RESUMO
A 73-year-old man was presented with epigastric pain and indicated high CA19-9 levels, and computed tomography detected a tumor in the uncinate process of the pancreas infiltrated duodenum and superior mesenteric artery. The patient was diagnosed with borderline resectable pancreatic carcinoma and received neoadjuvant chemotherapy with gemcitabine and S-1. During neoadjuvant chemotherapy, the patient also received radiotherapy to control duodenal bleeding. After neoadjuvant chemotherapy, stable disease(SD)was proven on the Response Evaluation Criteria in Solid Tumors(RECIST), and subtotal stomach-preserving pancreaticoduodenectomy was performed. The pathological findings showed pancreatic adenosquamous carcinoma. After 7 days postoperatively, hepatic metastasis was detected, and after 78 days postoperatively, the patient died.
Assuntos
Carcinoma Adenoescamoso , Neoplasias Pancreáticas , Masculino , Humanos , Idoso , Carcinoma Adenoescamoso/tratamento farmacológico , Carcinoma Adenoescamoso/cirurgia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Gencitabina , Pâncreas/patologia , Pancreaticoduodenectomia , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias PancreáticasRESUMO
Common bile duct (CBD) stone is a relatively common but potentially life-threatening disease. Endoscopic sphincterotomy (EST) has been performed as standard therapy for CBD stones, but the rate of recurrence of CBD stones is high. Risk factors have been poorly defined, and no effective means for the prevention of the recurrence of CBD stones have been established so far. We aimed to identify significant risk factors for the recurrence of bile duct stones. This study included 477 patients (231 women; mean age, 80.5 years) who underwent EST and cleared CBD stones on cholangiography. A retrospective analysis was performed for the consecutively collected data. During the follow-up period of 6-75 months, the recurrence of CBD stones was observed in 99 patients (20.8%). The median time to the recurrence was 19.0 months (range 4-72 months). Multivariate analysis identified the need for mechanical lithotripsy, which was used for stone fragmentation, as a risk factor. Mechanical lithotripsy caused cholangiography-negative small residua. Notably, saline solution irrigation of the bile duct reduced the recurrence of CBD stones. These results demonstrate that subsequent biliary irrigation after stone removal may prevent the recurrence of CBD stones by clearing small residual fragments.
Assuntos
Ducto Colédoco/patologia , Cálculos Biliares/prevenção & controle , Cálculos Biliares/cirurgia , Solução Salina/uso terapêutico , Irrigação Terapêutica , Idoso de 80 Anos ou mais , Ducto Colédoco/diagnóstico por imagem , Feminino , Cálculos Biliares/diagnóstico por imagem , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Análise Multivariada , Recidiva , Esfinterotomia Endoscópica , UltrassonografiaRESUMO
An 88-year-old woman was referred to our hospital for autoimmune hepatitis in 2016. She was treated with prednisolone. In 2018, she was rehospitalized owing to hepatitis relapse. Steroid pulse therapy was performed. She exhibited good recovery of hepatitis, but was transferred to a convalescent ward in a general hospital because of decreased activity of daily life. After a month later, she had high fever and cough. She was diagnosed as having tuberculosis because of positive Mycobacterium tuberculosis polymerase chain reaction. At our first medical examination in 2016, we performed enzyme-linked immunospot and the result was undeterminable. There is an increase in the opportunities to use immunosuppressant and biologic agents for elderly patients. Our case report should contribute to future medical care for elderly patients who are at risk of latent tuberculosis infection.
