RESUMO
Transgenic mice that over-express B cell leukemia/lymphomas (Bcl)-2 in myeloid cells under control of the human MRP8 promoter (hMRP8-Bcl-2) or in T lymphocytes under the E micro promoter (E micro -Bcl-2) were compared with C57BL/6 control mice following cecal ligation and puncture (CLP). There was a significant difference in outcome between the hMRP8-Bcl-2 and control mice with 100% survival in the hMRP8-Bcl-2 mice vs 25% survival in the control mice. In separate experiments there was a significant difference between E micro -Bcl-2 and control mice with 87.5 and 22.2% survival, respectively. Adoptive transfer of CD11b-positive bone marrow cells from hMRP8-Bcl-2 or C57BL/6 mice to C57BL/6 mice subjected to CLP resulted in 100 and 0% survival, respectively. Adoptive transfer of CD11b-positive cells from either hMRP8-Bcl-2 or C57BL/6 mice to Rag-1(-/-) mice (no mature T or B cells) subjected to CLP resulted in survival of 87.5 and 12.5%, respectively. The hMRP8-Bcl-2 mice had significantly more neutrophils and fewer bacteria in the peritoneum compared with C57BL/6 mice 24 h after CLP. These experiments show that Bcl-2 over-expression is protective in CLP and that protection is independent of lymphocytes. We propose that over-expression of Bcl-2 in T cells or myeloid cells induce release of a molecule(s) that protects against death following CLP.
Assuntos
Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sepse/genética , Sepse/prevenção & controle , Transferência Adotiva , Animais , Apoptose/genética , Líquido Ascítico/genética , Líquido Ascítico/microbiologia , Líquido Ascítico/patologia , Líquido Ascítico/prevenção & controle , Transplante de Medula Óssea/imunologia , Antígeno CD11b/biossíntese , Ceco , Contagem de Colônia Microbiana , Citocinas/análise , Proteínas de Homeodomínio/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Contagem de Leucócitos , Ligadura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células Mieloides/metabolismo , Lavagem Peritoneal , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Punções , Sepse/microbiologia , Sepse/patologia , Análise de Sobrevida , Linfócitos T/metabolismoRESUMO
C5a is implicated as a pathogenic factor in a wide range of immunoinflammatory diseases, including sepsis and immune complex disease. Agents that antagonize the effects of C5a could be useful in these diseases. We have developed some novel C5a antagonists and have determined the acute anti-inflammatory properties of a new small molecule C5a receptor antagonist against C5a- and LPS-induced neutrophil adhesion and cytokine expression, as well as against some hallmarks of the reverse Arthus reaction in rats. We found that a single i.v. dose (1 mg/kg) of this antagonist inhibited both C5a- and LPS-induced neutropenia and elevated levels of circulating TNF-alpha, as well as polymorphonuclear leukocyte migration, increased TNF-alpha levels and vascular leakage at the site of immune complex deposition. These results indicate potent anti-inflammatory activities of a new C5a receptor antagonist and provide more evidence for a key early role for C5a in sepsis and the reverse Arthus reaction. The results support a role for antagonists of C5a receptors in the therapeutic intervention of immunoinflammatory disease states such as sepsis and immune complex disease.
Assuntos
Reação de Arthus/prevenção & controle , Complemento C5a/antagonistas & inibidores , Proteínas Inativadoras do Complemento/farmacologia , Imunossupressores/farmacologia , Peptídeos Cíclicos/farmacologia , Receptores de Complemento/antagonistas & inibidores , Choque Séptico/prevenção & controle , Animais , Antígenos CD/química , Antígenos CD/metabolismo , Reação de Arthus/imunologia , Líquido Ascítico/imunologia , Líquido Ascítico/prevenção & controle , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Complemento C5a/metabolismo , Proteínas Inativadoras do Complemento/administração & dosagem , Proteínas Inativadoras do Complemento/metabolismo , Feminino , Humanos , Imunossupressores/administração & dosagem , Injeções Intravenosas , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/metabolismo , Ratos , Ratos Wistar , Receptor da Anafilatoxina C5a , Receptores de Complemento/química , Receptores de Complemento/metabolismo , Choque Séptico/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossínteseRESUMO
The matrix metalloproteinase inhibitor batimastat was administered to a human colorectal cancer ascites model, which was initiated by injection of C170HM2 cells into the peritoneal cavity of SCID mice and resulted in solid tumour deposits and ascites formation. The cell line expressed both the 72 and 92 kDa forms of gelatinase by zymography. Batimastat administered from day 0 (40 mg kg-1) reduced the volume of ascites to 21% of control in mice treated from day 0 (P < 0.002) but not day 10. Formation of solid peritoneal deposits was significantly reduced to 77% of vehicle control when batimastat was administered from day 0 (P < 0.01) and 69% of control when administered from day 10 (P < 0.05). Thus, batimastat has the ability to reduce the volume of ascites forming in SCID mice injected intraperitoneally with the human colorectal cell line, C170HM2, when administered from day 0 but not from day 10. Solid peritoneal tumour deposits were significantly reduced in both treatment groups, highlighting the therapeutic potential of batimastat in this clinical condition.
