RESUMO
BACKGROUND: Laparoscopic liver resection for hepatocellular carcinoma (HCC) in Child-Pugh A cirrhosis has been demonstrated as beneficial. However, the role of laparoscopy in Child-Pugh B cirrhosis is undetermined. The aim of this retrospective cohort study was to compare open and laparoscopic resection for HCC with Child-Pugh B cirrhosis. METHODS: Data on liver resections were gathered from 17 centres. A 1 : 1 propensity score matching was performed according to 17 predefined variables. RESULTS: Of 382 available liver resections, 100 laparoscopic and 100 open resections were matched and analysed. The 90-day postoperative mortality rate was similar in open and laparoscopic groups (4.0 versus 2.0 per cent respectively; P = 0.687). Laparoscopy was associated with lower blood loss (median 110 ml versus 400 ml in the open group; P = 0.004), less morbidity (38.0 versus 51.0 per cent respectively; P = 0.041) and fewer major complications (7.0 versus 21.0 per cent; P = 0.010), and ascites was lower on postoperative days 1, 3 and 5. For laparoscopic resections, patients with portal hypertension developed more complications than those without (26 versus 12 per cent respectively; P = 0.002), and patients with a Child-Pugh B9 score had higher morbidity rates than those with B8 and B7 (7 of 8, 10 of 16 and 21 of 76 respectively; P < 0.001). Median hospital stay was 7.5 (range 2-243) days for laparoscopic liver resection and 18 (3-104) days for the open approach (P = 0.058). The 5-year overall survival rate was 47 per cent for open and 65 per cent for laparoscopic resection (P = 0.142). The 5-year disease-free survival rate was 32 and 37 per cent respectively (P = 0.742). CONCLUSION: Patients without preoperative portal hypertension and Child-Pugh B7 cirrhosis may benefit most from laparoscopic liver surgery.
Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia , Laparoscopia , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Hepatectomia/efeitos adversos , Hepatectomia/métodos , Hepatectomia/mortalidade , Humanos , Hipertensão Portal/patologia , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Laparoscopia/mortalidade , Tempo de Internação/estatística & dados numéricos , Cirrose Hepática/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Pontuação de Propensão , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: In the absence of randomized controlled data and even propensity-matched data, indications for, and outcomes of, laparoscopic repeat liver resection for hepatocellular carcinoma (HCC) remain uncertain. This study aimed to clarify the current indications for laparoscopic repeat liver resection for HCC, and to evaluate outcomes. METHODS: Forty-two liver surgery centres around the world registered patients who underwent repeat liver resection for HCC. Patient characteristics, preoperative liver function, tumour characteristics, surgical method, and short- and long-term outcomes were recorded. RESULTS: Analyses showed that the laparoscopic procedure was generally used in patients with relatively poor performance status and liver function, but favourable tumour characteristics. Intraoperative blood loss (mean(s.d.) 254(551) versus 748(1128) ml; P < 0·001), duration of operation (248(156) versus 285(167) min; P < 0·001), morbidity (12·7 versus 18·1 per cent; P = 0·006) and duration of postoperative hospital stay (10·1(14·3) versus 11·8(11·8) days; P = 0·013) were significantly reduced for laparoscopic compared with open procedures, whereas survival time was comparable (median 10·04 versus 8·94 years; P = 0·297). Propensity score matching showed that laparoscopic repeat liver resection for HCC resulted in less intraoperative blood loss (268(730) versus 497(784) ml; P = 0·001) and a longer operation time (272(187) versus 232(129); P = 0·007) than the open approach, and similar survival time (12·55 versus 8·94 years; P = 0·086). CONCLUSION: Laparoscopic repeat liver resection is feasible in selected patients with recurrent HCC.