Assuntos
Hepatite Autoimune , Mycobacterium tuberculosis , Tuberculose , Idoso , Idoso de 80 Anos ou mais , ELISPOT , Feminino , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/tratamento farmacológico , Humanos , PrednisolonaRESUMO
OBJECTIVES: A nationwide survey was conducted to clarify the epidemiological features of patients with chronic pancreatitis (CP) in Japan. METHODS: Two sequential surveys were conducted. In the first survey, both the prevalence and incidence of CP in Japan in 2007 were estimated by a questionnaire, which was mailed to 3027 randomly chosen Japanese facilities. In the second survey, the second questionnaire was then mailed to 1110 facilities selected by the first survey to clarify the clinicoepidemiological features of the patients. RESULTS: The estimated annual prevalence of CP was 36.9 per 100,000; 53.2 in males and 21.2 in females. The estimated annual incidence was 11.9 per 100,000. The prevalence and the incidence of CP gradually increased in Japan as compared to former surveys. The sex ratio (male/female) of definitive and probable CP patients was 4.5, with a mean age of 59.4 years; 59.2 years in males and 60.2 years in females. Alcoholic (69.7%) was most the common and idiopathic (21.0%) was the second most common cause of CP. The proportion of alcoholic CP increased as compared to the 55.5% found in 1994. The clinical features of overall Japanese patients with CP were: abdominal pain (60.6%), malabsorbtion (12.2%), diabetes mellitus (39.7%) and pancreatolithiasis (75.7%). Alcoholic patients were characterized by high morbidity as compared to nonalcoholic patients: abdominal pain (alcoholic 65.0% vs nonalcoholic 53.0%, p < 0.0001), diabetes mellitus (44.8% vs 31.4%, p < 0.0001) and pancreatolithiasis (84.0% vs 60.8%, p < 0.0001). CONCLUSION: The prevalence and the incidence of CP, especially alcoholic CP, have been increasing in Japan.
Assuntos
Pancreatite Crônica/epidemiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Feminino , Inquéritos Epidemiológicos , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Pancreatite Crônica/etiologia , Vigilância da População , Prevalência , Razão de Masculinidade , Inquéritos e QuestionáriosRESUMO
BACKGROUND AND AIM: Previous studies have shown an association of variants in trypsin-associated genes, such as cationic trypsinogen (PRSS1) and serine protease inhibitor, Kazal type-1 (SPINK1) with pancreatitis. However, whether these genetic variants are associated with acute pancreatitis (AP) remains largely unknown, especially when the first attack is separated from recurrent attacks. METHODS: A total of 261 patients with AP (174 with a sentinel attack, and 87 with recurrent attacks) and healthy controls were genotyped for the p.R122H mutation in the PRSS1 gene, p.N34S and IVS3 + 2T > C variants in the SPINK1 gene, the p.G191R variant in the anionic trypsinogen gene, the p.E32del variant in the mesotrypsinogen (PRSS3) gene, and the -2518G > A variant in the monocyte chemoattractant protein-1 gene by polymerase chain reaction-restriction enzyme digestion and direct sequencing. RESULTS: Patients with recurrent attacks were younger. The proportions of biliary pancreatitis and severe cases were lower, and that of idiopathic pancreatitis was higher in patients with a sentinel attack than in those with recurrent attacks. The frequencies of the genetic variants examined did not differ between controls and patients with sentinel pancreatitis. The frequencies of the PRSS1 p.R122H mutation, SPINK1 p.N34S variant, and PRSS3 p.E32del variant, but not other genetic variants, were higher in patients with recurrent attacks than in controls or those with a sentinel attack. CONCLUSIONS: The PRSS1 p.R122H mutation, SPINK1 p.N34S, and PRSS3 p.E32del variants were associated with recurrent, but not sentinel AP. The genetic background could possibly be different between sentinel and recurrent AP.
Assuntos
Proteínas de Transporte/genética , Mutação , Pancreatite/genética , Tripsina/genética , Doença Aguda , Adulto , Idoso , Estudos de Casos e Controles , Quimiocina CCL2/genética , Distribuição de Qui-Quadrado , Análise Mutacional de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Razão de Chances , Pancreatite/enzimologia , Fenótipo , Recidiva , Medição de Risco , Fatores de Risco , Inibidor da Tripsina Pancreática de Kazal , Tripsinogênio/genética , Adulto JovemRESUMO
Situs inversus totalis (SIT) is a rare congenital anomaly in which all viscera are transposed to the opposite side of the body. This uncommon anatomy causes technical difficulties in endoscopic treatment. A 98-year-old woman with SIT was admitted to our hospital complaining of upper abdominal pain and fever. Blood examinations and findings of abdominal computed tomography imaging confirmed the diagnosis of acute pancreatitis and cholangitis associated with biliary stones. After recovering from pancreatitis and cholangitis with conservative treatment, she underwent therapeutic endoscopic retrograde cholangiopancreatography (ERCP) to remove the common bile duct (CBD) stones. The patient and the endoscopist were positioned in the usual ERCP position, and the scope was inserted into the duodenum with an approach in the direction opposite to the routine practice. Biliary cannulation was performed in the direction of 1 o'clock, and the cholangiography showed remarkably dilated CBD filled with numerous stones. Endoscopic papillary large balloon dilation was performed, and the CBD stones were successfully removed. There were no complications, such as bleeding, pancreatitis, or perforation. Over 3 years of follow-up, she had no recurrence of cholangitis or pancreatitis.
