasopressin was studied. V1b receptors were expressed in enterocytes and ganglia cells of the enteric nervous system of human and rat intestine. Expression levels were independent from inflammatory status. Colitis was less severe in rodents treated by either preventive or curative SSR149415 and in V1bâ»(/)â» mice. 2,4,6-Trinitrobenzene sulfonic acid induced a strong mortality in dehydrated animals that was reversed by preventive SSR149415 or mast cell stabilizer. Vasopressin significantly increased paracellular permeability in WT, but not in V1bâ»(/)â» mice. Preincubation of colon tissues with SSR149415 abolished the vasopressin effect. Similarly, vasopressin had no effect in colonic preparations from WT mice pretreated with mast cell stabilizers. Vasopressin, through V1b receptor interaction, has proinflammatory properties linked to mast cell activation and downstream alterations of the colonic epithelial barrier. These findings underline the potential interest of V1b receptor blockers in gut inflammatory diseases.
Assuntos
Colite/metabolismo , Haptenos , Doenças Inflamatórias Intestinais/metabolismo , Receptores de Vasopressinas/metabolismo , Vasopressinas/farmacologia , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Colite/induzido quimicamente , Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Indóis/farmacologia , Doenças Inflamatórias Intestinais/fisiopatologia , Camundongos , Inibidores de Fosfodiesterase/farmacologia , Pirrolidinas/farmacologia , Ratos , Receptores de Vasopressinas/genética , Tioxantenos/farmacologia , Ácido Trinitrobenzenossulfônico/toxicidade , Fator de Necrose Tumoral alfa/metabolismo , Vasopressinas/metabolismo , Privação de Água , Aumento de Peso , Xantonas/farmacologiaRESUMO
Oestradiol modulates paracellular permeability and tight junction (TJ) function in endothelia and reproductive tissues, but whether the ovarian hormones and cycle affect the paracellular pathway in the intestinal epithelium remains unclear. Oestrogen receptors (ERs) are expressed in intestinal epithelial cells, and oestradiol regulates epithelium formation. We examined the effects of oestrous cycle stage, oestradiol benzoate (EB), and progesterone (P) on colonic paracellular permeability (CPP) in the female rat, and whether EB affects expression of the TJ proteins in the rat colon and the human colon cell line Caco-2. In cyclic rats, CPP was determined through lumen-to-blood (51)Cr-labelled EDTA clearance, and in Ussing chambers for dextran permeability. CPP was also examined in ovariectomized (OVX) rats treated with P or EB, with and without the ER antagonist ICI 182,780, or with the selective agonists for ER beta (propyl pyrazole triol; PPT) or ER beta (diarylpropionitrile; DPN). In oestrus rats, CPP was reduced (P < 0.01) relative to dioestrus. In OVX rats, EB dose-dependently decreased CPP, an effect mimicked by DPN and blocked by ICI 182,780, whereas P had no effect. Oestradiol increased occludin mRNA and protein in the colon (P < 0.05), but not zona occludens (ZO)-1. Further, EB and DPN enhanced occludin and junctional adhesion molecule (JAM)-A expression in Caco-2 cells without change in ZO-1, an effect blocked by ICI 182,780. These data show that oestrogen reinforces intestinal epithelial barrier through ER beta-mediated up-regulation of the transmembrane proteins occludin and JAM-A determining paracellular spaces. These findings highlight the importance of the ER beta pathway in the control of colonic paracellular transport and mucosal homeostasis.