ANTECEDENTES: Dado que no existen ensayos clínicos controlados ni estudios de datos emparejados por puntaje de propensión, todavía hay dudas sobre las indicaciones y los resultados de la resección iterativa laparocópica de un carcinoma hepatocelular (hepatocellular carcinoma, HCC). Este estudio tuvo como objetivo esclarecer las indicaciones actuales y los resultados de la resección hepática laparoscópica iterativa del HCC. MÉTODOS: Se incluyeron los pacientes de 42 centros de cirugía hepática a nivel mundial en los que se había realizado una resección hepática iterativa por HCC. Se analizaron las características del paciente, la función hepática preoperatoria, las características del tumor, el abordaje quirúrgico y los resultados a corto y largo plazo. RESULTADOS: El análisis demostró que la vía laparoscópica generalmente se utilizaba en pacientes con carácteristicas tumorales favorables, pero con estado funcional y función hepatica relativamente peores. La pérdida de sangre intraoperatoria (254,3 ± 551,2 versus 748,0 ± 1127,7 mL, P < 0,001), la duración de la intervención (247,6 ± 155,8 versus 285,1 ± 167,0 minutos, P < 0,001), la morbilidad (12,7 versus 18,1%, P = 0,005) y la estancia hospitalaria postoperatoria (10,07 ± 14,29 versus 11,80 ± 11,79 días, P = 0,010) fueron significativamente menores para los pacientes tratados por via laparoscópica en comparacion con la vía abierta, mientra que el tiempo de supervivencia fue comparable (mediana 10,04 versus 8,94 años, P = 0,297). El estudio de emparejamiento por puntaje de propensión mostró que la resección hepática iterativa por vía laparoscópica de un HCC (frente a la vía abierta) conllevaba una menor pérdida sanguínea intraoperatoria (268,0 ± 730,2 versus 496,5 ± 784,2 mL, P = 0,01), una mayor duración de la intervención (272,1 ± 187,2 versus 231,8 ± 129,1 minutos , P = 0,07) y un tiempo de supervivencia similar (mediana 12,55 versus 8,94 años, P = 0,0855). CONCLUSIÓN: La resección hepática iterativa por vía laparoscópica es factible en pacientes seleccionados con HCC recidivado.
Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia/métodos , Laparoscopia/métodos , Neoplasias Hepáticas/cirurgia , Reoperação/métodos , Idoso , Feminino , Hepatectomia/efeitos adversos , Humanos , Laparoscopia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Reoperação/efeitos adversos , Resultado do TratamentoRESUMO
The objective of this study was to quantify, in vivo, constitutive and tumor necrosis factor alpha (TNF-alpha)-enhanced expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in different tissues from healthy wild-type mice (C57BL/6) as well as interleukin-10 (IL-10)-deficient mice with and without active colitis. Using the dual radiolabel monoclonal antibody technique, we found substantial constitutive expression of MAdCAM-1 in the intestine, colon, and mesenteric lymph nodes. MAdCAM-1 expression in these tissues was significantly enhanced, in a time-dependent manner, by systemic administration of TNF-alpha. Maximum surface expression was observed at 18 h after TNF-alpha administration and remained significantly elevated at 48 h post-TNF-alpha injection. No significant constitutive nor TNF-alpha-induced expression of MAdCAM-1 was detected in skeletal muscle, brain, or heart. In IL-10-deficient (IL-10 k/o) mice with no clinical or histological evidence of colitis, constitutive and TNF-alpha-induced expression of MAdCAM-1 in the intestine, cecum, and colon was not different from those values obtained with healthy wild-type controls. IL-10-deficient mice with active colitis exhibited a four- to fivefold greater expression of MAdCAM-1 in the cecum and colon compared with their healthy controls or to IL-10 k/o mice with no evidence of colitis. Taken together, these data demonstrate that TNF-alpha enhances surface expression of MAdCAM-1 in intestinal and colonic tissues to the same extent in both wild-type and IL-10 k/o mice with no colonic inflammation, whereas IL-10 k/o mice with active colitis exhibited a profound up-regulation of MAdCAM-1 in the colon.