Assuntos
Cálculos Biliares , Pancreatite , Situs Inversus , Doença Aguda , Idoso de 80 Anos ou mais , Cateterismo , Colangiopancreatografia Retrógrada Endoscópica , Dilatação , Feminino , Cálculos Biliares/complicações , Cálculos Biliares/diagnóstico por imagem , Cálculos Biliares/cirurgia , Humanos , Situs Inversus/complicações , Situs Inversus/diagnóstico por imagem , Resultado do TratamentoRESUMO
Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic inflammation and fibrosis. In the pancreas, in addition to oxidative metabolism, ethanol can be metabolized by esterification with fatty acids to form fatty acid ethyl esters such as palmitic acid ethyl ester (PAEE). We here examined the effects of ethanol (at 20 or 50 mM), acetaldehyde (at 200 microM), or PAEE (at 100 microM), on PSCs functions. PSCs did not express mRNAs for pancreatic triglyceride lipase and carboxyl ester lipase. Ethanol and acetaldehyde, but not PAEE, induced production of procollagen type I C-peptide. Ethanol, but not acetaldehyde or PAEE, induced interleukin-8 production. PAEE activated activator protein-1, but not nuclear factor kappaB. In addition, PAEE activated extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. Specific activation of signal transduction pathways and cell functions by ethanol and its metabolites may play a role in alcohol-induced pancreatic injury.
Assuntos
Etanol/farmacologia , Pâncreas/efeitos dos fármacos , Acetaldeído/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colágeno/metabolismo , Humanos , Interleucina-8/metabolismo , Lipase/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Palmitatos/farmacologia , Pâncreas/citologia , Pâncreas/metabolismo , Fragmentos de Peptídeos/metabolismo , Pró-Colágeno/metabolismo , Fator de Transcrição AP-1/metabolismoRESUMO
We previously reported that bone morphogenetic protein (BMP)-4 induces epithelial-mesenchymal transition in a pancreatic cancer cell line. To further investigate the detailed molecular mechanism of BMP action in pancreatic cancer, we carried out comprehensive microarray analysis in Panc-1 cells. The microarray analysis elucidated novel BMP target genes, and among them, the calcium-binding protein S100P was identified as an upregulated gene. S100P induction by BMP4 was confirmed by real-time reverse transcription-polymerase chain reaction and western blot analysis in Panc-1 and HPDE cells. Short interfering RNA-based knockdown of S100P expression sufficiently repressed BMP4-induced cell migration in Panc-1 cells. Because Panc-1 and HPDE cells express wild-type Smad4, we hypothesized that Smad4 might be indispensable for S100P induction by BMP4. S100P induction by BMP4 was not observed in the Smad4-null cell line BxPC3, and was sufficiently attenuated in short interfering RNA-based Smad4-knockdown Panc-1 cells. Interestingly, detailed promoter analysis revealed that upregulation of S100P by BMP4 was independent of the Smad-binding element, indicating that an additional unknown downstream factor of the Smad4-dependent pathway is necessary for this induction. These findings are the first of their kind, and this Smad4-dependent regulation of S100P by BMP signaling might explain the migratory mechanism of cancer cells, which is still unknown.
