RESUMEN
BACKGROUND: There are few data regarding the diagnostic delay and its predisposing factors in coeliac disease (CD). AIMS: To investigate the overall, the patient-dependant, and the physician-dependant diagnostic delays in CD. METHODS: CD adult patients were retrospectively enroled at 19 Italian CD outpatient clinics (2011-2021). Overall, patient-dependant, and physician-dependant diagnostic delays were assessed. Extreme diagnostic, i.e., lying above the third quartile of our population, was also analysed. Multivariable regression models for factors affecting the delay were fitted. RESULTS: Overall, 2362 CD patients (median age at diagnosis 38 years, IQR 27-46; M:F ratio=1:3) were included. The median overall diagnostic delay was 8 months (IQR 5-14), while patient- and physician-dependant delays were 3 (IQR 2-6) and 4 (IQR 2-6) months, respectively. Previous misdiagnosis was associated with greater physician-dependant (1.076, p = 0.005) and overall (0.659, p = 0.001) diagnostic delays. Neurological symptoms (odds ratio 2.311, p = 0.005) and a previous misdiagnosis (coefficient 9.807, p = 0.000) were associated with a greater extreme physician-dependant delay. Gastrointestinal symptoms (OR 1.880, p = 0.004), neurological symptoms (OR 2.313, p = 0.042), and previous misdiagnosis (OR 4.265, p = 0.000) were associated with increased extreme overall diagnostic delay. CONCLUSION: We identified some factors that hamper CD diagnosis. A proper screening strategy for CD should be implemented.
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Enfermedad Celíaca , Humanos , Adulto , Persona de Mediana Edad , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/epidemiología , Diagnóstico Tardío , Estudios Retrospectivos , Italia/epidemiología , Oportunidad RelativaRESUMEN
BACKGROUND: Vedolizumab registration trials were the first to include elderly patients with moderate-to-severe ulcerative colitis (UC) or Crohn's disease (CD), but few real-life data have been reported in this population. AIMS: We investigated the effectiveness and safety of vedolizumab in matched cohorts of elderly and nonelderly UC and CD patients. METHODS: The Long-term Italian Vedolizumab Effectiveness (LIVE) study is a retrospective-prospective study including UC and CD patients who started vedolizumab from April 2016 to June 2017. Elderly patients (≥65 years) were matched clinically 1:2 to nonelderly patients (18-64 years); the 2 groups were followed until drug discontinuation or June 2019. RESULTS: The study included 198 elderly (108 UC, 90 CD) and 396 matched nonelderly patients (205 UC, 191 CD). Nonelderly UC patients had a significantly higher persistence on vedolizumab compared to elderly patients (67.6% vs. 51.4%, p = 0.02). No significant difference in effectiveness was observed between elderly and nonelderly CD patients (59.4% vs. 52.4%, p = 0.32). Age ≥65 years was associated with lower persistence in UC; for CD, previous exposure to anti-TNF-α agents, Charlson comorbidity index >2 and moderate-to-severe clinical activity at baseline were associated with lower persistence. There were recorded 130 adverse events, with comparable rates between the two groups. A Charlson comorbidity index >2 was associated with an increased risk of adverse events. CONCLUSION: Vedolizumab can be considered a safe option in elderly IBD patients. Its effectiveness in elderly UC patients may be reduced, while no age-dependent effect on effectiveness was observed in CD.