Assuntos
Colite/metabolismo , Imunoglobulinas/biossíntese , Interleucina-10/deficiência , Mucoproteínas/biossíntese , Doença Aguda , Animais , Adesão Celular , Moléculas de Adesão Celular , Doença Crônica , Colite/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Retorno de Linfócitos/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
BACKGROUND: In the orthotopic mouse liver transplantation model, allografts are accepted without immunosuppression, and donor-specific tolerance is induced upto 40 days. Although FK 506 is a well-known immunosuppressive agent, its influence on tolerance induction is not known. In this study, we examined the influence of FK 506 on tolerance induction in a mouse liver transplant model. METHODS: Orthotopic liver transplantation was performed from B10.BR (H-2K) to B10.D2 (H-2D mice). In the experimental group, FK 506 (1 mg/kg/d) was given subcutaneously to the recipients from day 0 to day 21, whereas the control group received a placebo (1 mg/kg/d). On day 40, donor skin grafts were transplanted to the recipients to examine the survival times of the recipients and the skin grafts. On day 14, donor-type cells in recipient's blood, spleen, kidney, thymus, and lymph nodes were examined by RT-PCR using specific donor-type MHC class I and II primers. RESULTS: All recipients survived for more than 100 days. The mean survival time of skin grafts in the experimental group was significantly reduced compared to that of controls. On day 14, either donor-type MHC class I- or class II-positive cells were detected in the control group, whereas donor-derived MHC class II-positive cells disappeared in the experimental group. CONCLUSIONS: In the early period after mouse liver transplantation, FK 506 inhibits tolerance induction paradoxically. Some donor-derived MHC class II-positive cells might play an important role in tolerance induction.
Assuntos
Sobrevivência de Enxerto/imunologia , Transplante de Fígado/imunologia , Tacrolimo/uso terapêutico , Animais , Sobrevivência de Enxerto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Quimeras de Transplante , Tolerância ao Transplante/imunologia , Transplante Homólogo/imunologiaRESUMO
The objectives of this study were to quantify colonic cytokine and endothelial cell adhesion molecule (ECAM) expression in the colons of severe combined immunodeficient (SCID) mice reconstituted with different subsets of CD4+ T lymphocytes. We found that animals injected with CD45RBhigh but not CD45RBlow T cells or phosphate-buffered saline (PBS) developed clinical evidence of colitis at 6-8 weeks following reconstitution, as assessed by loss of body weight, development of loose stools and/or diarrhea, and histopathology. Concurrent with the onset of distal bowel inflammation was enhanced expression of a variety of Th1 and macrophage-derived cytokines including interferon gamma, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-12, and IL-18 lymphotoxin-beta. In addition, message levels and vascular surface expression of ICAM-1, VCAM-1, and MAdCAM-1 were all significantly enhanced in the colitic SCID mice reconstituted with CD45RBhigh T cells compared with SCID mice reconstituted with PBS or CD45RBlow T cells that did not develop disease. Significant increases in some of these ECAMs were also noted in the cecum and stomach and to a lesser degree in the small bowel. Our data confirm that reconstitution of SCID mice with CD45RBhigh but not CD45RBlow T cells induces chronic colitis, and that the colonic inflammation is associated with enhanced expression of proinflammatory cytokines and different ECAMs in the colon. Furthermore, our studies demonstrate that reconstitution of SCID mice with CD45RBhigh T cells enhances ECAM expression in tissues distant from the site of active inflammation.
Assuntos
Moléculas de Adesão Celular/biossíntese , Citocinas/biossíntese , Doenças Inflamatórias Intestinais/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Moléculas de Adesão Celular/análise , Citocinas/análise , Modelos Animais de Doenças , Humanos , Molécula 1 de Adesão Intercelular/análise , Molécula 1 de Adesão Intercelular/imunologia , Camundongos , Camundongos SCIDRESUMO
It is becoming increasingly apparent that the chronic gut inflammation observed in the idiopathic inflammatory bowel diseases (e.g. ulcerative colitis, Crohn's disease) is associated with enhanced production of leukocyte-derived oxidants. Oxidants such as hydrogen peroxide are known to activate certain transcription factors such as nuclear transcription factor kappa beta. Nuclear transcription factor kB (NF-kappa B) is a ubiquitous transcription factor and pleiotropic regulator of numerous genes involved in the immune and inflammatory responses. This transcription factor is activated via the selective phosphorylation, ubiquination and degradation of its inhibitor protein I-kB thereby allowing translocation of NF-kappa B into the nucleus where it upregulates the transcription of a variety of adhesion molecules (e.g. ICAM-1, VCAM-1), cytokines (TNF, IL-1, IL-6) and enzymes (iNOS). The proteolytic degradation of the post-translationally modified I-kappa B is known to be mediated by the 26S proteasome complex. Based upon work from our laboratory, we propose that inhibition of NF-kappa B activation produces significant anti inflammatory activity which may be mediated by the inhibition of transcription of certain pro-inflammatory mediators and adhesion molecules.