Assuntos
Antineoplásicos/uso terapêutico , Líquido Ascítico/tratamento farmacológico , Neoplasias Colorretais/complicações , Metaloendopeptidases/antagonistas & inibidores , Fenilalanina/análogos & derivados , Tiofenos/uso terapêutico , Animais , Líquido Ascítico/prevenção & controle , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos SCID , Fenilalanina/uso terapêutico , Células Tumorais CultivadasRESUMO
Fifty-four patients with gastrointestinal carcinomas were treated with intraperitoneal chemotherapy through devices, and an implantable port system which had been used subcutaneously. The complications of the implantable ports were analysed in this study. There were 1 bowel perforation, 2 cases of retention of ascites, 2 infections, 2 inflow obstructions and 8 cases of pain, especially in the perineal or lower abdominal area. The number of patients requiring removal of the device due to complications were 7; 1 perforation, 2 ascites, 2 infections and 2 for pain. The strategy for reducing the complications due to the device were analysed as follows. A soft catheter should be selected. The catheter in the abdominal cavity should not be long, not as long as the tip of catheter touch the bottom of pelvic organs. Due care for kinking of the catheter should be taken in the implanting procedure. Antibiotics should be applied in and around the port. Steroids should be added to the solution for intraperitoneal chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Líquido Ascítico/prevenção & controle , Bombas de Infusão Implantáveis/efeitos adversos , Perfuração Intestinal/prevenção & controle , Dor/prevenção & controle , Idoso , Antibacterianos/uso terapêutico , Líquido Ascítico/etiologia , Cisplatino/administração & dosagem , Fluoruracila/administração & dosagem , Neoplasias Gastrointestinais/terapia , Humanos , Infusões Parenterais , Perfuração Intestinal/etiologia , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Dor/etiologiaRESUMO
We examined the distribution of Lipo-CBDCA after intraperitoneal administration and antitumor effects in rats. The serum levels of platinum in Lipo-CBDCA were lower than in free-CBDCA intraperitoneal or intravenous administration at 15 and 30 min. after administration. After 3 hours, Lipo-CBDCA showed higher levels of serum platinum than free-CBDCA. These data showed the slow release of Lipo-CBDCA. The antitumor effects of Lipo-CBDCA were studied in rats with peritoneal dissemination due to AH 130 tumors. Intraperitoneal treatment with Lipo-CBDCA prolonged the life span significantly compared with Lipo-CBDCA. No side effects of chemotherapy were found in the liver, kidney, spleen or small intestine. A gastric cancer patient suffering from carcinomatous peritonitis with remarkable ascites was treated with Lipo-CBDCA intraperitoneally. After several injections of Lipo-CBDCA, the ascites disappeared completely and the CEA level of ascites decreased dramatically. These results indicate that intraperitoneal chemotherapy with Lipo-CBDCA may be more effective than free-CBDCA to manage carcinomatous peritonitis, and may be therapeutically useful without toxic side effects.
Assuntos
Antineoplásicos/administração & dosagem , Carboplatina/administração & dosagem , Peritonite/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Líquido Ascítico/tratamento farmacológico , Líquido Ascítico/etiologia , Líquido Ascítico/prevenção & controle , Carboplatina/farmacocinética , Portadores de Fármacos , Humanos , Infusões Parenterais , Lipossomos , Masculino , Pessoa de Meia-Idade , Peritonite/etiologia , Peritonite/prevenção & controle , Ratos , Neoplasias Gástricas/complicaçõesAssuntos
Líquido Ascítico/prevenção & controle , Clostridioides difficile/isolamento & purificação , Infecções por Clostridium/etiologia , Enterocolite Pseudomembranosa/etiologia , Norfloxacino/efeitos adversos , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/microbiologia , Enterocolite Pseudomembranosa/tratamento farmacológico , Enterocolite Pseudomembranosa/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Norfloxacino/uso terapêutico , Vancomicina/uso terapêuticoRESUMO
The glycoprotein processing inhibitor castanospermine (CS) and the monosaccharide mannose-6-phosphate (M6P), as well as some sulfated polysaccharides (SPS), have been shown to inhibit inflammation in rat models of experimental autoimmune encephalomyelitis and adjuvant-induced arthritis. Here, the anti-inflammatory effects of these agents have been further explored in murine models of allograft rejection and elicitation of peritoneal exudates. CS, M6P and the SPS, fucoidan, partially inhibited rejection of permanently accepted thyroid allografts induced by the i.p. injection of donor strain (H-2d) spleen cells with a reduction in leucocyte infiltration of 25-36%. However none of these agents reduced the more extensive leucocyte infiltration induced by the i.p. injection of P815 (H-2d) unless recipient mice were pretreated with the immunosuppressant, cyclosporin A (CsA). Elicitation of peritoneal exudates by thioglycollate was inhibited by CS, M6P and fucoidan with sustained leucopenia being induced by CS. In contrast, CS and fucoidan, but not M6P, inhibited antigen-elicited peritoneal exudates. These results suggest that CS, M6P and the SPS fucoidan exhibit subtle differences in their anti-inflammatory activity but probably inhibit inflammation at the level of leucocyte extravasation.