Assuntos
Moléculas de Adesão Celular/metabolismo , Colo/efeitos dos fármacos , Colo/fisiologia , Estradiol/análogos & derivados , Receptor beta de Estrogênio/metabolismo , Proteínas de Membrana/metabolismo , Animais , Sequência de Bases , Células CACO-2 , Primers do DNA/genética , Estradiol/farmacologia , Estro/fisiologia , Feminino , Humanos , Imunoglobulinas/metabolismo , Moléculas de Adesão Juncional , Proteínas de Membrana/genética , Ocludina , Ovariectomia , Permeabilidade/efeitos dos fármacos , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Progesterona/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de Superfície Celular , Regulação para Cima/efeitos dos fármacos , Proteína da Zônula de Oclusão-1RESUMO
BACKGROUND AND AIMS: Sex steroids influence IBD symptoms. Macrophage migration inhibitory factor (MIF), a target of sex steroids in other inflammatory models, promotes interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha release in colitis. We investigated whether estradiol and progesterone influence MIF, IL-1beta, and TNF-alpha production in experimental colitis. METHODS: Colonic MIF, IL-1beta, and TNF-alpha levels were measured in cyclic and ovariectomized rats, with or without estradiol benzoate (EB) or progesterone (P) replacement. MIF distribution was assessed by immunohistochemistry. Cytokines, myeloperoxidase activity, macroscopic damage, and plasma corticosterone were assessed 24 hours after intrarectal trinitrobenzene sulfonic acid (TNBS), with and without neutralizing anti-MIF antibody. Effects of EB and P on myeloperoxidase activity and MIF concentration were also assessed at 7 days in dextran sulfate sodium-induced colitis. RESULTS: Basal IL-1beta and TNF-alpha contents did not fluctuate during the estrous cycle, while MIF concentrations increased from estrus (estrogen dominance) to metestrus (P dominance; P < .05). EB and P treatment mimicked these effects in ovariectomized rats, and similarly altered MIF immunostaining. Progesterone dominance aggravated TNBS colitis in comparison with estrogen. Progesterone enhanced TNBS-induced MIF (P < .001) and TNF-alpha (P < .01) production, while EB decreased MIF (P < .01) and IL-beta levels (P < .01). Anti-MIF antibody prevented P-mediated up-regulation of TNF-alpha, improved TNBS colitis, and enhanced plasma corticosterone. At 7 days after dextran sulfate sodium, EB decreased myeloperoxidase activity and MIF concentration, while P had no effect. CONCLUSIONS: Estrogen decreases while progesterone increases MIF production in the female rat colon. Changes in basal MIF contents may affect colon susceptibility to inflammation, by modulating TNF-alpha and IL-1beta production during early stages of colitis.
Assuntos
Colite/metabolismo , Colo/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Interleucina-1beta/metabolismo , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Colite/induzido quimicamente , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Corticosterona/sangue , Sulfato de Dextrana , Modelos Animais de Doenças , Estradiol/análogos & derivados , Estradiol/metabolismo , Ciclo Estral/metabolismo , Feminino , Hormônios Esteroides Gonadais/farmacologia , Imuno-Histoquímica , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Fatores Inibidores da Migração de Macrófagos/imunologia , Ovariectomia , Peroxidase/metabolismo , Progesterona/metabolismo , Ratos , Ratos Wistar , Índice de Gravidade de Doença , Fatores Sexuais , Fatores de Tempo , Ácido TrinitrobenzenossulfônicoRESUMO
Sepsis is associated with bacterial translocation (BT) and changes in colonic paracellular permeability (CPP), but the link between these effects is unknown. The present study aimed to identify whether changes in CPP after lipopolysaccharide (LPS) administration triggers BT, colonic inflammation, visceral pain, and sickness behavior and to evaluate the role of myosin light chain kinase (MLCK) in colonocyte cytoskeleton contraction. Rats received the MLCK inhibitor ML-7 alone or combined with LPS. CPP was measured for 6 hours after administration. Visceral pain, food intake, BT, electron microscopy of tight junctions of colonocytes, cytokine levels, and Western blotting of phosphorylated MLC from colonic mucosa were assessed in a time range of 0 to 3 hours after treatment. Sepsis increased CPP at 0 to 6 hours after LPS and associated with tight junction morphological changes, increased MLC phosphorylation, and mucosal release of proinflammatory cytokines. Massive BT, visceral hyperalgesia, and reduced food intake were also observed. Addition of ML-7 prevented all LPS-induced effects, except for changes in food intake. In conclusion, LPS-mediated effects on CPP include gut inflammation, BT, and visceral hyperalgesia. Inhibition of MLCK-dependent colonocyte cytoskeleton contraction by ML-7 prevents the LPS-induced alterations of CPP and its subsequent effects.