Assuntos
Regulação da Expressão Gênica , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Humanos , Mediadores da Inflamação/metabolismo , Leucócitos/metabolismo , NF-kappa B/metabolismoRESUMO
BACKGROUND: We hypothesized that endothelin-1 (ET-1) is an important mediator in renal dysfunction under septic conditions. This study clarified the pathophysiologic role of ET-1 in renal function under conditions of surgical stress, especially sepsis. METHODS: We investigated the correlation between ET-1 levels and renal function and the effect of anti-ET-1 antibody (AwET-1N40) on renal function in a septic shock rat model. RESULTS: The plasma ET-1 level increased significantly at 30 minutes and remained significantly elevated for 24 hours, reaching a peak (195 +/- 24.4 pg/ml) 3 hours after the endotoxin (lipopolysaccharide derived from Escherichia coli) injection. Increases in plasma creatinine concentration and blood urea nitrogen (BUN) level and decreases in urine volume and urinary sodium excretion were also observed in the early phase after endotoxin injection. The plasma creatinine concentration and the plasma ET-1 level increased significantly at 30 minutes, reached a peak at 3 hours, and then decreased. Anti-ET-1 antibody administration (5 nmol/kg body, four times intravenously) decreased plasma creatinine concentration and BUN level and increased urine volume and urinary sodium excretion 3 hours after endotoxin injection (creatinine, p = 0.07; BUN, p < 0.05; urine volume, p < 0.01; urinary sodium excretion, p < 0.01; anti-ET-1 vs shams). CONCLUSIONS: These results suggest that the increase in endogenous ET-1 induced by sepsis plays an important role in renal dysfunction in the septic state.
Assuntos
Endotelinas/fisiologia , Rim/fisiopatologia , Choque Séptico/fisiopatologia , Animais , Anticorpos/imunologia , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Endotelinas/sangue , Endotelinas/imunologia , Endotoxinas , Hemodinâmica , Lipopolissacarídeos , Masculino , Ratos , Ratos Wistar , Choque Séptico/sangue , Choque Séptico/induzido quimicamenteRESUMO
Interleukin (IL)-10 is known to inhibit the production of proinflammatory cytokines by macrophages suggesting that endogenous IL-10 may act as an antiinflammatory agent. Because endothelial cell adhesion molecules (ECAMs) play a key role in the recruitment of leukocytes into tissue in response to an inflammatory stimulus (i.e., lipopolysaccharide (LPS)) and the following cytokine production, we wished to assess the importance of IL-10 as an endogenous modulator of ECAM expression using IL-10 deficient mice. Constitutive and LPS-stimulated expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and E-selectin were measured in wild type C57BL/6 and IL-10 deficient mice with no signs of active enterocolitis, using the dual radiolabeled monoclonal antibody technique. We found that constitutive expression of these ECAMs did not differ between IL-10 deficient and WT mice for all organs tested. However, we demonstrated larger increments in LPS-induced expression of ICAM-1 and VCAM-1 in the vasculature of the small intestine in IL-10 deficient mice compared to WT mice. These findings suggest that endogenous IL-10 does not modulate constitutive or LPS-induced expression of ECAMs in most tissues, however it does appear to play an inhibitory role in LPS-stimulated expression of ICAM-1 and VCAM-1 in the intestinal vasculature.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Interleucina-10/deficiência , Lipopolissacarídeos/farmacologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossíntese , Animais , Anticorpos Monoclonais/metabolismo , Regulação para Baixo , Endotélio Vascular/química , Mediadores da Inflamação/fisiologia , Molécula 1 de Adesão Intercelular/análise , Interleucina-10/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Distribuição Aleatória , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/análiseRESUMO
Hepatocellular carcinoma often arises in cirrhotic livers. Patients with severe liver cirrhosis who undergo hepatectomy often develop postoperative liver failure, even if the hepatectomy is limited. Here, we report six patients with severe liver cirrhosis (Child-Pugh B/C and indocyanine green retention rate at 15 min ≥ 40%) who underwent pure laparoscopic hepatectomy. Their perioperative course was favorable and comparable to that of other hepatocellular carcinoma patients with mild-moderate liver cirrhosis. In patients with severe liver cirrhosis, pure laparoscopic hepatectomy minimizes the disturbance in collateral blood and lymphatic flow caused by laparotomy and liver mobilization, as well as the mesenchymal injury caused by compression of the liver. It limits complications such as massive ascites, which can lead to severe postoperative liver failure. Good candidates for the procedure include patients with severe liver cirrhosis who have tumors on the liver surface and in whom adaptation to ablation therapy is difficult and/or who experience local recurrence after repeat treatments.
Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia/métodos , Laparoscopia , Cirrose Hepática/complicações , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Carcinoma Hepatocelular/complicações , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/complicações , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
A growing body of experimental evidence indicates that leukocyte-endothelial cell interactions may play an important role in the pathogenesis of NSAID-induced gastropathy. Using a newly described, dual radiolabeled monoclonal antibody technique to quantify adhesion molecule surface expression in vivo, we have demonstrated increases in surface expression of ICAM-1 and P-selectin in the gastric mucosa after oral administration of indomethacin. We have also found that CD18-, ICAM-1-, or P-selectin-deficient mice are less sensitive to the ulcerogenic effects of orally administered indomethacin. Although there is virtually no information regarding the regulation of expression of endothelial cell adhesion molecules (ECAMs) in experimental NSAID-induced gastropathy, the nuclear transcription factor KB (NFKB) may represent a potential modulator of transcriptional activation of ECAM expression. We have demonstrated that two structurally distinct yet highly selective proteasome inhibitors (MG341, lactacystin) inhibit tumor necrosis factor (TNF)-induced NFKB activation as well as ECAM expression in human endothelial cells in vitro. In addition, we found that these proteasome inhibitors significantly reduced indomethacin-induced gastric mucosal injury as well as gastric mucosal ICAM-1 expression in the rat in vivo. We conclude from these studies that indomethacin activates NFKB (possibly via TNF synthesis) in gastric microvascular endothelial cells, thereby enhancing surface expression of ICAM-1 which binds the CD18 on polymorphonuclear leukocytes (PMNs). These adherent PMNs are then believed to mediate endothelial and/or epithelial cell injury either directly or indirectly.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Indometacina/efeitos adversos , Gastropatias/induzido quimicamente , Animais , Adesão Celular , Leucócitos/patologia , Camundongos , Modelos Moleculares , Ratos , Gastropatias/patologiaRESUMO
It is now well appreciated that chronic gut inflammation is characterized by enhanced production of reactive metabolites of oxygen and nitrogen. Some of these oxidants are known to modulate the expression of a variety of genes that are involved in the immune and inflammatory responses. For example, certain oxidants are known to activate the nuclear transcription factor kappa B, which regulates the expression of a variety of different adhesion molecules, cytokines, and enzymes. Oxidants are also known to activate another transcription factor, activator protein-1. This transcription factor is composed of products from the fos and jun proto-oncogene family and is believed to be important in regulating cell growth and proliferation. Finally, oxidants are believed to promote intestinal epithelial cell apoptosis, and the B-cell lymphoma/leukemia-2 gene product is believed to inhibit this phenomenon in an antioxidant-dependent manner. Taken together, these observations suggest that nontoxic concentrations of reactive metabolites of oxygen and nitrogen play an important role in regulating the expression of genes involved in the inflammatory response and in modulating apoptosis.