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Fármacos Gastrointestinales , Enfermedades Inflamatorias del Intestino , Anciano , Anticuerpos Monoclonales Humanizados , Enfermedad Crónica , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/efectos adversos , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Estudios Prospectivos , Estudios Retrospectivos , Resultado del Tratamiento , Inhibidores del Factor de Necrosis TumoralRESUMEN
BACKGROUND AND STUDY AIM: The traditional endoscopic therapy of anastomotic strictures (AS) after orthotopic liver transplantation (OLT) is multiple ERCPs with the insertion of an increasing number of plastic stents side-by-side. Fully covered self-expanding metal stents (cSEMS) could be a valuable option to decrease the number of procedures needed or non-responders to plastic stents. This study aims to retrospectively analyse the results of AS endoscopic treatment by cSEMS and to identify any factors associated with its success. PATIENTS AND METHODS: Ninety-one patients (mean age 55.9 ± 7.6 SD; 73 males) from nine Italian transplantation centres, had a cSEMS positioned for post-OLT-AS between 2007 and 2017. Forty-nine (54%) patients were treated with cSEMS as a second-line treatment. RESULTS: All the procedures were successfully performed without immediate complications. After ERCP, adverse events occurred in 11% of cases (2 moderate pancreatitis and 8 cholangitis). In 49 patients (54%), cSEMSs migrated. After cSEMS removal, 46 patients (51%) needed further endoscopic (45 patients) or radiological (1 patient) treatments to solve the AS. Lastly, seven patients underwent surgery. Multivariable stepwise logistic regression showed that cSEMS migration was the only factor associated with further treatments (OR 2.6, 95% CI 1.0-6.6; p value 0.03); cSEMS implantation before 12 months from OLT was associated with stent migration (OR 5.2, 95% CI 1.7-16.0; p value 0.004). CONCLUSIONS: cSEMS appears to be a safe tool to treat AS. cSEMS migration is the main limitation to its routinary implantation and needs to be prevented, probably with the use of new generation anti-migration stents.
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Colestasis , Trasplante de Hígado , Colangiopancreatografia Retrógrada Endoscópica/efectos adversos , Colestasis/etiología , Colestasis/cirugía , Constricción Patológica/cirugía , Humanos , Trasplante de Hígado/efectos adversos , Masculino , Persona de Mediana Edad , Plásticos , Estudios Retrospectivos , Silicatos , Stents/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVE: Arthritis is the most frequent extra-intestinal manifestation in patients with inflammatory bowel diseases (IBD). The coexistence of intestinal and articular inflammation advocates the need for a multidisciplinary management of patients with IBD-associated spondyloarthritis. METHODS: Consecutive IBD patients were evaluated jointly by the gastroenterologist and the rheumatologist in a combined clinic. All the patients were assessed and screened for articular involvement, disease activity and health related quality of life. After the prescription of a shared treatment, patients with spondyloarthritis were followed up for 24â¯months. RESULTS: Two hundred sixty-two IBD patients, including 80 who were classified as affected by spondyloarthritis according to the ASAS criteria, were included in the study. At baseline, patients with both IBD and spondyloarthritis showed worse quality of life in both the physical and mental domains. The multidisciplinary management provided a significant improvement of gastrointestinal and articular manifestations, as well as the health-related quality of life. Moreover, global and gastrointestinal-specific quality of life significantly correlated with articular disease activity. CONCLUSION: The multidisciplinary management significantly improves both articular and gastrointestinal disease activities and the quality of life of patients with IBD-associated spondyloarthritis. An appropriate screening strategy and the integrated management of these patients should be encouraged and employed in clinical practice.
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Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Espondiloartritis/tratamiento farmacológico , Adulto , Antirreumáticos/efectos adversos , Antirreumáticos/uso terapéutico , Productos Biológicos/efectos adversos , Productos Biológicos/uso terapéutico , Colitis Ulcerosa/diagnóstico , Vías Clínicas , Enfermedad de Crohn/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Grupo de Atención al Paciente , Medición de Resultados Informados por el Paciente , Calidad de Vida , Inducción de Remisión , Espondiloartritis/diagnóstico , Factores de Tiempo , Resultado del Tratamiento , Flujo de TrabajoRESUMEN
BACKGROUND: The most appropriate endo-therapeutic approach to biliary anastomotic strictures is yet to be defined. AIM: To retrospectively report on the endo-therapy of duct-to-duct anastomotic strictures during 2013 in Italy. METHODS: Data were collected from 16 Endoscopy Units at the Italian Liver Transplantation Centers (BASALT study group). RESULTS: Complete endo-therapy and follow-up data are available for 181 patients: 101 treated with plastic multistenting, 26 with fully covered self-expandable metal stenting and 54 with single stenting. Radiological success was achieved for 145 patients (80%), that is, 88% of plastic multistenting, 88% of self-expandable metal stenting and 61% of single stenting (P < 0.001 vs plastic multistenting; P < 0.05 vs self-expandable metal stenting). After first-line endo-therapy failure, the patients underwent a second-line endo-therapy with plastic multistenting for 25%, fully covered self-expandable metal stenting for 53% and single stenting for 22% of cases, and radiological success was achieved for 84%, that is, 100%, 85% and 63% with plastic multistenting, self-expandable metal stenting and single stenting (P < 0.05 vs plastic multistenting or self-expandable metal stenting) respectively. Procedure-related complications occurred in 7.8% of endoscopic retrograde cholangiopancreatographies. Overall, clinical success was achieved in 87% of patients after a median follow-up of 25 months. CONCLUSION: Plastic multistenting is confirmed as the preferred first-line treatment, while fully covered self-expandable metal stenting as rescue option for biliary anastomotic strictures. Single stenting has sub-optimal results and should be abandoned.