Assuntos
Proteína Morfogenética Óssea 4/farmacologia , Proteínas de Ligação ao Cálcio/genética , Carcinoma Ductal Pancreático/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/metabolismo , Linhagem Celular Tumoral , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Pancreáticas/patologia , Proteína Smad4/fisiologiaRESUMO
Periostin is a secretory protein that has been suggested to function as a cell adhesion molecule and promote the invasiveness or growth rate of tumors. However, little is known about the association of its expression and epithelial to mesenchymal transition (EMT), which is considered to play a crucial role in cancer cell metastasis. Thus, the authors investigated whether periostin could be involved in the process of EMT and the role of this gene in pancreatic cancer development. The expression of periostin was observed mainly in stromal cells but very little in cancer cells by immunohistochemistry and real-time RT-PCR. In vitro, pancreatic stellate cells (PSCs) exhibited a much higher basal expression of periostin compared with cancer cells. Periostin secreted in the supernatant from 293T cells that expressed periostin (approximately 150 ng/ml) inhibited the migration of pancreatic cancer cells. Coculture assay revealed that periostin expression in PSC was induced by pancreatic cancer cells. To assess the direct role of periostin in pancreatic cancer cells, the authors generated pancreatic cancer cell lines that stably express periostin. The induced expression of periostin (to 150 ng/ml) altered the morphology of cancer cells, changing them from mesenchymal to epithelial phenotypes with the induction of epithelial markers and a reduction of mesenchymal markers, and showed reduced cell migration in vitro and formed smaller tumors as well as suppressed metastasis in vivo. On the other hand, high concentration of recombinant periostin (1 microg/ml) promoted cell migration with AKT activation. The findings suggest that periostin has biphasic effect on the development of pancreatic cancer.
Assuntos
Adenocarcinoma/patologia , Moléculas de Adesão Celular/fisiologia , Movimento Celular/fisiologia , Epitélio/patologia , Mesoderma/fisiologia , Neoplasias Pancreáticas/patologia , Animais , Sequência de Bases , Linhagem Celular Tumoral , Técnicas de Cocultura , Primers do DNA , Humanos , Camundongos , Ratos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Toll-like receptors (TLRs) are proteins involved in recognition of foreign pathogen-associated molecular patterns (PAMPs) and activation of innate immunity. This study aimed to clarify whether pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, expressed TLRs and responded to PAMPs. METHODS: PSCs were isolated from rat pancreas tissue, and expression of TLRs was examined. PSCs were treated with lipoteichoic acid (a ligand for TLR2), polyinosinic-polycytidylic acid (a ligand for TLR3), lipopolysaccharide (a ligand for TLR4), or flagellin (a ligand for TLR5). The effects of the TLR ligands on key cell functions and activation of signaling pathways were examined. The ability of PSCs to perform endocytosis and phagocytosis was also examined. RESULTS: PSCs expressed TLR2, 3, 4, and 5, as well as the associated molecules CD14 and MD2. All of the TLR ligands activated nuclear factor-kappaB, and three classes of mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase). TLR ligands induced expression of monocyte chemoattractant protein 1, cytokine-induced neutrophil chemoattractant 1 (a rat homolog of interleukin-8), and inducible nitric oxide synthase, but not proliferation or type I collagen production. PSCs could perform fluid-phase and receptor-mediated endocytosis, as well as phagocytosis of Escherichia coli. CONCLUSIONS: PSCs expressed a variety of TLRs and responded to TLR ligands, leading to the activation of signaling pathways and proinflammatory responses. PSCs could process exogenous antigens by endocytosis and phagocytosis. PSCs might play a role in the immune functions of the pancreas through the recognition of PAMPs.
Assuntos
Expressão Gênica , Pâncreas/metabolismo , RNA/genética , Receptores Toll-Like/genética , Animais , Western Blotting , Proliferação de Células , Células Cultivadas , Quimiocina CCL2/metabolismo , Eletroforese em Gel de Poliacrilamida , Imunidade Inata/genética , Ligantes , Receptores de Lipopolissacarídeos/imunologia , Antígeno 96 de Linfócito/imunologia , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Pâncreas/citologia , Pâncreas/imunologia , Fagocitose/genética , Reação em Cadeia da Polimerase , Ratos , Ratos Wistar , Receptor 2 Toll-Like/biossíntese , Receptor 2 Toll-Like/genética , Receptor 3 Toll-Like/biossíntese , Receptor 3 Toll-Like/genética , Receptor 4 Toll-Like/biossíntese , Receptor 4 Toll-Like/genética , Receptor 5 Toll-Like/biossíntese , Receptor 5 Toll-Like/genética , Receptores Toll-Like/biossínteseRESUMO