Assuntos
Doenças Inflamatórias Intestinais/metabolismo , NF-kappa B/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição AP-1/biossíntese , Animais , Apoptose , Radicais Livres , Regulação da Expressão Gênica , Humanos , Leucócitos/metabolismo , Proto-Oncogene MasRESUMO
BACKGROUND: Neutrophil-endothelial cell interactions are thought to play a critical role in the pathophysiology of non-steroidal anti-inflammatory drug (NSAID) induced gastropathy. AIMS: To optimise a mouse model of NSAID induced gastropathy and to evaluate the importance of adhesion molecules using adhesion molecule deficient mice. METHODS: Gastropathy was induced in C57BL/6 mice or their adhesion molecule deficient counterparts via oral administration of indomethacin (20 mg/kg). Lesion scores, mucosal permeability, and histopathology were used to assess gastric mucosal injury. RESULTS: Intragastric administration of indomethacin induced linear haemorrhagic mucosal lesions, primarily in the corpus of the stomach that were first observed at six hours. These lesions continued to develop over the next six hours with maximal lesion scores and mucosal permeabilities at 12 hours. When indomethacin was administered to mice deficient in CD18, intercellular adhesion molecule 1 (ICAM-1), or P-selectin, there were significant decreases in lesion scores compared with their C57BL/6 controls. In addition, mucosal permeabilities were found to be significantly lower in CD18 or ICAM-1 deficient mice observed at 12 hours. CONCLUSION: Certain leucocyte and endothelial cell adhesion molecules are important determinants for full expression of indomethacin induced gastropathy. It is proposed that this modification of the mouse model may be useful for the investigation of other pathophysiological mechanisms of NSAID induced gastropathy.
Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Moléculas de Adesão Celular/fisiologia , Inibidores de Ciclo-Oxigenase/toxicidade , Indometacina/toxicidade , Gastropatias/induzido quimicamente , Animais , Antígenos CD18/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Molécula 1 de Adesão Intercelular/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Selectina-P/fisiologia , Permeabilidade/efeitos dos fármacos , Gastropatias/metabolismo , Gastropatias/patologiaRESUMO
The objective of this study was to quantify E-selectin surface expression in the colon as well as other tissues in a CD4(+) T-cell model of chronic colitis in mice using the newly developed dual radiolabel monoclonal antibody technique. Male SCID mice were reconstituted with either 5 x 10(5) CD4(+) CD45RB(low) or CD45RB(high) T-cells isolated from normal CB-17 donor mouse spleens and subsequently monitored for clinical signs of colitis. We found that animals injected with CD45RB(high) but not CD45RB(low) T-cells nor PBS developed colitis at 6-8 weeks following reconstitution as assessed by loss of body weight, development of loose stools and/or diarrhea, and histopathology. Concurrent with the onset of distal bowel inflammation was enhanced expression of E-selectin compared to SCID mice injected with PBS or reconstituted with CD45RB(low) T-cells, both of which did not develop colitis. We also observed significant increases in E-selectin expression in cecum, small intestine, mesentery, and liver of colitic mice. Our data confirm that reconstitution of SCID mice with CD45RB(high) but not CD45RB(low) T-cells induces chronic colitis and demonstrate that this chronic colitis is associated with enhanced expression of an endothelial cell-specific adhesion molecule. Furthermore, our studies demonstrate that reconstitution of SCID mice with CD45RB(high) T-cells enhances E-selectin expression in a variety of tissues distant from the site of active inflammation.
Assuntos
Colite/metabolismo , Selectina E/biossíntese , Animais , Moléculas de Adesão Celular/metabolismo , Doença Crônica , Colite/patologia , Modelos Animais de Doenças , Endotélio/metabolismo , Feminino , Masculino , Camundongos , Camundongos SCID , Radioimunoensaio/métodosRESUMO
BACKGROUND & AIMS: Intercellular adhesion molecule (ICAM)-dependent adhesion of circulating neutrophils to microvascular endothelial cells is thought to be critical in causing indomethacin (nonsteroidal anti-inflammatory drug [NSAID])-induced gastropathy. Indomethacin stimulates tumor necrosis factor (TNF)-alpha expression, which may enhance adhesiveness of gastric capillaries for neutrophils by activating ICAM expression on endothelial cells. Stimulation of ICAM expression is mediated by activation of the transcription factor NF-kappaB. Because activation of NF-kappaB requires proteolytic degradation of IkappaB by the ubiquitin-proteasome pathway of intracellular proteolysis, treatment with proteasome inhibitors was evaluated for efficacy in preventing NSAID gastropathy. METHODS: The effect of proteasome inhibitors on gastric injury caused by oral indomethacin was measured, along with their effects on gastric mucosal permeability measured by the blood to lumen EDTA clearance. Gastric ICAM expression was measured in vivo using infusion of a labeled rat ICAM antibody. RESULTS: Proteasome inhibitors prevented NSAID gastropathy if administered from 0 to 12 hours before indomethacin. Equivalent efficacy was observed with intravenous and oral administration of proteasome inhibitors. There was a strong correlation between the potency of proteasome inhibitors in preventing NSAID gastropathy and their potency in inhibiting intracellular proteolysis or their anti-inflammatory potency. All three classes of proteasome inhibitors, peptide boronates, aldehydes, and the mechanistically different lactacystin, prevented NSAID gastropathy. Proteasome inhibitor treatment also abolished the increase in gastric mucosal permeability and the increase in gastric endothelial ICAM expression induced by indomethacin. CONCLUSIONS: Indomethacin-induced gastric injury and increased ICAM expression are inhibited by inhibition of the proteasome.
Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Cisteína Endopeptidases/fisiologia , Inibidores de Cisteína Proteinase/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Indometacina/toxicidade , Complexos Multienzimáticos/fisiologia , Animais , Molécula 1 de Adesão Intercelular/análise , Leupeptinas/farmacologia , Masculino , NF-kappa B/fisiologia , Complexo de Endopeptidases do Proteassoma , Ratos , Ratos Sprague-DawleyRESUMO
A growing body of experimental evidence suggests that neutrophilic polymorphonuclear leukocyte (PMN)-endothelial cell interactions play a critical role in the pathophysiology of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. The objective of this study was to directly determine whether the expression of endothelial cell adhesion molecules is enhanced in a model of NSAID-induced gastropathy. Gastropathy was induced in male Sprague-Dawley rats via oral administration of indomethacin (Indo, 20 mg/kg). Lesion scores, blood-to-lumen clearance of 51Cr-EDTA (mucosal permeability), and histological analysis (epithelial necrosis) were used as indexes of gastric mucosal injury. Gastric mucosal vascular expression of intercellular adhesion molecule 1 (ICAM-1) or P-selectin were determined at 1 and 3 h after Indo administration using the dual radiolabeled monoclonal antibody (MAb) technique. For some experiments, a blocking MAb directed at either ICAM-1 (1A29) or P-selectin (RMP-1) or their isotype-matched controls was injected intravenously 10 min before Indo administration. We found that P-selectin expression was significantly increased at 1 h but not 3 h after Indo administration, whereas ICAM-1 expression was significantly increased at both 1 and 3 h after Indo treatment. The blocking ICAM-1 and P-selectin MAbs both inhibited Indo-induced increases in lesion score, mucosal permeability, and epithelial cell necrosis. However, the Indo-induced gastropathy was not associated with significant PMN infiltration into the gastric mucosal interstitium, nor did Indo reduce gastric mucosal blood flow. We propose that NSAID-induced gastric mucosal injury may be related to the expression of P-selectin and ICAM-1; however, this mucosal injury does not appear to be dependent on the extravasation of inflammatory cells or mucosal ischemia.
Assuntos
Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Molécula 1 de Adesão Intercelular/biossíntese , Selectina-P/biossíntese , Úlcera Gástrica/metabolismo , Animais , Anti-Inflamatórios não Esteroides , Mucosa Gástrica/irrigação sanguínea , Indometacina , Masculino , Neutrófilos/metabolismo , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Úlcera Gástrica/induzido quimicamenteRESUMO
We describe herein the case of a patient in whom recurrent liver metastases from gastric cancer were successfully treated by performing repeated hepatic resections. A 63-year-old man underwent a total gastrectomy with regional lymph node dissection for an advanced gastric cancer on November 17, 1992, the pathological findings of which confirmed a diagnosis of well-differentiated tubular adenocarcinoma, ss, INFalpha, ly1, v0, n1(+). Follow-up computer tomography (CT) and ultrasonography scans done 7 months after the gastrectomy revealed a metastasis in the liver S5, and a partial resection of S5 was performed on July 5, 1993. Subsequently, on November 17, 1994, an anterior segmentectomy of the liver was performed for a liver metastasis in the liver S8, then on August 11, 1998, a partial resection of the liver S6 was performed for a metastasis in the liver S6. The pathological findings of each liver specimen resected were compatible with metastatic adenocarcinoma from the primary gastric cancer. The liver tumors were expansive-growing tumors with capsules and massive necrosis. The patient is currently well with no evidence of recurrence on repeat CT scans, 6 years 6 months since-the initial gastrectomy, and 5 years 10 months since the first hepatic resection.
