ABSTRACT
OBJECTIVE: The objective of this study was to evaluate whether an uncontrolled activation of mast cells and macrophages through protease-activated receptor-2 (PAR-2) during acute pancreatitis could develop lung injury. METHODS: Pancreatitis was induced in rats by intraductal infusion of sodium taurocholate. In a group of animals, PAR-2 antagonist or trypsin (TRP) inhibitor was intravenously administered before the pancreatitis induction. In additional groups, the animals were treated with PAR-2-activating peptide or pancreatic TRP. The myeloperoxidase (MPO) activity was measured to evaluate the progression of inflammation. RESULTS: Plasma from the animals with pancreatitis and pancreatic TRP induced the secretion of mast cells and alveolar macrophages as well as increased the density of PAR-2 in the plasma membrane. The treatment of alveolar macrophages with TRP, tryptase, as well as PAR-1- and PAR-2-activating peptide led to an increase in calcium-triggered exocytosis. Similar results were obtained in acinar cells. The intravenous injection of PAR-2-activating peptide and TRP induced an increase in MPO activity in the lung. The intravenous injection of PAR-2 antagonist or TRP inhibitor before the pancreatitis induction could prevent the increase in MPO activity in the pancreas and the lung. CONCLUSIONS: The TRP generated during acute pancreatitis could be involved in the progression of lung injury through the activation of PAR-2 in alveolar macrophages.
Subject(s)
Lung Diseases/metabolism , Lung/metabolism , Pancreatitis/metabolism , Receptor, PAR-2/metabolism , Acinar Cells/drug effects , Acinar Cells/metabolism , Acute Disease , Animals , Calcium/metabolism , Calcium/pharmacology , Cell Line , Cell Line, Tumor , Exocytosis/drug effects , Immunohistochemistry , Lung/drug effects , Lung/physiopathology , Lung Diseases/physiopathology , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/metabolism , Male , Mast Cells/drug effects , Mast Cells/metabolism , Microscopy, Confocal , Oligopeptides/pharmacology , Pancreatitis/chemically induced , Pancreatitis/physiopathology , Peroxidase/metabolism , Rats, Wistar , Receptor, PAR-2/physiology , Taurocholic Acid , Trypsin/metabolism , Trypsin/pharmacologyABSTRACT
La pancreatitis crónica (PC) es una enfermedad compleja, con un amplio espectro de manifestaciones clínicas, que abarca desde pacientes asintomáticos a pacientes con síntomas inhabilitantes o con complicaciones serias. El manejo de la PC frecuentemente difiere entre áreas geográficas e incluso entre centros. Ello se debe a la escasez de estudios de calidad y guías de práctica clínica que aborden el diagnóstico y tratamiento de esta enfermedad. El objetivo del Club Español Pancreático fue elaborar recomendaciones basadas en la evidencia para el manejo de la PC. Dos coordinadores eligieron un panel multidisciplinario de 24 expertos en esta enfermedad. Estos expertos se seleccionaron por su experiencia clínica e investigadora en PC. Se elaboró una lista de preguntas, cada una de las cuales se revisó por 2 panelistas. Con ello se produjo un borrador que se discutió en una reunión presencial por todos los participantes. Los niveles de evidencia se basaron en la clasificación del Oxford Centre for Evidence-Based Medicine. En la segunda parte del consenso se dieron recomendaciones para el manejo del dolor, seudoquistes, estenosis biliar y duodenal, fístula pancreática y ascitis, hipertensión portal izquierda, diabetes mellitus, insuficiencia pancreática exocrina y soporte nutricional en PC (AU)
Chronic pancreatitis (CP) is a complex disease with a wide spectrum of clinical manifestations ranging from asymptomatic disease to disabling forms or serious complications. The management of CP frequently differs among geographical areas and even among centers. These differences are due to the scarcity of high-quality studies and clinical practice guidelines that focus on the diagnosis and treatment of this disease. The aim of the Spanish Pancreatic Club was to create evidence-based recommendations for the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. These experts were selected on the basis of their clinical and research experience in CP. A list of questions was drawn up and each question was then reviewed by two panelists. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. Levels of evidence were based on the classification of the Oxford Centre for Evidence-Based Medicine. In the second part of the consensus process, recommendations were established for the management of pain, pseudocysts, biliary and duodenal stenosis, pancreatic fistula and ascites, left portal hypertension, diabetes mellitus, exocrine pancreatic insufficiency, and nutritional support in CP (AU)
Subject(s)
Humans , Pancreatitis, Chronic/diagnosis , Pancreatitis, Chronic/therapy , Practice Patterns, Physicians' , Consensus , Exocrine Pancreatic Insufficiency , Pancreatic Fistula , Hypertension, PortalABSTRACT
Chronic pancreatitis (CP) is a complex disease with a wide spectrum of clinical manifestations ranging from asymptomatic disease to disabling forms or serious complications. The management of CP frequently differs among geographical areas and even among centers. These differences are due to the scarcity of high-quality studies and clinical practice guidelines that focus on the diagnosis and treatment of this disease. The aim of the Spanish Pancreatic Club was to create evidence-based recommendations for the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. These experts were selected on the basis of their clinical and research experience in CP. A list of questions was drawn up and each question was then reviewed by two panelists. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. Levels of evidence were based on the classification of the Oxford Centre for Evidence-Based Medicine. In the second part of the consensus process, recommendations were established for the management of pain, pseudocysts, biliary and duodenal stenosis, pancreatic fistula and ascites, left portal hypertension, diabetes mellitus, exocrine pancreatic insufficiency, and nutritional support in CP.