INTRODUCTION: Invasion and metastasis of cancer cells require cell motility and adhesion. The small GTPase Rho and one of its effector molecules ROCK regulate cytoskeleton and actomyosin contractility, and play a crucial role in cell adhesion and motility. Results of previous studies showed that the elevated activity of ROCK-1, one of the isomers of ROCK kinases, led to an increase in the activity of invasion and metastasis of cancer cell lines. AIM: To investigate the importance of ROCK-1 in cancer invasion and metastasis. METHODOLOGY: We investigated the expression of ROCK-1 in two cancer cell lines and 31 human pancreatic tissues (21 pancreatic cancers [PC] and 10 histologically normal tissues) by immunoblotting and immunohistochemistry. We also examined by haptotaxis assay whether the migratory activity of PC cells could be suppressed by treatment with the morpholino antisense oligonucleotide in vitro. RESULTS: The expression of ROCK-1 was found in 18 of 21 PC tissues (85.7%), but not in normal pancreatic tissues by immunoblotting and immunohistochemistry. Antisense oligo against ROCK-1 significantly inhibited the haptotaxis of Panc-1 in a dose-dependent manner, compared with the control oligo. CONCLUSION: These results suggest that ROCK-1 may contribute to pancreatic cancer cell invasion and/or metastasis by facilitating cancer cell migration.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Oligonucleotídeos Antissenso/farmacologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Serina-Treonina Quinases/genética , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Immunoblotting , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular , Oligonucleotídeos Antissenso/genética , Pâncreas/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Transfecção , Quinases Associadas a rhoRESUMO
INTRODUCTION: Invasion and metastasis of pancreatic cancer (PC) require cell motility and adhesion, which depend on the activity of cytoskeleton. A cytoskeletal component indispensable for these processes is myosin II, the cytoplasmic analogue of smooth and skeletal muscle myosin. AIMS AND METHODOLOGY: Because the activity of myosin II is accelerated by phosphorylation of myosin II on its regulatory light chain (RLC) by myosin light chain kinase (MLCK), we used two specific MLCK inhibitors, ML-7 and ML-9, for suppression of motility and adhesion of PC cell lines. RESULTS: Both drugs were potent inhibitors, as measured by in vitro motility assay and adhesion assay. When treated with the same concentration of ML-7, the PC cells were rounded up, and the number of stress fibers was reduced markedly. The in vitro migration and adhesion of PC cells were inhibited by ML-7 and ML-9 in a dose-dependent manner, supporting a specific and competitive inhibition of MLCK by these drugs. The inhibition occurred at nontoxic concentrations. CONCLUSIONS: These results highlight the importance of myosin II in the invasion and metastasis of PC cells and suggest the possibility that blocking of myosin II activity by a specific MLCK inhibitor may be a therapeutic strategy for preventing the invasion and metastasis of PC.
Assuntos
Inibidores Enzimáticos/farmacologia , Quinase de Cadeia Leve de Miosina/antagonistas & inibidores , Neoplasias Pancreáticas/patologia , Células Tumorais Cultivadas/efeitos dos fármacos , Azepinas/farmacologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Integrina beta1/análise , Naftalenos/farmacologia , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias Pancreáticas/metabolismoRESUMO
INTRODUCTION: Adenosine plays important roles in a variety of pathophysiologic conditions through receptor-mediated mechanisms. Recent studies have shown that adenosine exerts potent anti-inflammatory properties that are chiefly brought about through the occupancy of the A2a receptor. AIM: To examine the effect of A2a receptor stimulation or inhibition on the pathologic findings during acute pancreatitis. METHODOLOGY: Rats were randomized into three groups and received a selective A2a receptor agonist CGS-21680 (CGS), a selective A2a antagonist 3,7-dimethyl-1-[2-propynyl]-xanthine (DMPX), or saline. Thirty minutes after the injection, acute pancreatitis was produced in the rats by seven intraperitoneal injections of caerulein. The severity of acute pancreatitis was evaluated by serum amylase activity, pancreas myeloperoxidase (MPO) activity, Evans blue extravasation, and pathologic changes of the pancreas. In addition, we investigated the effects of CGS on the pathologic findings of caerulein pancreatitis induced in neutrophil-depleted rats. RESULTS: Administration of caerulein produced hyperamylasemia and morphologic changes of the pancreas including interstitial edema, acinar cell vacuolization, and infiltration of inflammatory cells. In CGS-treated rats, the pancreatic edema and the Evans blue extravasation were aggravated significantly compared with those of saline-treated rats, whereas leukocyte infiltration and MPO activity of the pancreas were decreased. In contrast to CGS, administration of DMPX ameliorated the pancreatic edema and Evans blue extravasation. Treatment with CGS accelerated the pancreatic edema in pancreatitis even after the depletion of neutrophils. CONCLUSION: The activation of adenosine A2a receptors modulates the pathology of acute pancreatitis through at least two diverse properties. One is an anti-inflammatory effect involving neutrophils, and the other is a propagating effect for pancreatic edema formation. The actions of the A2a receptor pathways are unique, and they may have an important role in the progression of acute pancreatitis.