Assuntos
Adenocarcinoma/secundário , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Neoplasias Gástricas/patologia , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/cirurgia , Gastrectomia , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/cirurgia , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVES: 1) To determine if endothelial expression of adhesion molecules involved in leukocyte recruitment is increased in the brain and other organs in four different models of experimental colitis, and 2) to investigate whether leukocyte infiltration occurs in the brain of colitic animals. METHODS: Endothelial vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression was quantified, using the dual radiolabeled antibody technique in rats with trinitrobenzenesulfonic acid (TNBS)-induced colitis, in mice with dextran sulfate sodium (DSS)-induced colitis, in SCID mice reconstituted with CD45RBhigh T-cells, and in IL-10-/- mice. Leukocyte infiltration in the brain of TNBS-induced colitic rats was assessed by myeloperoxidase activity and immunohistochemical staining with anti-CD45 monoclonal antibody. RESULTS: Marked upregulation of brain endothelial VCAM-1 (2- to 5.5-fold) was consistently found in colitic animals in the four models studied. Brain VCAM-1 strongly correlated with colon VCAM-1 and colon weight. By contrast, upregulation of brain ICAM-1 in colitic animals was only observed in the CD45RBhigh transfer (3-fold) and the TNBS-induced (1.5-fold models). Heart and muscle VCAM-1 and ICAM-1 were not upregulated in colitic animals in the majority of models studied. There was no leukocyte infiltration into the brain of TNBS-induced colitic rats. CONCLUSIONS: Our study demonstrates a marked and specific upregulation of endothelial VCAM-1 in the brain of colitic animals. This activation of cerebral endothelial cells was not associated with an infiltration of leukocytes into brain tissue.
Assuntos
Encéfalo/metabolismo , Colite/metabolismo , Endotélio Vascular/metabolismo , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão de Célula Vascular/biossíntese , Animais , Barreira Hematoencefálica , Encéfalo/irrigação sanguínea , Encefalite/metabolismo , Masculino , Camundongos , Camundongos SCID , Ratos , Ratos Sprague-DawleyRESUMO
Inflammatory bowel disease (IBD) is associated with Th1/Th2 cytokine dysregulation, leukocyte extravasation, and tissue edema, but the mechanisms for cytokine-mediated vascular dysfunction are not understood. To investigate how cytokines might control edema in IBD, we determined vascular permeability and IFN-gamma expression in two models of murine colitis: SCID mice reconstituted with CD45RB(high T-lymphocytes (CD45RB(high)/SCID mice), and interleukin-10 gene deficient (IL-10(-/-)) mice. We also investigated the in vitro effects of IFN-gamma and IL-10 on human endothelial solute barrier and junction protein expression. Vascular permeability in CD45RB(high)/SCID and IL-10(-/-) mice was quantified using tissue (131)I-IgG accumulation. The IFN-gamma message was quantified using the ribonuclease protection assay. Endothelial barrier integrity in vitro was measured by transmonolayer electrical resistance, and junctional proteins were examined by immunoblotting and fluorescence microscopy. Both CD45RB(high)/SCID and IL-10(-/-) mice exhibit enhanced colonic microvascular leakage and IFN-gamma message levels compared to their respective controls. In vitro, IFN-gamma also reduced endothelial barrier (monolayer electrical resistance, increased albumin permeability) and reduced tight junction (occludin) expression and staining. These effects were reversed by pretreatment of monolayers with IL-10. Therefore, in vivo IFN-gamma and IL-10 may modulate microvascular leakage in IBD partly by controlling the expression of intestinal endothelial tight junctional proteins.