Subject(s)
Pancreatitis, Chronic/therapy , Decision Trees , Humans , Nutritional SupportABSTRACT
La pancreatitis crónica (PC) es una enfermedad relativamente infrecuente, compleja y muy heterogénea. La ausencia de un patrón oro aplicable a las fases iniciales de la PC hace que su diagnóstico precoz sea difícil. Algunas de sus complicaciones, en particular el dolor crónico, pueden ser difíciles de manejar. Hay mucha variedad en el diagnóstico y tratamiento de la PC y de sus complicaciones entre los diferentes centros y profesionales. El Club Español Pancreático ha desarrollado un consenso sobre el manejo de la PC. Dos coordinadores eligieron un panel multidisciplinario de 24 expertos en esta enfermedad. Se elaboró una lista de preguntas. Cada pregunta fue revisada por 2 expertos. Con ello se elaboró un borrador compartido con todo el panel de expertos y discutido en una reunión presencial. En la primera parte del consenso se aborda el diagnóstico de la PC y de sus complicaciones (AU)
Chronic pancreatitis (CP) is a relatively uncommon, complex and highly heterogeneous disease. There is no clear pattern applicable to the initial stages of CP, which hampers its early diagnosis. Some of the complications of CP, especially chronic pain, can be difficult to manage. There is wide variation in the diagnosis and treatment of CP and its complications among centers and health professionals. The Spanish Pancreatic Club has developed a consensus document on the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. A list of questions was drawn up. Each question was reviewed by two experts. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. The first part of the consensus document focusses on the diagnosis of CP and its complications (AU)
Subject(s)
Humans , Pancreatitis, Chronic/diagnosis , Pancreatitis, Chronic/drug therapy , Exocrine Pancreatic Insufficiency/diagnosis , Exocrine Pancreatic Insufficiency/drug therapy , Practice Patterns, Physicians'ABSTRACT
Chronic pancreatitis (CP) is a relatively uncommon, complex and highly heterogeneous disease. There is no clear pattern applicable to the initial stages of CP, which hampers its early diagnosis. Some of the complications of CP, especially chronic pain, can be difficult to manage. There is wide variation in the diagnosis and treatment of CP and its complications among centers and health professionals. The Spanish Pancreatic Club has developed a consensus document on the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. A list of questions was drawn up. Each question was reviewed by two experts. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. The first part of the consensus document focusses on the diagnosis of CP and its complications.
Subject(s)
Pancreatitis, Chronic/diagnosis , HumansABSTRACT
Bacterial peritonitis is a severe complication in patients with cirrhosis and ascites and despite antibiotic treatment, the inflammatory response to infection may induce renal dysfunction leading to death. This investigation evaluated the effect of TNF-α blockade on the inflammatory response and mortality in cirrhotic rats with induced bacterial peritonitis treated or not with antibiotics. Sprague-Dawley rats with carbon-tetrachloride-induced cirrhosis were treated with an intraperitoneal injection of 10(9) CFU of Escherichia coli diluted in 20 mL of sterile water to induce bacterial peritonitis and randomized to receive subcutaneously-administered placebo, ceftriaxone, anti-TNF-α mAb and ceftriaxone, or anti-TNF-α mAb alone. No differences were observed between groups at baseline in respect to renal function, liver hepatic tests, serum levels of nitrite/nitrate and TNF-α. Treatment with ceftriaxone reduced mortality (73.3%) but differences did not reach statistical significance as compared to placebo. Mortality in rats treated with ceftriaxone and anti-TNF-α mAb was significantly lower than in animals receiving placebo (53% vs. 100%, p<0.01). Serum TNF-α decreased significantly in surviving rats treated with ceftriaxone plus anti-TNF-α mAb but not in treated with antibiotics alone. Additional studies including more animals are required to assess if the association of antibiotic therapy and TNF-α blockade might be a possible approach to reduce mortality in cirrhotic patients with bacterial peritonitis.