Assuntos
Translocação Bacteriana/efeitos dos fármacos , Colo/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Quinase de Cadeia Leve de Miosina/metabolismo , Junções Íntimas/efeitos dos fármacos , Animais , Azepinas/farmacologia , Western Blotting , Permeabilidade da Membrana Celular/efeitos dos fármacos , Colo/citologia , Colo/ultraestrutura , Diarreia/induzido quimicamente , Ingestão de Alimentos/efeitos dos fármacos , Eletromiografia , Inibidores Enzimáticos/farmacologia , Inflamação/etiologia , Inflamação/patologia , Injeções Intraperitoneais , Interferon gama/análise , Interferon gama/metabolismo , Interleucina-1/análise , Interleucina-1/metabolismo , Interleucina-6/análise , Interleucina-6/metabolismo , Mucosa Intestinal/enzimologia , Mucosa Intestinal/patologia , Mucosa Intestinal/ultraestrutura , Cinética , Lipopolissacarídeos/administração & dosagem , Masculino , Contração Muscular , Músculo Esquelético/fisiologia , Naftalenos/farmacologia , Medição da Dor , Fosforilação , Proteínas/análise , Proteínas/metabolismo , Ratos , Ratos Wistar , Junções Íntimas/ultraestrutura , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Although annexin l exerts extracellular anti-inflammatory properties, little is known about its release in inflammatory diseases. Here, we characterized annexin 1 secretion in ulcerative colitis (UC) patients. Annexin 1 was detected by immunoblotting, in tissue homogenates and supernatants of colonic biopsies incubated in culture media, and in luminal colonic perfusates of UC patients. Annexin 1 was released by inflamed colonic biopsies from patients having severe UC but not by biopsies from healthy colon of the same patient or by biopsies from non-UC patients or from patients with slight or moderate UC. Annexin 1 was detected in luminal colonic perfusates of patients having moderate or slight UC but not in perfusates from control patients. The level of annexin 1 expression and secretion was unrelated to long-term glucocorticoid treatment, but annexin 1 secretion in perfusates was induced, in some patients, by short-term glucocorticoid exposure. These results show that annexin 1 is secreted endogenously in the colon of patients with UC. This secretion, which occurs both in vitro and in vivo, depends on the severity of inflammation. Given the anti-inflammatory effects of annexin 1, this protein may serve to down-regulate the inflammatory response in the course of inflammatory bowel disease.
Assuntos
Anexina A1/metabolismo , Colite Ulcerativa/fisiopatologia , Adulto , Idoso , Anexina A1/biossíntese , Estudos de Casos e Controles , Colonoscopia , Regulação para Baixo , Feminino , Humanos , Immunoblotting , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: This epidemiological investigation aims to measure the prevalence of irritable bowel syndrome (IBS) in the general population using the Rome II criteria and to evaluate the medical management including treatments and the impact of IBS on patient life. METHODS: A nationally representative sample of 20,000 French subjects, aged 18 years and over, were interviewed by SOFRES (French Public Opinion Poll Institute) in May 2001. In a second phase (June/July 2001), a 48-question self-administered questionnaire was given to the subjects who have been selected during the first phase as suffering from IBS (Rome II criteria). RESULTS: The prevalence of IBS was 4.7% (confidence interval, 4.36-5.04% with 5% risk) with a predominance in women (5.7% versus 3.7%, P < 0.01). The abdominal pain was often longstanding (> 5 years, 50%), intense (43%) and nocturnal (35%). During the most recent painful episode the levels of associated transit problems were almost equally divided between diarrhoea (36%), constipation (29%) and alternate episodes of both (31%). Apart from pain, bloating was given as the most frequent (73%) and most troublesome (24%) symptom. Since the onset, 80% of subjects with IBS had consulted a doctor (90% consulted a general physician, 57% a gastroenterologist, 50% both) and of these, 80% consulted within the previous 12 months. Sixty-seven per cent of subjects underwent additional investigations since the start of their illness (average of 3.4 examinations per patient examined: colonoscopy, 34.1%; laboratory tests, 34%; and abdominal ultrasound, 27.7%). Over the previous 12 months, 8% of the subjects had been admitted to hospital (average length of stay, 6.6 days), 11% of employed subjects had to take time off, 93% of subjects had taken prescribed medication (87%), but 43% of people thought it was ineffective. The effect on daily life was considerable (score, 6.2/10; close to the score for flu, 7/10). Two-thirds of the individuals changed their diet; 54% said it affected their social life and 29% their professional life. Seventy-four per cent of patients trusted their doctor, with a satisfaction index of 63%, but 45% of patients would like to have more information on IBS. CONCLUSION: This study confirmed that the Rome II criteria detected IBS with a prevalence of 4.7%. The recruited subjects had severe symptoms (frequency, intensity and duration) that had a considerable effect on their daily life. The high level of referrals and initial consultations in all categories and the patient's attitudes towards the illness and its treatment emphasize the relative ineffectiveness of care for patients suffering from IBS.
