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1.
Crit Care Med ; 39(1): 126-34, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20890188

RESUMO

OBJECTIVE: Mortality in sepsis remains high and efforts to modulate the inflammatory response so far mostly failed to improve survival. The human chorionic gonadotropin-related tetrapeptide LQGV was recently shown to exert anti-inflammatory activity. The aim of this study was to assess the effect of LQGV on cecal ligation and puncture-induced mortality and inflammation. DESIGN: Animal study. SETTING: University research laboratory. SUBJECTS: Male C57BL/6 mice. INTERVENTIONS: To examine the effect of LQGV by itself on cecal ligation and puncture-induced mortality and inflammation, C57BL/6 mice were exposed to a moderate cecal ligation and puncture procedure (40% ligation and double puncture) with a mortality rate of approximately 80% within 5 days in control mice. In addition, to examine whether LQGV was of additive value to standard sepsis care (antibiotics and fluid resuscitation), a more severe cecal ligation and puncture procedure was used (80% ligation and double puncture), yielding approximately 100% mortality within 12 days in control mice. LQGV (5 mg/kg body weight), phosphate-buffered saline (as control), or dexamethasone (2.5 mg/kg body weight) was administered perioperatively. Survival was monitored for 21 days and inflammatory markers were determined in plasma, peritoneal cavity, and lungs. MEASUREMENTS AND MAIN RESULTS: LQGV significantly improved survival from 20% to 50% during the first 5 days after moderate cecal ligation and puncture. This was associated with reduced cytokine and E-selectin levels in peritoneal lavage fluid, lungs, and, to a lesser extent, in plasma. LQGV treatment also reduced pulmonary nuclear factor-κB activation and pulmonary damage. In the severe cecal ligation and puncture model, LQGV combined with fluid resuscitation and antibiotics resulted in significantly better survival (70%) than that observed with fluid resuscitation and antibiotics alone (30%). CONCLUSIONS: LQGV improves survival after cecal ligation and puncture. This is likely established by a modest reduction of the acute inflammatory response through a nuclear factor-κB-dependent mechanism. Furthermore, LQGV may be a valuable additive next to the standard care in polymicrobial sepsis.


Assuntos
Gonadotropina Coriônica Humana Subunidade beta/farmacologia , Dexametasona/farmacologia , Imunidade Inata/imunologia , Sepse/tratamento farmacológico , Sepse/mortalidade , Animais , Ceco/cirurgia , Citocinas/análise , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica , Ligadura/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Lavagem Peritoneal , RNA Bacteriano/análise , Distribuição Aleatória , Valores de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sepse/imunologia , Sepse/microbiologia , Estatísticas não Paramétricas , Taxa de Sobrevida , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/microbiologia , Síndrome de Resposta Inflamatória Sistêmica/mortalidade
2.
Am J Physiol Gastrointest Liver Physiol ; 298(2): G177-81, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19940028

RESUMO

Plasma clearance of D-sorbitol, a nontoxic polyol, occurs predominantly in the liver and has been used to measure functional liver blood flow after bolus and steady- state intravenous administration. However, it is not known which of these two administration methods is superior. Therefore, plasma D-sorbitol clearance was studied in an animal model both after a bolus dose and under steady-state (SS) conditions and compared directly with liver blood flow, under normal conditions, and after the induction of endotoxin (LPS) sepsis. Adult male Wistar rats (526 +/- 38 g body wt; n = 27) were anesthetized and mechanically ventilated. Hemodynamics, hepatic arterial flow, and portal venous flow were measured. Two groups were studied, namely healthy animals that served as controls and a sepsis group that received 5 mg/kg LPS intravenously (Escherichia coli O127:B8). Each animal received either a SS infusion (0.1 mg/100 g body wt per min) or a bolus (3 mg/100 g body wt) of a 5% D-sorbitol solution intravenously in a randomized order. After the initial measurements and a 60-min pause time in between (T(1/2,sorbitol) = 9 min), a crossover was done. The hepatic clearance of D-sorbitol in the control group showed a good correlation between bolus and SS (Spearman's r = 0.7681, P = 0.0004), and both techniques correlated well with total liver blood flow (TLBF) (r = 0.7239, P = 0.0023 and r = 0.7226, P = 0.0023, respectively). Also in the sepsis group there was a good correlation between bolus and SS sorbitol clearance (r = 0.6655, P = 0.0182). In the sepsis group, only the SS clearance correlated with TLBF (r = 0.6434, P = 0.024). In conclusion, in normal and under septic conditions, hepatic clearance of D-sorbitol either by bolus or a SS infusion is comparable. In healthy animals, this also correlated well with TLBF but not in septic conditions. However, this is expected because of the changes in the liver microcirculation, shunting, and decreased hepatocyte function in sepsis.