Assuntos
Líquido Ascítico/prevenção & controle , Glucosidases/antagonistas & inibidores , Rejeição de Enxerto/prevenção & controle , Indolizinas/farmacologia , Manosefosfatos/farmacologia , Polissacarídeos/farmacologia , Glândula Tireoide/transplante , Animais , Líquido Ascítico/induzido quimicamente , Quimiotaxia de Leucócito/efeitos dos fármacos , Ciclosporina/farmacologia , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Modelos Biológicos , Transplante de Neoplasias , Organismos Livres de Patógenos Específicos , Tioglicolatos/toxicidade , Glândula Tireoide/patologia , Transplante HomólogoAssuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas/prevenção & controle , Descontaminação/métodos , Doenças do Sistema Digestório/prevenção & controle , Cirrose Hepática/complicações , Líquido Ascítico/etiologia , Líquido Ascítico/microbiologia , Líquido Ascítico/prevenção & controle , Infecções Bacterianas/etiologia , Doenças do Sistema Digestório/etiologia , Doenças do Sistema Digestório/microbiologia , Infecções por Enterobacteriaceae/etiologia , Infecções por Enterobacteriaceae/prevenção & controle , Hemorragia Gastrointestinal/complicações , Humanos , Transplante de Fígado/efeitos adversos , Norfloxacino/uso terapêuticoAssuntos
Líquido Ascítico/complicações , Cirrose Hepática/complicações , Peritonite/etiologia , Antibacterianos , Líquido Ascítico/microbiologia , Líquido Ascítico/prevenção & controle , Diagnóstico Diferencial , Quimioterapia Combinada/uso terapêutico , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/isolamento & purificação , Humanos , Peritonite/microbiologia , Peritonite/prevenção & controle , Prognóstico , Sepse/etiologiaRESUMO
Systemic endotoxemia has been observed in patients with acute and chronic liver failure, and bacterial endotoxin is known to increase vascular permeability. We investigated in the normal rat the effects of intraportal endotoxin administration and the possible mediation of these effects by platelet-activating factor. Injection of endotoxin lipopolysaccharide (10 and 25 mg per kg) in the rat resulted in rapid ascites formation, as well as systemic hypotension, hemoconcentration and acute erosions of the gastrointestinal mucosa. These effects were significantly attenuated by pretreatment with L652,731 and CF-3988, specific platelet-activating factor antagonists. Administration of 25 mg per kg endotoxin also resulted in significant elevations of platelet-activating factor biosynthesis in vitro by samples of duodenum, liver and lung. The effects of endotoxin were mimicked by intraportal infusion of platelet-activating factor (50 ng per kg per min), which induced ascites and gastrointestinal lesions. Platelet-activating factor reduced circulating plasma volume and increased peritoneal permeability to albumin as assessed by the ascites to plasma ratio of labeled albumin. These results, therefore, support a role for platelet-activating factor in mediating endotoxin-induced ascites and gastrointestinal erosions.
Assuntos
Líquido Ascítico/etiologia , Lipopolissacarídeos/farmacologia , Fator de Ativação de Plaquetas/metabolismo , Salmonella typhi , Animais , Líquido Ascítico/metabolismo , Líquido Ascítico/prevenção & controle , Duodeno/metabolismo , Furanos/farmacologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Hipotensão/etiologia , Hipotensão/prevenção & controle , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Éteres Fosfolipídicos/farmacologia , Fator de Ativação de Plaquetas/antagonistas & inibidores , Fator de Ativação de Plaquetas/biossíntese , Fator de Ativação de Plaquetas/farmacologia , Ratos , Ratos EndogâmicosRESUMO
An intraperitoneal inflammatory exudate has been repeatedly observed in infertile women without mechanical compromise of the pelvic viscera, particularly with endometriosis. This is manifested by increases in the peritoneal fluid volume, leukocyte number, and proteolytic enzyme concentrations. We tested the hypothesis that the stimulus responsible for eliciting this intraperitoneal inflammation is retrograde menstruation by measuring the peritoneal fluid volume and leukocyte count in 16 infertile women with endometriosis before and after ovulation suppression with medroxyprogesterone acetate, 30 mg/day for 4 months. Medroxyprogesterone acetate therapy significantly reduced the peritoneal fluid volume (22.5 +/- 4.1 versus 6.8 +/- 0.9 ml mean +/- SE, p less than 0.0001), the peritoneal fluid leukocyte count (30.7 +/- 6.5 versus 7.1 +/- 0.7 x 10(6) cells per patient, p less than 0.0001), and American Fertility Society score (23.2 +/- 5.1 versus 15.4 +/- 4.1, p less than 0.0002). We conclude that medroxyprogesterone acetate treatment reduces the intraperitoneal exudate associated with endometriosis. These results support the contention that the stimulus eliciting the intraperitoneal inflammation in infertile women with endometriosis is retrograde menstruation.