Assuntos
Síndrome do Intestino Irritável/epidemiologia , Adulto , Efeitos Psicossociais da Doença , Feminino , França/epidemiologia , Humanos , Síndrome do Intestino Irritável/psicologia , Síndrome do Intestino Irritável/terapia , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Prevalência , Qualidade de Vida , Encaminhamento e Consulta , Distribuição por Sexo , Estresse Psicológico , Falha de TratamentoRESUMO
BACKGROUND & AIMS: Maternal deprivation (MD) increases nerve growth factor (NGF) expression and colonic mast cell density and alters visceral sensitivity. This study aimed to establish whether NGF overexpression induced by neonatal stress is involved in altered visceral sensitivity and gut mucosal integrity in adult rats. METHODS: Male Wistar rat pups were either submitted to MD and treated with anti-NGF antibodies or left with their dam and treated daily with NGF. All rats were tested 10 weeks later for visceral sensitivity and 12 weeks later for gut permeability, myeloperoxidase activity, and mast cell numbers. Colonic NGF and NGF receptor expression were determined at 14 days and 12 weeks of age. To determine the involvement of colonic NGF overexpression and mast cell hyperplasia in visceral hyperalgesia induced by MD, neonatally deprived adult rats received anti-NGF antibodies or doxantrazole. RESULTS: MD increased visceral sensitivity to rectal distention, gut permeability, colonic myeloperoxidase activity, and mast cell density, and anti-NGF antibodies abolished these effects. Neonatal daily treatment with NGF mimicked the alterations induced by MD on both rectal sensitivity and mucosal barrier. In deprived compared with nondeprived rats, colonic NGF immunostaining and NGF messenger RNA were increased at 14 days and 12 weeks. Overexpression of NGF receptor messenger RNA, present at 14 days, was not observed later. Moreover, adult deprived rats treated with doxantrazole or anti-NGF antibodies exhibited normal gut permeability and visceral sensitivity to rectal distention. CONCLUSIONS: These data indicate that NGF triggers and maintains long-term alterations of visceral sensitivity and gut mucosal integrity induced by MD.