Assuntos
Adenosina/análogos & derivados , Pancreatite/metabolismo , Receptores Purinérgicos P1/metabolismo , Teobromina/análogos & derivados , Adenosina/farmacologia , Amilases/sangue , Amilases/metabolismo , Animais , Ceruletídeo , Edema/induzido quimicamente , Leucócitos/imunologia , Masculino , Pancreatite/induzido quimicamente , Pancreatite/imunologia , Pancreatite/patologia , Fenetilaminas/farmacologia , Agonistas do Receptor Purinérgico P1 , Antagonistas de Receptores Purinérgicos P1 , Ratos , Ratos Wistar , Teobromina/farmacologiaRESUMO
INTRODUCTION: Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic fibrosis. AIMS: To examine the role of PSCs in pancreatic inflammation by determining whether activated PSCs express intercellular adhesion molecule-1 (ICAM-1). METHODOLOGY: Culture-activated rat PSCs were treated with interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), ethanol, or acetaldehyde. ICAM-1 expression was analyzed by flow cytometry. The induction of mRNA was assessed by Northern blot analysis. The binding activity of transcription factors was examined by electrophoretic mobility shift assay. The activation of mitogen-activated protein kinases was assessed by Western blotting with use of antiphosphospecific antibodies. The adhesion of MOLT-4 cells to activated PSCs was also assessed. RESULTS: Culture-activated PSCs expressed ICAM-1. The expression was increased in response to IL-1 beta and TNF-alpha but not to alcohol, with comparable mRNA induction. IL-1 beta and TNF-alpha increased the nuclear factor-kappa B (NF-kappa B)-specific and activator protein-1-specific DNA binding activity, whereas the NF-IL6 activity was not altered. Alcohol did not increase NF-kappa B binding activity. IL-1 beta and TNF-alpha activated extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stress-activated protein kinase, and p38 mitogen-activated protein kinase. Inducible ICAM-1 expression was blocked by pyrrolidine dithiocarbamate, a specific inhibitor of NF-kappa B activation, but not by inhibitors of mitogen-activated protein kinase pathways. IL-1 beta and TNF-alpha increased the ICAM-1-mediated binding of MOLT-4 cells to activated PSCs, indicating a role of ICAM-1 in the adhesion of leukocytes to PSCs. CONCLUSION: Our results suggest that activated PSCs express ICAM-1 mainly through the activation of NF-kappa B, thus playing a role in the pathogenesis of pancreatic inflammation.
Assuntos
Molécula 1 de Adesão Intercelular/genética , Pâncreas/citologia , Pancreatite/fisiopatologia , Acetaldeído/farmacologia , Doença Aguda , Animais , Antineoplásicos/farmacologia , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Técnicas In Vitro , Interleucina-1/farmacologia , Leucócitos/citologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Pâncreas/efeitos dos fármacos , Pancreatite/etiologia , RNA Mensageiro/metabolismo , Ratos , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
INTRODUCTION: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor that controls growth, differentiation, and inflammation in different tissues. Roles of PPAR-gamma activation in pancreatic acinar cells are poorly characterized. AIMS: To examine the effects of PPAR-gamma activation on the induction of apoptosis in rat pancreatic AR42J cells. METHODOLOGY: AR42J cells were treated with ligands of PPAR-gamma, and induction of apoptosis was evaluated by cell viability, DNA-fragmentation, and flow cytometry. RESULTS: Treatment of the cells with ligands of PPAR-gamma (15-deoxy-open triangle12,14-prostaglandin J2 or troglitazone) induced apoptosis in a dose-dependent manner. Troglitazone-induced apoptosis was not blocked by inhibitors of caspases (acetyl-DEVD-aldehyde and benzoyloxycarbonyl-VAD-fluoromethylketone). Troglitazone induced the expression of pancreatitis-associated protein-1 and clusterin mRNAs. Troglitazone activated c-Jun NH2-terminal kinase/stress-activated protein kinase, but inhibited the activation of extracellular signal-regulated kinases 1/2. Troglitazone did not activate NF-kappaB, suggesting a role of NF-kappaB-independent pathways. In AR42J cells and isolated pancreatic acini, PPAR-gamma gene and protein were detected. In addition, troglitazone increased the PPAR-dependent transcriptional activity, suggesting that PPAR-gamma is functional in AR42J cells. CONCLUSION: These results indicate that activation of PPAR-gamma induces apoptosis in AR42J cells and imply that PPAR-gamma may be a potential therapeutic target of pancreatic inflammation, because of its anti-inflammatory effects in addition to its proapoptotic effects.