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Colangiopancreatografia Retrógrada Endoscópica/instrumentación , Constricción Patológica/cirugía , Trasplante de Hígado/efectos adversos , Stents Metálicos Autoexpandibles , Stents/clasificación , Adulto , Anciano , Enfermedades de las Vías Biliares/etiología , Enfermedades de las Vías Biliares/cirugía , Colestasis/etiología , Constricción Patológica/etiología , Femenino , Humanos , Italia , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Plásticos , Estudios Retrospectivos , Encuestas y Cuestionarios , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenAsunto(s)
Conductos Biliares/cirugía , Colangiopancreatografia Retrógrada Endoscópica/estadística & datos numéricos , Colestasis/cirugía , Constricción Patológica/cirugía , Trasplante de Hígado/efectos adversos , Complicaciones Posoperatorias/cirugía , Conductos Biliares/diagnóstico por imagen , Conductos Biliares/patología , Colangiopancreatografia Retrógrada Endoscópica/instrumentación , Colangiopancreatografia Retrógrada Endoscópica/métodos , Colestasis/diagnóstico por imagen , Colestasis/etiología , Constricción Patológica/diagnóstico por imagen , Constricción Patológica/etiología , Estudios de Seguimiento , Hospitales de Alto Volumen/estadística & datos numéricos , Humanos , Italia , Angiografía por Resonancia Magnética , Selección de Paciente , Complicaciones Posoperatorias/diagnóstico por imagen , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Stents , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
BACKGROUND: Abstract: Up to 80% of Crohn's disease (CD) patients require at least one surgical intervention in their lifetime and up to 70% of these patients develop postoperative endoscopic recurrence within 1 year. METHODS: The most important predictors of early postoperative recurrence are represented by smoking, prior intestinal surgery, penetrating disease and perianal location. Genetic factors, gut microbiota structure and immunological alterations may be involved in the pathogenesis of postoperative recurrence of CD, although their specific roles have to be determined yet. RESULTS: Different drugs, such as metronidazole, thiopurines and anti-tumor necrosis factor α (anti- TNFα) have been shown to reduce the risk of recurrence in many clinical trials, although the choice of the drug should take into consideration the benefits, the potential side effects and also the costs. Patients who are at high risk for postoperative recurrence should be considered for early medical prophylaxis with thiopurines or anti-TNFα drugs; on the contrary, patients who do not have risk factors may receive no treatment or receive a course of antibiotic or mesalazine followed by tailored therapy based on endoscopy at 6 months. CONCLUSION: Therefore, stratifying patients according to their risk of recurrence and tailoring therapy are at present the ideal and most cost-effective ways to treat operated CD patients, although many aspects require further evaluation.