Assuntos
Colo/fisiopatologia , Doenças do Colo/fisiopatologia , Fator de Crescimento Neural/genética , Estresse Psicológico/fisiopatologia , Animais , Animais Recém-Nascidos , Colo/citologia , Colo/metabolismo , Doenças do Colo/metabolismo , Doenças do Colo/patologia , Feminino , Motilidade Gastrointestinal/fisiologia , Imuno-Histoquímica , Absorção Intestinal/fisiologia , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/fisiopatologia , Masculino , Mastócitos/citologia , Privação Materna , Fator de Crescimento Neural/metabolismo , Fator de Crescimento Neural/farmacologia , Peroxidase/metabolismo , Gravidez , RNA Mensageiro/análise , Ratos , Ratos Wistar , Receptor de Fator de Crescimento Neural , Receptor trkA/genética , Receptores de Fator de Crescimento Neural/genéticaRESUMO
Capsaicin-sensitive afferent nerves are described as being protective against gastric inflammation; their destruction leads to an exacerbation of inflammatory processes. However, these nerves have been shown to exert a pro-inflammatory action on stress-induced gastritis in rats. Our study aimed to investigate the role of capsaicin-sensitive afferent nerves in different experimental models of gastritis in rats. Functional ablation of sensory nerves was achieved by systemic capsaicin treatment (100 mg/kg). Gastritis was induced by mild (iodoacetamide, diquat, surgical duodeno-gastric reflux [DGR]) and strong (70% ethanol, indomethacin) inflammatory agents. Antagonists of the CGRP1 and NK1 receptors, hCGRP8-37 and SR140333, were administered in rats treated with iodoacetamide and ethanol. Macroscopic damage scores (MDS), myeloperoxidase (MPO) activity and malondialdehyde (MDA) concentration were evaluated after sacrifice. Macroscopic lesions appeared only in ethanol and indomethacin gastritis and were enhanced by capsaicin treatment. Gastric MPO activity was significantly increased by all agents compared to controls. Capsaicin treatment did not have any effect on MPO activity in indomethacin-treated rats or in rats submitted to surgery for duodeno-gastric reflux. However, it abolished the increase in MPO induced by iodoacetamide and diquat, and significantly enhanced that induced by ethanol. hCGRP8-37 and SR140333 abolished the increase in MPO activity and MDA concentration in iodoacetamide treated rats. In ethanol-treated rats, SR140333 diminished MPO activity. These results indicate that, depending upon the nature and duration of the experimental inflammation, capsaicin-sensitive afferent nerves may act differently to control gastric inflammatory processes, suggesting the involvement of a neurogenic component in some forms of gastric inflammation.
Assuntos
Capsaicina/farmacologia , Mucosa Gástrica/fisiopatologia , Gastrite/fisiopatologia , Receptores de Neuropeptídeos/metabolismo , Células Receptoras Sensoriais/metabolismo , Fibras Aferentes Viscerais/metabolismo , Animais , Biomarcadores , Peptídeo Relacionado com Gene de Calcitonina/análogos & derivados , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Denervação/métodos , Modelos Animais de Doenças , Mucosa Gástrica/inervação , Mucosa Gástrica/patologia , Gastrite/induzido quimicamente , Gastrite/metabolismo , Mediadores da Inflamação/farmacologia , Masculino , Malondialdeído/metabolismo , Antagonistas dos Receptores de Neurocinina-1 , Neurotoxinas/farmacologia , Peroxidase/metabolismo , Ratos , Ratos Wistar , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Receptores da Neurocinina-1/metabolismo , Receptores de Neuropeptídeos/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Substância P/análogos & derivados , Substância P/metabolismo , Fibras Aferentes Viscerais/efeitos dos fármacosRESUMO
Hormonal cycling may be related to a higher incidence of pain syndrome in female. As tachykinins are pivotal in stress-induced colonic dysfunction, we investigated whether ovarian steroids influence stress-induced visceral hypersensitivity to rectal distension (RD) in female rats and further, whether this influence involves NK1 receptors. Female Wistar rats, either intact or ovariectomized (OVX), were equipped for abdominal muscle electromyography and submitted to 2-h partial restraint stress (PRS) or sham-PRS. First, the effect of PRS was evaluated in intact rats. Second, abdominal response to RD was recorded in OVX rats treated with either, progesterone, 17beta-estradiol, 17beta-estradiol-plus-progesterone, or vehicle, in both basal and PRS conditions. Third, the NK1 receptor-antagonist, SR140333, was tested in PRS-intact and PRS-OVX rats under 17beta-estradiol or 17beta-estradiol-plus-progesterone treatment. PRS induced visceral hypersensitivity to RD and this effect was prevented by ovariectomy. OVX rats treated with 17beta-estradiol or 17beta-estradiol-plus-progesterone, but not progesterone alone, exhibited visceral hypersensitivity after PRS similar to that of intact rats. Both stress-induced visceral hypersensitivity in intact rats and the hormonally-restored visceral hyper-responsiveness of OVX rats were antagonized by SR140333. It is concluded, therefore, that stress-induced visceral hypersensitivity in female rats is estrogens-dependent and mediated through NK1 receptor activation.