Assuntos
Apoptose/fisiologia , Proteínas I-kappa B , Fatores Imunológicos/farmacologia , Pâncreas/citologia , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Tiazolidinedionas , Fatores de Transcrição/metabolismo , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Anexina A5/genética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Inibidores de Caspase , Linhagem Celular , Cromanos/farmacologia , Clusterina , Inibidores de Cisteína Proteinase/farmacologia , Proteínas de Ligação a DNA/metabolismo , Expressão Gênica/efeitos dos fármacos , Glicoproteínas/genética , Ligantes , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno , Proteína Quinase 8 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Chaperonas Moleculares/genética , Inibidor de NF-kappaB alfa , Oligopeptídeos/farmacologia , Proteínas Associadas a Pancreatite , RNA Mensageiro/metabolismo , Ratos , Tiazóis/farmacologia , TroglitazonaRESUMO
The pathophysiologic mechanisms that underlie acute and chronic pancreatitis arising from alcohol abuse are poorly understood. The reasons for this state of knowledge result historically from a lack of models for experimental investigation. Ethanol feeding alone, even at high doses, has minimal and inconsistent effects on morphologic findings in the pancreas in experimental animals. This experience, plus the fact that alcohol abuse causes pancreatic pathology in only a minority of patients, suggest that ethanol acts to sensitize the pancreas to the deleterious effects of other stimuli. In this article, we discuss findings to support this concept of ethanol as a sensitizing agent and experimental models developed that can be used to investigate the effects of ethanol on the pathologic processes of pancreatitis. These pathologic processes include inflammation, cell death, intrapancreatic digestive enzyme activation, and fibrosis.
Assuntos
Pancreatite Alcoólica/fisiopatologia , Animais , Modelos Animais de Doenças , Humanos , Pancreatite Alcoólica/patologiaRESUMO
BACKGROUND: Recent studies have shown that inosine, a purine nucleoside produced during the breakdown of adenosine, has immunomodulatory and anti-inflammatory properties. The aim of this study was to examine the effects of inosine on the course of acute pancreatitis. METHODS: Edematous pancreatitis was induced by the intraperitoneal injection of caerulein (50 micro g/kg), seven times, at 1-h intervals, in male Wistar rats (caerulein pancreatitis). Inosine (100 mg/kg) was administered 30 min before or 1 h after the first injection of caerulein. The effects of inosine on the severity of pancreatitis were assessed by serum amylase, pancreatic edema (wet/dry ratio), myeloperoxidase activity, cytokine-induced neutrophil chemoattractant-1 concentrations, and histological changes. RESULTS: Prophylactic administration of inosine significantly decreased the elevation of serum amylase, myeloperoxidase activity, and cytokine-induced neutrophil chemoattractant-1 concentrations in the pancreas and the lung. Inosine did not significantly affect edema formation. Histologically, vacuole formation in pancreatic acinar cells, infiltration of inflammatory cells in the pancreas and the lung, and alveolar wall thickening in the lung were reduced. Inosine improved the histological findings and reduced myeloperoxidase activity even if it was administered 1 h after the first injection of caerulein. CONCLUSIONS: Inosine reduced the severity of acute pancreatitis, suggesting a possible application of this compound in the treatment of acute pancreatitis.