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Terapia Biológica/métodos , Enfermedad de Crohn , Prevención Secundaria/métodos , Algoritmos , Ensayos Clínicos como Asunto , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/etiología , Enfermedad de Crohn/cirugía , Humanos , Recurrencia , Factores de Riesgo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresAsunto(s)
Erupciones por Medicamentos/etiología , Fármacos Gastrointestinales/efectos adversos , Infliximab/efectos adversos , Micosis Fungoide/inducido químicamente , Neoplasias Cutáneas/inducido químicamente , Adulto , Colitis Ulcerosa/inducido químicamente , Diagnóstico Diferencial , Erupciones por Medicamentos/diagnóstico , Humanos , Masculino , Micosis Fungoide/diagnóstico , Neoplasias Cutáneas/diagnósticoRESUMEN
Ulcerative Colitis (UC) and Crohn's Disease (CD) are chronic, progressive and disabling disorders characterized by a heterogeneous clinical course. Some years ago the main goal of the therapy was to achieve and maintain clinical remission, whereas at present the main goal of therapy is represented by the deep remission, characterized by sustained clinical remission, complete mucosal healing and normalization of serological markers of inflammation. In the last years new therapeutic approaches have been introduced which have led to a reduction in the mortality rate and have modified the natural history of Inflammatory Bowel Diseases (IBD). In addition, several prognostic factors have been identified which have allowed to better stratify the disease and to choose the most appropriate therapy for the single patient. Moreover, early treatment with immunosuppressive drugs and/or biologics has changed, at least in the short term, the course of the disease by reducing hospitalization rate and the need for surgery. Therefore, the development of biologic therapies has represented an important step in the treatment of IBD, since these drugs induce remission and response rates that are not achieved by other therapies. Since their use can result in significant adverse events that increase morbidity, patients must be aware of the risks associated with treatment and must be strictly monitored. Although treatment with biologic drugs is not successful in all patients and many of them lose clinical response, new therapies are currently under evaluation.
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Productos Biológicos/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/inmunología , Animales , Productos Biológicos/efectos adversos , Productos Biológicos/farmacología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inmunología , Humanos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
OBJECTIVES: SSc is a clinically heterogeneous and generalized disease, characterized by thickness of the connective tissue of the skin and internal organs, such as the digestive tract, impairing gastrointestinal (GI) motility. Our aim is to evaluate retrospectively abnormalities of oesophageal motility, gastric emptying, oro-cecal transit time (OCTT) and small intestine bacterial overgrowth (SIBO) in a large cohort of SSc patients. METHODS: Ninety-nine SSc patients were included in the study. Forty-two patients underwent oesophageal conventional manometry, 45 performed a [(13)C]octanoic acid breath test to measure gastric emptying time and all 99 patients performed a lactulose breath test in order to evaluate OCTT and SIBO. Data were compared with healthy controls. RESULTS: In SSc patients, median lower oesophageal sphincter (LOS) pressure [14 mmHg (25th-75th; 8-19) vs 24 mmHg (19-28); P < 0.01] and median wave amplitude [30 mmHg (16-70) vs 72 mmHg (48-96); P < 0.01] were lower than in controls. Oesophageal involvement, defined as reduced LOS pressure and ineffective oesophageal motility pattern, was encountered in 70% of SSc patients. A delayed gastric emptying time was present in 38% of SSc patients: mean t½ was 141 ± 79 min vs 90 ± 40 min of controls (P < 0.01). Also, OCTT was significantly delayed in SSc: median OCTT was 160 min (25th-75th; 135-180) vs 105 min (25th-75th; 90-135) of controls (P < 0.01). SIBO was observed in 46% of SSc compared with 5% of controls (P < 0.01). CONCLUSION: GI involvement is very frequent in SSc patients. Oesophagus and small bowel are more frequently impaired, whereas delayed gastric emptying is less common.