Subject(s)
Antibodies, Monoclonal/pharmacology , Ceftriaxone/pharmacology , Escherichia coli/drug effects , Liver Cirrhosis/complications , Peritonitis/drug therapy , Peritonitis/physiopathology , Animals , Carbon Tetrachloride/toxicity , Immunoassay , Liver Cirrhosis/chemically induced , Male , Peritonitis/etiology , Peritonitis/microbiology , Rats , Rats, Sprague-Dawley , Statistics, Nonparametric , Treatment Outcome , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/immunologySubject(s)
Fluid Therapy/methods , Isotonic Solutions/administration & dosage , Pancreatitis, Acute Necrotizing/complications , Pancreatitis, Acute Necrotizing/pathology , Pancreatitis, Acute Necrotizing/therapy , Sodium Chloride/administration & dosage , Systemic Inflammatory Response Syndrome/epidemiology , Systemic Inflammatory Response Syndrome/prevention & control , Female , Humans , MaleABSTRACT
La derivación portosistémica percutánea intrahepática (DPPI o TIPS en inglés) es actualmente un tratamiento cada día más utilizado en el manejo de las complicaciones de la hipertensión portal. Sin embargo, una de las complicaciones de esta técnica es la aparición de una encefalopatía hepática resistente o recurrente de difícil manejo médico. Presentamos un caso clínico de un paciente que tras la colocación de un TIPS para el control de una hemorragia por varices esofágicas presentó un cuadro de encefalopatía hepática resistente que requirió la reducción del calibre del TIPS para su control médico (AU)
Insertion of a transjugular intrahepatic portosystemic shunt (TIPS) is an increasingly used treatment in the management of the complications of portal hypertension. However, one of the complications of this technique is refractory or recurrent hepatic encephalopathy, which poses a difficult clinical problem. We report the case of a patient who underwent TIPS insertion to control bleeding due to esophageal varices. The patient subsequently developed refractory hepatic encephalopathy, requiring reduction of the caliber of the shunt (AU)
Subject(s)
Humans , Hepatic Encephalopathy/surgery , Portasystemic Shunt, Surgical , Endovascular Procedures/methods , Liver Cirrhosis/surgery , Hypertension, Portal/etiologyABSTRACT
BACKGROUND: Gut is the major source of endogenous bacteria causing infections in advanced cirrhosis. Intestinal barrier dysfunction has been described in cirrhosis and account for an increased bacterial translocation rate. HYPOTHESIS AND AIMS: We hypothesize that microbiota composition may be affected and change along with the induction of experimental cirrhosis, affecting the inflammatory response. ANIMALS AND METHODS: Progressive liver damage was induced in Balb/c mice by weight-controlled oral administration of carbon tetrachloride. Laparotomies were performed at weeks 6, 10, 13 and 16 in a subgroup of treated mice (nâ=â6/week) and control animals (nâ=â4/week). Liver tissue specimens, mesenteric lymph nodes, intestinal content and blood were collected at laparotomies. Fibrosis grade, pro-fibrogenic genes expression, gut bacterial composition, bacterial translocation, host's specific butyrate-receptor GPR-43 and serum cytokine levels were measured. RESULTS: Expression of pro-fibrogenic markers was significantly increased compared with control animals and correlated with the accumulated dose of carbon tetrachloride. Bacterial translocation episodes were less frequent in control mice than in treated animals. Gram-positive anaerobic Clostridia spp count was decreased in treated mice compared with control animals and with other gut common bacterial species, altering the aerobic/anaerobic ratio. This fact was associated with a decreased gene expression of GPR43 in neutrophils of treated mice and inversely correlated with TNF-alpha and IL-6 up-regulation in serum of treated mice along the study protocol. This pro-inflammatory scenario favoured blood bacterial translocation in treated animals, showing the highest bacterial translocation rate and aerobic/anaerobic ratio at the same weeks. CONCLUSIONS: Gut microbiota alterations are associated with the development of an inflammatory environment, fibrosis progression and bacterial translocation in carbon tetrachloride-treated mice.