Assuntos
Inosina/uso terapêutico , Pneumopatias/tratamento farmacológico , Pancreatite/tratamento farmacológico , Doença Aguda , Amilases/sangue , Animais , Ceruletídeo , Quimiocinas CXC/metabolismo , Ensaio de Imunoadsorção Enzimática , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pulmão/patologia , Pneumopatias/prevenção & controle , Masculino , Pâncreas/patologia , Pancreatite/induzido quimicamente , Peroxidase/metabolismo , Ratos , Ratos WistarRESUMO
OBJECTIVES: The usefulness of early severity assessment of acute pancreatitis (AP) by contrast-enhanced computed tomography (CECT) was investigated. METHODS: Data were obtained from a 2007 nationwide survey in Japan. Clinical data of 983 patients with AP were analyzed. All were examined by CECT on the day of admission. RESULTS: Early findings of CECT demonstrated that low enhanced pancreatic parenchyma (LEPP) was associated with the incidence of organ failure (OF), multiple OF, and infectious complications as well as mortality (P < 0.0001). Next, patients were further divided into 4 groups according to the CECT findings, which focused on the LEPP and peripancreatic collections (PPCs). The LEPP/PPC (+/+) group was characterized as high morbidity and high mortality. The incidence of OF (28.2%), multiple OF (15.5%), and mortality (11.4%) in patients assigned to the (+/+) group was significantly higher than in those assigned to the other groups. The incidence of infectious complications was significantly higher in patients assigned to the (+/+) group (16.7%), the (+/-) group (9.0%), and the (-/+) group (7.0%) than those assigned to the (-/-) group (1.8%). CONCLUSIONS: The detection of LEPP and PPC was a useful CECT finding for the early assessment of the severity of AP.
Assuntos
Meios de Contraste , Pâncreas/diagnóstico por imagem , Pancreatite/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Doença Aguda , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
OBJECTIVES: A nationwide epidemiological survey was conducted to estimate the number of patients treated for acute pancreatitis (AP) in 2007 in Japan and to clarify the clinicoepidemiological features of AP. METHODS: In the first survey, a simple questionnaire was used to inquire about the number of patients with AP who visited the hospital in the year 2007. This questionnaire was directly mailed to the heads of 3027 facilities. The second questionnaire was forwarded to those facilities from which patients with AP were reported on the first questionnaire. RESULTS: The estimated total number of patients treated for AP in 2007 was 57,560 (95% confidence interval, 48,571-66,549), with an overall prevalence rate of 45.1 per 100,000 population. The sex ratio (male-female) of the patients was 2.0, with a mean age of 56.6 years in men and 64.6 years in women. Alcoholic AP was most common in men and gallstone AP in women. The overall mortality rate of AP was 1.9% and, in severe cases, 8.0%. CONCLUSION: The number of patients with AP increased about 3-fold during this decade (19,500 in 1998 to 57,560 in 2007), and the mortality rate of AP was reduced from 7.4% in 1998 and 2.9% in 2003 to 1.9% in 2007.
Assuntos
Pancreatite/epidemiologia , Pancreatite/patologia , Inquéritos e Questionários , Doença Aguda , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/efeitos adversos , Criança , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Cardiopatias/epidemiologia , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Pancreatite/etiologia , Pancreatite Crônica/epidemiologia , Prevalência , Fatores de Risco , Análise de Sobrevida , Adulto JovemRESUMO
This study evaluated the association of the polymorphisms in the Toll-like receptor (TLR)2 and TLR4 genes with acute pancreatitis (AP) in Japan. The numbers of guanine-thymine [(GT)n] repeats in intron 2 of the TLR2 gene were counted in 202 unrelated patients with AP (80 with severe and 122 with mild disease) and in 286 healthy controls, using polymerase chain reaction and Genescan analysis. The alleles were divided into three subclasses: (GT)16 or less as the S allele; between (GT)17 and (GT)22 as the M allele; and (GT)23 or more as the L allele. Asp299Gly and Thr399Ile polymorphisms in the TLR4 gene were examined by polymerase chain reaction-restriction fragment length polymorphism analysis. Patients with AP had more S alleles (p < 0.001; odds ratio = 2.37; 95% confidence interval = 1.78-3.17) and fewer M alleles (p < 0.001; odds ratio = 0.40; 95% confidence interval 0.31-0.52) than did healthy controls. Genotypes SS and SL were more common, whereas MM and ML were less common in patients with AP. In subgroup analyses, the genotypes including S alleles were more common in patients with severe AP than in controls. No Asp299Gly and Thr399Ile polymorphisms were detected. In conclusion, microsatellite polymorphism in intron 2 of the TLR2 gene was associated with susceptibility to AP and its severity in Japan.