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Enfermedades Gastrointestinales/complicaciones , Motilidad Gastrointestinal/fisiología , Tránsito Gastrointestinal/fisiología , Esclerodermia Sistémica/complicaciones , Adulto , Anciano , Femenino , Enfermedades Gastrointestinales/microbiología , Enfermedades Gastrointestinales/fisiopatología , Humanos , Intestino Delgado/microbiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Esclerodermia Sistémica/microbiología , Esclerodermia Sistémica/fisiopatologíaRESUMEN
The aim of this study is to assess the associations between chronic spontaneous urticaria (CSU), Helicobacter pylori infection and small intestinal bacterial overgrowth. Forty- eight patients with CSU were studied by scoring the urticaria activity and assesing the quality of life. Patients with H. pylori infection (n=11) or small intestinal bacterial overgrowth (n=13) were specifically treated for one week and clinically evaluated both before and 4 weeks after the eradication therapy. Eradication of H. pylori infection led to a significant improvement in CSU (p<0.002). In contrast, eradication of small intestinal bacterial overgrowth was not associated with any clinical improvement in CSU, despite the fact that these patients had statistically significant more urticaria activity at baseline. Thus there is no evidence to support the eradication of small intestinal bacterial overgrowth in CSU, but eradication of H. pylori infection may result in an improvement of the disease.
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Infecciones por Helicobacter/microbiología , Helicobacter pylori/crecimiento & desarrollo , Intestino Delgado/microbiología , Urticaria/microbiología , Antibacterianos/uso terapéutico , Enfermedad Crónica , Femenino , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/epidemiología , Humanos , Intestino Delgado/efectos de los fármacos , Italia/epidemiología , Masculino , Prevalencia , Estudios Prospectivos , Calidad de Vida , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Urticaria/diagnóstico , Urticaria/epidemiologíaRESUMEN
Paraoxonase-1 (PON1) plays an antioxidant and anti-inflammatory role. Aim of the study was to investigate the alteration of paraoxonase-1 activity in celiac disease (CD), an intestinal disorder characterized by toxic injury exerted by gluten peptides. Activities of PON1, levels of biochemical markers of lipid peroxidation and total antioxidant capacity were evaluated in serum obtained from 27 celiac patients (11 at diagnosis, 16 treated with gluten free diet) and 25 healthy subjects. Moreover, the serum susceptibility of Cu(2+)-induced lipid peroxidation was investigated in controls and patients. The results showed a lower PON1 activity in serum of both groups of celiac patients with respect to control subjects. PON1 activity in CD was related with markers of disease severity and was negatively correlated with the levels of lipid hydroperoxide and with the susceptibility of serum to lipid peroxidation induced in vitro by metal ions. The alteration of PON1 activity and markers of lipid peroxidation realized at lower extent in patients who were on a gluten-free diet.
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Cholangiocarcinoma is a strongly aggressive malignancy with a very poor prognosis. Effective therapeutic strategies are lacking because molecular mechanisms regulating cholangiocarcinoma cell growth are unknown. Furthermore, experimental in vivo animal models useful to study the pathophysiologic mechanisms of malignant cholangiocytes are lacking. Leptin, the hormone regulating caloric homeostasis, which is increased in obese patients, stimulates the growth of several cancers, such as hepatocellular carcinoma. The aim of this study was to define if leptin stimulates cholangiocarcinoma growth. We determined the expression of leptin receptors in normal and malignant human cholangiocytes. Effects on intrahepatic cholangiocarcinoma (HuH-28) cell proliferation, migration, and apoptosis of the in vitro exposure to leptin, together with the intracellular pathways, were then studied. Moreover, cholangiocarcinoma was experimentally induced in obese fa/fa Zucker rats, a genetically established animal species with faulty leptin receptors, and in their littermates by chronic feeding with thioacetamide, a potent carcinogen. After 24 weeks, the effect of leptin on cholangiocarcinoma development and growth was assessed. Normal and malignant human cholangiocytes express leptin receptors. Leptin increased the proliferation and the metastatic potential of cholangiocarcinoma cells in vitro through a signal transducers and activators of transcription 3-dependent activation of extracellular signal-regulated kinase 1/2. Leptin increased the growth and migration, and was antiapoptotic for cholangiocarcinoma cells. Moreover, the loss of leptin function reduced the development and the growth of cholangiocarcinoma. The experimental carcinogenesis model induced by thioacetamide administration is a valid and reproducible method to study cholangiocarcinoma pathobiology. Modulation of the leptin-mediated signal could be considered a valid tool for the prevention and treatment of cholangiocarcinoma.