Subject(s)
Bacteria/genetics , Bacterial Translocation , Gastrointestinal Tract/microbiology , Gastrointestinal Tract/pathology , Inflammation/pathology , Liver Cirrhosis/pathology , Metagenome/genetics , Animals , Bacteria/classification , Bacteria/metabolism , Biodiversity , Biomarkers/metabolism , Carbon Tetrachloride Poisoning , DNA, Bacterial/genetics , Feces/microbiology , Female , Gene Expression Profiling , Inflammation/complications , Laparotomy , Liver Cirrhosis/chemically induced , Liver Cirrhosis/complications , Liver Cirrhosis/surgery , Mice , Mice, Inbred BALB C , Real-Time Polymerase Chain ReactionABSTRACT
OBJECTIVES: Although aggressive fluid therapy during the first days of hospitalization is recommended by most guidelines and reviews on acute pancreatitis (AP), this recommendation is not supported by any direct evidence. We aimed to evaluate the association between the amount of fluid administered during the initial 24 h of hospitalization and the incidence of organ failure (OF), local complications, and mortality. METHODS: This was a prospective cohort study. We included consecutive adult patients admitted with AP. Local complications and OF were defined according to the Atlanta Classification. Persistent OF was defined as OF of >48-h duration. Patients were divided into three groups according to the amount of fluid administered during the initial 24 h: group A: <3.1 l (less than the first quartile), group B: 3.1-4.1 l (between the first and third quartiles), and group C: >4.1 l (more than the third quartile). RESULTS: A total of 247 patients were analyzed. Administration of >4.1 l during the initial 24 h was significantly and independently associated with persistent OF, acute collections, respiratory insufficiency, and renal insufficiency. Administration of <3.1 l during the initial 24 h was not associated with OF, local complications, or mortality. Patients who received between 3.1 and 4.1 l during the initial 24 h had an excellent outcome. CONCLUSIONS: In our study, administration of a small amount of fluid during the initial 24 h was not associated with a poor outcome. The need for a great amount of fluid during the initial 24 h was associated with a poor outcome; therefore, this group of patients must be carefully monitored.
Subject(s)
Fluid Therapy , Pancreatitis, Acute Necrotizing/therapy , Adult , Aged , Aged, 80 and over , Cohort Studies , Evidence-Based Medicine , Female , Fluid Therapy/adverse effects , Humans , Male , Middle Aged , Pancreatitis, Acute Necrotizing/etiology , Predictive Value of Tests , Prognosis , Prospective Studies , Severity of Illness Index , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Blood translocation of bacterial-DNA has been described in patients with Crohn's disease (CD). The host's immune cell types cooperate to respond against bacterial insults. Some antimicrobial peptides are inducible after culture with bacterial products and a linkage has been established between them and NOD2/CARD15. The aim was to test whether defensins and cathelicidin (LL-37) expression and NOD2/CARD15 mutations in blood neutrophils are related to molecular bacterial translocation events in CD patients. METHODS: Fifty consecutively admitted CD patients and 15 healthy controls were included. Clinical and analytical characteristics of patients were considered. NOD2/CARD15 genotyping, presence of bacterial-DNA, defensin and cathelicidin gene, and protein levels in neutrophils and serum cytokine levels were studied. RESULTS: Twenty patients (40%) presented bacterial-DNA in blood. Eleven were active and 9 were in remission. Bacterial-DNA was not present in controls. NOD2/CARD15 mutations were identified in 25 patients (50%), 15 of which were in remission. Sixty percent of bacterial-DNA(+) and 43% of bacterial-DNA(-) patients showed a NOD2/CARD15 mutation. ß-Defensin 2 and LL-37 mRNA and protein levels were upregulated in bacterial-DNA(+) patients. ß-Defensin 2 and LL-37 expression correlated with bacterial-DNA concentration only in patients with a wildtype NOD2/CARD15 genotype. Cultured neutrophils of bacterial-DNA(-) patients confirmed the muramyl dipeptide-independent association between DEFB2 and LL-37 with bacterial-DNA concentration in wildtype NOD2/CARD15 patients. Cytokine levels were increased in bacterial-DNA(+) patients and correlated with bacterial-DNA concentration. NOD2/CARD15 genotype did not influence this correlation. CONCLUSIONS: ß-Defensin 2, LL-37, and proinflammatory cytokines are increased in CD patients with bacterial-DNA in a concentration-dependent manner. NOD2/CARD15 plays a key role in the regulation of this response.
Subject(s)
Crohn Disease/genetics , Crohn Disease/immunology , DNA, Bacterial/immunology , Nod2 Signaling Adaptor Protein/genetics , RNA, Messenger/blood , Adult , Antimicrobial Cationic Peptides/genetics , Antimicrobial Cationic Peptides/metabolism , Cells, Cultured , Crohn Disease/blood , Cytokines/blood , DNA, Bacterial/blood , Female , Genotype , Humans , Interferon-gamma/blood , Interleukins/blood , Male , Middle Aged , Neutrophils/immunology , Neutrophils/metabolism , Polymorphism, Single Nucleotide , Severity of Illness Index , Tumor Necrosis Factor-alpha/blood , Young Adult , beta-Defensins/blood , beta-Defensins/genetics , CathelicidinsABSTRACT
Insertion of a transjugular intrahepatic portosystemic shunt (TIPS) is an increasingly used treatment in the management of the complications of portal hypertension. However, one of the complications of this technique is refractory or recurrent hepatic encephalopathy, which poses a difficult clinical problem. We report the case of a patient who underwent TIPS insertion to control bleeding due to esophageal varices. The patient subsequently developed refractory hepatic encephalopathy, requiring reduction of the caliber of the shunt.