Assuntos
Estrogênios/metabolismo , Receptores da Neurocinina-1/metabolismo , Estresse Fisiológico/metabolismo , Fibras Aferentes Viscerais/metabolismo , Músculos Abdominais/efeitos dos fármacos , Músculos Abdominais/metabolismo , Animais , Estrogênios/farmacologia , Feminino , Antagonistas dos Receptores de Neurocinina-1 , Ovariectomia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Estimulação Física/métodos , Ratos , Ratos Wistar , Restrição Física , Fibras Aferentes Viscerais/efeitos dos fármacosRESUMO
Intestinal infections often trigger functional bowel disorders. The nematode Nippostrongylus brasiliensis induces post-infective alterations mainly consisting in an intestinal mast cell hyperplasia. Mast cells contact vagal afferent nerve fibres. Therefore, it is possible that the anatomical sequels of intestinal nematode infection induce long term alterations in the mediation of afferent signals from the gut to the brain. To test this hypothesis, we examined hindbrain expression of Fos immunoreactivity following systemic cholecystokinin (CCK) administration in control rats and 35 days after N. brasiliensis infection. In controls, Fos was expressed in the area postrema and the nucleus of solitary tract. After infection, this expression was increased by 262 and 157%, respectively. We conclude that an intestinal infection, at least in this model, is followed by an enhancement of the activation of hindbrain sites by CCK.
Assuntos
Vias Aferentes/metabolismo , Colecistocinina/metabolismo , Intestinos/parasitologia , Bulbo/metabolismo , Neurônios Aferentes/metabolismo , Nippostrongylus/patogenicidade , Infecções por Strongylida/metabolismo , Nervo Vago/metabolismo , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiopatologia , Animais , Contagem de Células , Células Quimiorreceptoras/efeitos dos fármacos , Células Quimiorreceptoras/metabolismo , Colecistocinina/farmacologia , Quarto Ventrículo/efeitos dos fármacos , Quarto Ventrículo/metabolismo , Quarto Ventrículo/fisiopatologia , Imuno-Histoquímica , Intestinos/inervação , Intestinos/fisiopatologia , Masculino , Mastócitos/metabolismo , Mastócitos/parasitologia , Bulbo/efeitos dos fármacos , Bulbo/fisiopatologia , Neurônios Aferentes/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Núcleo Solitário/fisiopatologia , Infecções por Strongylida/fisiopatologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiopatologiaRESUMO
BACKGROUND & AIMS: PAR-2s are highly expressed throughout the gastrointestinal tract. These receptors are cleaved by trypsin and mast cell tryptase and can be activated by peptides corresponding to the tethered ligand of the receptor (SLIGRL-NH2 for rat). The aim of this study was to determine whether colonic administration of PAR-2 agonists affects visceral sensitivity to rectal distention in conscious rats. METHODS: Abdominal contractions (a criteria of visceral pain) were recorded in rats equipped with intramuscular electrodes. Rectal distention was performed at various times after intracolonic infusion of SLIGRL-NH2 and trypsin. Inflammation parameters and permeability were followed in the colon after the intracolonic injections. Fos expression at a spinal level (L4-L6) was also studied 2 hours after intracolonic injection of SLIGRL-NH2. RESULTS: Rectal distention significantly increased abdominal contractions starting at the RD volume of 0.8 mL. Intracolonic injection of SLIGRL-NH2 (200 microg/rat) and trypsin (200 U/rat), but not vehicle, LRGILS-NH2 (control peptide), boiled trypsin, or SLIGRL-NH2 injected IP, significantly increased (P < 0.05) abdominal contractions for high volumes of distention, 10- and 24-hour postinfusion. SLIGRL-NH2-induced hyperalgesia was inhibited by a NK1 receptor antagonist (SR 140333) but not by indomethacin. Intracolonic injection of SLIGRL-NH2 elevated spinal Fos expression and caused increased intestinal permeability but did not cause detectable inflammation. CONCLUSIONS: Intracolonic infusion of subinflammatory doses of PAR-2 agonists activated spinal afferent neurons and produced a delayed rectal hyperalgesia that involves changes in intestinal permeability and the activation of NK1 receptors. These results identify a possible role for proteinases and PAR-2 in the genesis of visceral hyperalgesia.