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Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Proliferación Celular , Colangiocarcinoma/patología , Leptina/fisiología , Animales , Neoplasias de los Conductos Biliares/metabolismo , Conductos Biliares/citología , Conductos Biliares/metabolismo , Conductos Biliares Intrahepáticos/metabolismo , Colangiocarcinoma/inducido químicamente , Colangiocarcinoma/metabolismo , Técnica del Anticuerpo Fluorescente , Humanos , Quinasas Janus/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Zucker , Receptores de Leptina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3/metabolismo , Tioacetamida/farmacologíaRESUMEN
Liver fibrosis may be considered as a dynamic and integrated cellular response to chronic liver injury. The activation of hepatic stellate cells and the consequent deposition of large amounts of extracellular matrix play a major role in the fibrogenic process, but it has been shown that other cellular components of the liver are also involved. Although the pathogenesis of liver damage usually depends on the underlying disease, oxidative damage of biologically relevant molecules might represent a common link between different forms of chronic liver injury and hepatic fibrosis. In fact, oxidative stress-related molecules may act as mediators able to modulate all the events involved in the progression of liver fibrosis. In addition, chronic liver diseases are often associated with decreased antioxidant defenses. Although vitamin E levels have been shown to be decreased in chronic liver diseases of different etiology, the role of vitamin E supplementation in these clinical conditions is still controversial. In fact, the increased serum levels of alpha-tocopherol following vitamin E supplementation not always result in a protective effect on liver damage. In addition, clinical trials have usually been performed in small cohorts of patients, thus making definitive conclusions impossible. At present, treatment with vitamin E or other antioxidant compounds could be proposed for nonalcoholic fatty liver disease (NAFLD), the most frequent hepatic lesion in western countries which can progress to nonalcoholic steatohepatitis and cirrhosis due to the production of large amounts of oxidative stress products. However, although some studies have shown encouraging results, multicentric and long-term clinical trials are needed.
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Antioxidantes/metabolismo , Cirrosis Hepática/metabolismo , Hepatopatías/metabolismo , Vitamina E/metabolismo , Animales , Enfermedad Crónica , HumanosRESUMEN
The aim of this study was to evaluate the effect of cariporide, a selective Na(+)/H(+) exchange inhibitor, on isolated and cultured hepatic stellate cells (HSCs) and in 2 in vivo models of rat liver fibrosis. Platelet-derived growth factor (PDGF)-induced HSC proliferation, evaluated by measuring the percentage of bromodeoxyuridine-positive cells, was significantly inhibited by cariporide, with a maximal effect at 10 micromol/L. Incubation with cariporide did not inhibit PDGF-induced extracellular-regulated kinase 1/2 (ERK1/2), Akt (a downstream component of the phosphatidylinositol [PI]-3 kinase pathway), and protein kinase C (PKC) activation but reduced PDGF-induced activation of the Na(+)/H(+) exchanger, with a maximal effect at 10 micromol/L. Rats treated with dimethylnitrosamine (DMN; 10 mg/kg) for 1 and 5 weeks received a diet with or without 6 ppm cariporide. Treatment with cariporide reduced the degree of liver injury, as determined by alanine aminotransferase (ALT) values, also when administered after the induction of hepatic damage. This was associated with reduced HSC activation and proliferation and reduced collagen deposition, as determined by morphometric evaluation of alpha-smooth muscle actin (SMA)/proliferating cell nuclear antigen-positive cells and percentage of Sirius red-positive parenchyma, respectively. Moreover, cariporide was also able to reduce alpha(1)I procollagen messenger RNA (mRNA) expression. Similar effects were observed in bile duct-ligated (BDL) rats. In conclusion, selective inhibition of the Na(+)/H(+) exchanger by cariporide may represent an effective therapeutic strategy in the treatment of hepatic fibrosis.