Subject(s)
Endovascular Procedures/methods , Hepatic Encephalopathy/surgery , Portasystemic Shunt, Transjugular Intrahepatic/methods , Postoperative Complications/surgery , Ascites/drug therapy , Ascites/etiology , Endovascular Procedures/instrumentation , Equipment Design , Esophageal and Gastric Varices/etiology , Esophageal and Gastric Varices/surgery , Furosemide/therapeutic use , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/surgery , Hepatic Encephalopathy/etiology , Humans , Hypertension, Portal/complications , Hypertension, Portal/surgery , Jugular Veins , Liver Circulation , Liver Cirrhosis, Alcoholic/complications , Male , Middle Aged , Polytetrafluoroethylene , Portasystemic Shunt, Transjugular Intrahepatic/adverse effects , Portasystemic Shunt, Transjugular Intrahepatic/instrumentation , Postoperative Complications/etiology , Propranolol/therapeutic use , Reoperation , Spironolactone/therapeutic use , StentsABSTRACT
UNLABELLED: Patients with cirrhosis receiving norfloxacin show a restored inflammatory balance that likely prevents clinical complications derived from an excessive proinflammatory response to bacterial product challenges. This study sought to investigate associated inflammatory control mechanisms established in patients with cirrhosis receiving norfloxacin. A total of 62 patients with cirrhosis and ascites in different clinical conditions were considered. Blood samples were collected and intracellular and serum norfloxacin were measured. Inflammatory mediators were evaluated at messenger RNA and protein levels. Neutrophils from all patients were cultured with lipopolysaccharide (LPS) and anti-interleukin-10 (anti-IL-10) monoclonal antibody in different conditions. IL-10 and heme oxygenase-1 (HO-1) were up-regulated in patients receiving norfloxacin and correlated with norfloxacin in a concentration-dependent manner, whereas proinflammatory inducible nitric oxide synthase, cyclooxygenase-2, and nuclear factor-κB behaved inversely. Higher IL-10 levels correlated with lower white blood cell count and higher mean arterial pressure. No correlations were found between IL-10 and disease clinical scores or liver function markers in blood. Neutrophilic in vitro assays showed that the effect of LPS on proinflammatory mediator levels in the presence of norfloxacin was abrogated by significantly increasing IL-10 and HO-1 expression. After stimulation with LPS plus anti-IL-10, proinflammatory mediators were dramatically increased in patients receiving norfloxacin, and increasing intracellular norfloxacin concentrations did not decrease the expression levels of these proinflammatory molecules. Unblocking IL-10 restored proinflammatory mediator and HO-1 expression to previously observed levels in response to LPS stimulation. CONCLUSION: Although the described association does not necessarily mean causality, an IL-10-mediated HO-1-induced anti-inflammatory mechanism is present in patients with cirrhosis receiving norfloxacin, that is directly associated with cell-modulating events in these patients.