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Guanidinas/farmacología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Proteínas Serina-Treonina Quinasas , Intercambiadores de Sodio-Hidrógeno/antagonistas & inhibidores , Sulfonas/farmacología , Animales , Conductos Biliares , División Celular/efectos de los fármacos , Células Cultivadas , Dimetilnitrosamina/farmacología , Activación Enzimática/efectos de los fármacos , Ligadura , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/etiología , Masculino , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosforilación/efectos de los fármacos , Factor de Crecimiento Derivado de Plaquetas/farmacología , Proteína Quinasa C/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Ratas , Ratas Sprague-Dawley , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Intercambiadores de Sodio-Hidrógeno/efectos de los fármacos , Intercambiadores de Sodio-Hidrógeno/metabolismoRESUMEN
BACKGROUND/AIMS: Pirfenidone has been recently shown to reduce dimethynitrosamine-induced liver fibrosis in the rat, but no information are available on the effect of this drug on cultured hepatic stellate cells (HSC). METHODS: HSC proliferation was evaluated by measuring bromodeoxyuridine incorporation; PDGF-receptor autophosphorylation, extracellular signal-regulated kinase (ERK1/2) and pp70(S6K) activation were evaluated by western blot; protein kinase C activation was evaluated by western blot and by ELISA; type I collagen accumulation and alpha1(I) procollagen mRNA expression were evaluated by ELISA and northern blot, respectively. RESULTS: Pirfenidone significantly inhibited PDGF-induced HSC proliferation, starting at a concentration of 1 microM, with a maximal effect at 1000 microM, without affecting HSC viability and without inducing apoptosis. The inhibition of PDGF-induced HSC proliferation was associated neither with variations in PDGF-receptor autophosphorylation, or with ERK1/2 and pp70(S6K) activation. On the other hand, pirfenidone was able to inhibit PDGF-induced activation of the Na(+)/H(+) exchanger, which is involved in PDGF-induced HSC proliferation in HSC, with a maximal effect at 1000 microM and inhibited PDGF-induced protein kinase C activation. Pirfenidone 100 and 1000 microM inhibited type I collagen accumulation in the culture medium induced by transforming growth factor(beta1) by 54% and 92%, respectively, as well as TGF(beta1)-induced alpha1(I) procollagen mRNA expression. RESULTS: Pirfenidone could be a new candidate for antifibrotic therapy in chronic liver diseases.
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Antineoplásicos/farmacología , Colágeno Tipo I/genética , Hepatocitos/citología , Hepatocitos/metabolismo , Piridonas/farmacología , Animales , Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Células Cultivadas , Colágeno Tipo I/metabolismo , Medios de Cultivo/metabolismo , Expresión Génica/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosforilación/efectos de los fármacos , Factor de Crecimiento Derivado de Plaquetas/farmacología , Proteína Quinasa C/metabolismo , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Intercambiadores de Sodio-Hidrógeno/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Factor de Crecimiento Transformador beta1RESUMEN
BACKGROUND/AIMS: Cytoskeletal reorganization plays an important role in the regulation of different cell functions, such as proliferation and migration. Since platelet-derived growth factor (PDGF) stimulates both proliferation and chemotaxis of hepatic stellate cells (HSC), we investigated the effects of this cytokine on cytoskeletal components of cultured rat HSC. METHODS/RESULTS: Exposure of HSC to PDGF induced the formation of stress fibres and of a ruffled configuration of the plasma membrane, evaluated by both fluorescence and electron microscopy. These modifications were also induced by exposure to the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate (PMA) and abolished by pretreatment with the PKC inhibitor calphostin C, with the Rho inhibitor C3 exoenzyme and with the intracellular calcium chelator MAPTAM, but not with the PI-3 kinase inhibitor wortmannin or with the mitogen-activated protein kinase kinase inhibitor PD 98059. PDGF induced a translocation of Rho from the cytosol to the membrane which was inhibited by C3 exoenzyme and by calpostin C, and which was also induced by PMA. Moreover, PDGF induced a rearrangement of vinculin which was prevented by C3 exoenzyme and calphostin C. CONCLUSIONS: PDGF-induced cytoskeletal reorganization in HSC is dependent on PKC and Rho, thus suggesting that these two pathways may play an important role in the response of liver to injury.