Subject(s)
Heme Oxygenase-1/physiology , Interleukin-10/physiology , Liver Cirrhosis/drug therapy , Norfloxacin/therapeutic use , Aged , Antibodies, Monoclonal/pharmacology , Cells, Cultured , Cyclooxygenase 2/metabolism , DNA, Bacterial/blood , Down-Regulation , Female , Heme Oxygenase-1/blood , Humans , Inflammation Mediators/metabolism , Interleukin-10/blood , Interleukin-10/immunology , Leukocyte Count , Lipopolysaccharides/pharmacology , Liver Cirrhosis/complications , Male , Middle Aged , NF-kappa B/metabolism , Nitric Oxide Synthase Type II , Norfloxacin/blood , Peritonitis/prevention & control , Prospective Studies , Up-RegulationABSTRACT
BACKGROUND: Bacterial infections are common complications arising in patients with cirrhosis and ascites. Translocation of bacterial DNA is a dynamic process that is associated with an increased inflammatory response and a poor prognosis in this setting. The aim of this study was to study whether peritoneal macrophages remain in a chronic primed status to allow a rapid response to subsequent events of bacterial translocation. PATIENTS AND METHODS: Peritoneal monocyte-derived macrophages were isolated from 25 patients with cirrhosis and non-infected ascites and compared with donor's blood monocytes. Activation cell-surface markers were screened using flow-cytometry, and the phosphorylation state of ERK 1/2, p38 MAP Kinase, PKB/Akt and transcription factors c-Jun and p65 NFκB were evaluated using Western blot. Synthesis of tumour necrosis factor alpha, interleukin 6 (IL-6) and interleukin-10 (IL-10) at baseline and in response to bacterial stimuli was evaluated using ELISA. RESULTS: A high expression of CD54, CD86 and HLA-DR at baseline was displayed by peritoneal macrophages. Increased phosphorylated levels of ERK1/2, protein kinase B (PKB) and c-Jun, together with IL-6 production, were observed in peritoneal macrophages at baseline compared with donors' blood monocytes. A positive correlation was established between basal IL-6 levels and extracellular signal-regulated kinase (ERK) phosphorylation in peritoneal macrophages from patients with cirrhosis (r=0·9; P=0·005). Addition of lipopolysaccharide induced higher phosphorylation levels of all studied signalling intermediates than synthetic-oligodeoxydinucleotides, but similar end-stage p65 NFκB. CONCLUSIONS: A sustained immune response is present in ascitic fluid of cirrhotic patients, even in the temporal absence of bacterial antigens. This would facilitate a fast response, probably controlled by IL-6, against repeated bacterial-DNA translocation or in liver chronic inflammation.
Subject(s)
Ascitic Fluid/immunology , Bacterial Translocation/immunology , Liver Cirrhosis/immunology , Macrophages, Peritoneal/immunology , Mitogen-Activated Protein Kinases/immunology , Adult , Aged , Cytokines/immunology , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Interleukin-6/metabolism , Male , Middle Aged , Monocytes/immunology , Phosphorylation , Prospective StudiesABSTRACT
UNLABELLED: Presence of bacterial DNA in noninfected patients with cirrhosis and ascites is associated with a marked inflammatory response including activation of the inducible form of nitric oxide synthase and release of nitric oxide, similar to that observed in patients with spontaneous bacterial peritonitis. Although presence of bacterial DNA is associated with an impaired prognosis, no information is available regarding its hemodynamic consequences. Systemic and hepatic hemodynamics before and after a liquid test meal were assessed in a series of 75 noninfected patients with cirrhosis (55 with ascites). Bacterial DNA was measured by polymerase chain reaction. Bacterial DNA was detected only in patients with ascites. Clinical data and liver function were similar in ascitic patients with presence (n = 21) or absence of bacterial DNA (n = 34). Bacterial-DNA(+) patients had significantly lower mean arterial pressure (P = 0.002) and systemic vascular resistance (P = 0.03) than bacterial-DNA(-) patients. Cardiac output, cardiopulmonary pressures, hepatic venous pressure gradient (HVPG), and hepatic blood flow were similar in both groups. Thirty minutes after the test meal, in response to increased blood flow caused by postprandial hyperemia, there was a significantly greater increase in HVPG and impaired hepatic vasorelaxation in bacterial-DNA(+) as compared with bacterial-DNA(-) patients, which indicates hepatic endothelial dysfunction. Indeed, the increase in HVPG after the test meal significantly correlated with serum bacterial DNA concentration. CONCLUSION: Presence of bacterial DNA, a marker of bacterial translocation, is associated with aggravation of peripheral vasodilation and with worsening of intrahepatic endothelial dysfunction.
Subject(s)
Bacterial Infections/physiopathology , Bacterial Translocation , DNA, Bacterial/metabolism , Hemodynamics , Liver Circulation/physiology , Liver Cirrhosis/physiopathology , Liver/physiopathology , Adult , Aged , Ascites/physiopathology , Female , Humans , Male , Middle Aged , Postprandial Period , Vascular ResistanceABSTRACT
AIM: To study the activation of pancreatic and pulmonary mast cells and the effect of mast cell inhibition on the activation of peritoneal and alveolar macrophages during acute pancreatitis. METHODS: Pancreatitis was induced by intraductal infusion of 5% sodium taurodeoxycholate in rats. The mast cell inhibitor cromolyn was administered intraperitoneally (i.p.) 30 min before pancreatitis induction. The pancreatic and pulmonary tissue damage was evaluated histologically and mast cells and their state of activation were evaluated. Peritoneal and alveolar macrophages were obtained and the expression of tumor necrosis factor alpha was determined. Myeloperoxidase activity was measured to evaluate the effect of mast cell inhibition on the progression of the inflammatory process. Finally, the effect of plasma on cultured mast cells or macrophages was evaluated in vitro. RESULTS: The mast cell stabilizer significantly reduced inflammation in the pancreas and lung and the activation of alveolar macrophages but had no effect on peritoneal macrophages. Mast cell degranulation was observed in the pancreas during pancreatitis but no changes were observed in the lung. Plasma from rats with pancreatitis could activate alveolar macrophages but did not induce degranulation of mast cells in vitro. CONCLUSION: Pancreatic mast cells play an important role in triggering the local and systemic inflammatory response in the early stages of acute pancreatitis. In contrast, lung mast cells are not directly involved in the inflammatory response related to pancreatic damage.
Subject(s)
Lung/cytology , Mast Cells/physiology , Pancreas/cytology , Pancreatitis/immunology , Animals , Anti-Asthmatic Agents/pharmacology , Cell Degranulation/drug effects , Cells, Cultured , Cholagogues and Choleretics/adverse effects , Cromolyn Sodium/pharmacology , Disease Models, Animal , Lung/immunology , Macrophages, Alveolar/cytology , Macrophages, Alveolar/immunology , Macrophages, Peritoneal/cytology , Macrophages, Peritoneal/immunology , Male , Mast Cells/cytology , Mast Cells/drug effects , Pancreas/immunology , Pancreatitis/chemically induced , Rats , Rats, Wistar , Taurodeoxycholic Acid/adverse effects , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
UNLABELLED: The aim of our study was to investigate the dynamics of brain water content assessed by magnetic resonance imaging (MRI) applications in patients with cirrhosis and overt episodic hepatic encephalopathy (HE). METHODS: Twenty-four patients with cirrhosis and overt HE, 9 healthy controls and 9 controls with cirrhosis but without HE were included. All patients underwent laboratory analysis, MRI and (1)H MRS in the first 24h after the diagnosis of encephalopathy. Five of them were studied again 5days after the resolution of HE. RESULTS: The values of glutamine/glutamate (Glx) increased progressively (healthy controls: 1.8; cirrhotic controls: 2.4; HE: 4.4; p=0.0001). Values of myo-inositol were lower among cirrhotics than in healthy controls (healthy: 0.6; cirrhotic: 0.3; HE: 0.4; p=0.01). Patients with overt HE showed a decrease in MTR in several brain locations. A significant correlation was observed between MTR values and Glx/creatine ratios (r=-0.54; P=0.004). Five days after the resolution of HE, there were no changes in brain Glx/Cr or MTR but a significant decrease of median ADC in parietal grey matter was observed (acute HE: 121.9 vs. 5days later: 100.5; p<0.05). CONCLUSIONS: Cirrhotic patients with overt HE have a disturbance in the brain osmolyte homeostasis, reflecting a low-grade brain edema. Shortly after the clinical resolution of the episode of HE low-grade brain edema still persists, but there is a decrease in the ADC value in the parietal grey matter, suggesting water flux from extracellular to intracellular compartments and the existence of a vasogenic brain edema.
Subject(s)
Brain Edema/metabolism , Brain/metabolism , Hepatic Encephalopathy/metabolism , Body Water/metabolism , Brain/pathology , Brain Edema/complications , Brain Edema/pathology , Case-Control Studies , Diffusion Tensor Imaging , Female , Fibrosis/complications , Fibrosis/metabolism , Fibrosis/pathology , Hepatic Encephalopathy/complications , Hepatic Encephalopathy/pathology , Humans , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy/methods , Male , Middle Aged , Nerve Fibers, Unmyelinated/metabolism , Parietal Lobe/metabolism , Parietal Lobe/pathology , Prospective Studies , Protons , Time FactorsABSTRACT
BACKGROUND AND AIM: Prophylactic treatment of variceal bleeding in cirrhotic patients with beta-blockers is effective in only some patients. Our aim was to determine whether the response of the hepatic venous pressure gradient (HVPG) to the intravenous administration of propranolol predicts the response after chronic oral propranolol treatment. PATIENTS AND METHODS: We included prospectively cirrhotic patients with esophageal varices under primary prophylaxis (PP) and secondary prophylaxis (SP). The HVPG was measured at baseline and after a propranolol bolus (0.15 mg/kg intravenous). A patient was considered a good-responder if HVPG decreased to 12 mmHg or 20% from baseline. Patients then received oral propranolol (heart rate titrated). Poor-responders under SP were also included in a variceal band ligation program. After at least 3 months, a second hemodynamic study was conducted. RESULTS: Fifty-six patients were included (36 SP and 20 PP). Response rate was similar (32.1 and 41.9%, P=0.7) and the Pearson's correlation coefficient was 0.61 (P=0.001). In 81.4% patients, the first study predicted the response status of the second. Six patients rebled on follow-up between the studies, all of them were poor responders to intravenous propranolol. CONCLUSION: A single hemodynamic study using intravenous propranolol seems to predict chronic response to propranolol.
Subject(s)
Adrenergic beta-Antagonists/administration & dosage , Esophageal and Gastric Varices/drug therapy , Esophageal and Gastric Varices/etiology , Liver Cirrhosis/complications , Propranolol/administration & dosage , Administration, Oral , Esophageal and Gastric Varices/prevention & control , Female , Follow-Up Studies , Heart Rate/drug effects , Humans , Injections, Intravenous , Male , Middle Aged , Pilot Projects , Predictive Value of Tests , Prospective Studies , Treatment Outcome , Venous Pressure/drug effectsABSTRACT
Bacterial translocation in patients with cirrhosis induces a marked proinflammatory activity that may be different against viable bacteria or bacterial products. The aim of this study is to identify new markers of bacterial translocation by investigating bacterial-driven peptides and correlate their presence with the inflammatory response. Patients with cirrhosis and ascites were included. An analysis by two-dimensional polyacrylamide gel electrophoresis of ascitic fluid total protein from patients (n = 47) and from frequently detected bacterial strains was performed. Two-dimensional maps were digitally compared. The identification of possible markers was performed by mass spectrometry. TNF-alpha, IFN-gamma, IL-12, nitric oxide, and proteins of the complement and lipopolysaccharide-binding protein levels were measured in ascitic fluid samples of patients by enzyme-linked immunosorbent assay. Patients were distributed according to the presence (group I, n = 16) and absence (group II, n = 31) of serum and ascitic fluid bacterial DNA. Among clinical and analytical differences between groups, only mean arterial pressure was significantly higher in patients from group II. Identified bacterial peptides were associated with bacterial protection against immune defenses and included glyceraldehyde-3-phosphate dehydrogenase A, Porin OmpC, and HSP60. Eight patients from group I also showed bacterial peptides, whereas none from group II did. All studied mediators of immune activation were significantly higher in patients with bacterial DNA than in patients without bacterial DNA. TNF-alpha, IFN-gamma, and proteins of the complement were significantly increased in patients with bacterial peptides versus those without bacterial peptides. Bacterial peptide translocation is present in the ascitic fluid of a subgroup of patients with advanced cirrhosis and is associated with an increased immune response.
Subject(s)
Ascites/microbiology , Bacterial Proteins/analysis , Bacterial Translocation , Liver Cirrhosis/complications , Liver Cirrhosis/microbiology , Peritonitis/diagnosis , Proteomics/methods , Adult , Aged , Amino Acid Sequence , Ascites/immunology , Ascitic Fluid/immunology , Ascitic Fluid/microbiology , Bacterial Proteins/isolation & purification , Cytokines/immunology , Escherichia coli/physiology , Female , Humans , Klebsiella pneumoniae/physiology , Liver Cirrhosis/immunology , Male , Middle Aged , Molecular Sequence Data , Peptides/analysis , Peptides/isolation & purification , Peritonitis/etiology , Peritonitis/microbiologyABSTRACT
BACKGROUND/AIMS: The long-term evolution of cirrhotic patients with extrapyramidal signs has not yet been studied. We have investigated the influence of extrapyramidal signs on the prognosis, evolution, and quality of life of patients with liver cirrhosis. METHODS: Forty-six patients with cirrhosis were followed up and 18 of them were reevaluated, a mean of 45 months later. Cognitive impairment was measured with psychometric tests (Trail-Making Test part A, Grooved-Pegboard, Block-Design, Oral Symbol Digit and Stroop Test). Extrapyramidal signs were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS). Health-related quality of life was measured using the SF-36 scale and the Chronic Liver Disease Questionnaire. RESULTS: Eleven of the 46 patients who were followed up developed overt hepatic encephalopathy (HE) during the follow-up. The presence of extrapyramidal signs was the unique factor that predicted overt HE and patients with basal higher score in the part 3 of the UPDRS developed overt HE more frequently [hazard ratio=1.29; 95% confidence interval (1.04-1.60) P=0.023]. In the 18 reevaluated patients, there was an increase in the score of the UPDRS part 3 after follow-up. There was a worsening in the score values of the block design and the Number Connection Test. In health-related quality of life scales, patients scored better in the area of mental health of the SF-36 scale. Patients with extrapyramidal signs persisted with worse scores in several items of the SF-36 scale and the Chronic Liver Disease Questionnaire. CONCLUSION: The presence of extrapyramidal signs in patients with liver cirrhosis predicts the development of overt HE. These signs increased along the follow-up, and remain a bad influence on quality of life.