Assuntos
Circulação Hepática/fisiologia , Fígado/irrigação sanguínea , Fígado/metabolismo , Sepse/fisiopatologia , Sorbitol/farmacocinética , Animais , Modelos Animais de Doenças , Injeções Intravenosas , Lipopolissacarídeos/farmacologia , Fígado/diagnóstico por imagem , Masculino , Taxa de Depuração Metabólica , Microcirculação/fisiologia , Ratos , Ratos Wistar , Sepse/induzido quimicamente , Sepse/metabolismo , Sorbitol/sangue , Ultrassonografia Doppler
3.
Shock ; 31(3): 285-91, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18654091

RESUMO

Severe hemorrhagic shock (HS) followed by resuscitation induces a massive inflammatory response, which may culminate into systemic inflammatory response syndrome, multiple organ dysfunction syndrome, and, finally, death. Treatments that effectively prevent this inflammation are limited so far. In a previous study, we demonstrated that synthetic oligopeptides related to the primary structure of human chorionic gonadotropin (HCG) can inhibit the inflammatory response and mortality that follow high-dose LPS-induced inflammation. Considering this powerful anti-inflammatory effect, we investigated whether administration of similar synthetic HCG-related oligopeptides (LQGV, AQGV, LAGV) during HS were able to attenuate the inflammatory response associated with this condition. Hemorrhagic shock was induced in rats for 60 min by blood withdrawal until a MAP of 40 mmHg was reached. Rats received a single injection with one of the hCG-related oligopeptides (LQGV, AQGV or LAGV) or 0.9% NaCl solution as control 30 min after induction of HS. Treatment with LQGV, AQGV, or LAGV prevented systemic release of TNF-[alpha] and IL-6 and was associated with reduced TNF-[alpha], IL-6, and E-selectin mRNA transcript levels in the liver. LQGV treatment prevented neutrophil infiltration into the liver and was associated with reduced liver damage. Our data suggest that HCG-related oligopeptides, in particular LQGV, have therapeutic potential by attenuating the life-threatening inflammation and organ damage that is associated with (trauma) HS and resuscitation.


Assuntos
Gonadotropina Coriônica/farmacologia , Hepatopatias/tratamento farmacológico , Oligopeptídeos/farmacologia , Ressuscitação , Choque Hemorrágico/tratamento farmacológico , Ferimentos e Lesões/tratamento farmacológico , Animais , Selectina E/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Fígado/lesões , Fígado/metabolismo , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Choque Hemorrágico/complicações , Choque Hemorrágico/metabolismo , Choque Hemorrágico/patologia , Fator de Necrose Tumoral alfa/metabolismo , Ferimentos e Lesões/complicações , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologia
4.
Am J Transplant ; 5(5): 987-94, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15816878

RESUMO

In mycophenolate mofetil (MMF)-treated organ transplant recipients, lower mycophenolic acid (MPA) plasma concentrations have been found in cyclosporine (CsA) compared with tacrolimus (Tac)-based immunosuppressive regimens. We previously demonstrated that CsA decreases exposure to MPA and increases exposure to its metabolite MPA-glucuronide (MPAG), possibly by interfering with the biliary excretion of MPAG. To elucidate the role of the multidrug resistance-associated protein (Mrp)-2 in the interaction between MMF and CsA, we treated three groups of 10 Mrp2-deficient rats (TR- rat) for 6 days with either vehicle, CsA (8 mg/kg) or Tac (4 mg/kg) by oral gavage. Hereafter, co-administration with MMF (20 mg/kg) was started in all groups and continued through day 14. The 24-h MPA/MPAG area under the concentration-time curve (AUC) was determined after single (day 7) and multiple MMF doses (day 14). On both study days, there were no significant differences in the mean MPA and MPAG AUC between CsA and Tac-treated animals. We conclude that the pharmacokinetics of MMF are comparable in Mrp2-deficient rats receiving either CsA or Tac as co-medication. This finding suggests that CsA-mediated inhibition of the biliary excretion of MPAG by the Mrp2 transporter is the mechanism responsible for the interaction between CsA and MMF.


Assuntos
Ciclosporina/farmacocinética , Sinergismo Farmacológico , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacocinética , Animais , Área Sob a Curva , Bilirrubina/sangue , Ácido Edético/farmacologia , Glucuronídeos/química , Rejeição de Enxerto , Imunossupressores/farmacologia , Masculino , Proteína 2 Associada à Farmacorresistência Múltipla , Ácido Micofenólico/farmacologia , Transplante de Órgãos , Placebos , Ratos , Ratos Wistar , Tacrolimo/farmacologia , Fatores de Tempo
5.
Transpl Int ; 15(12): 595-601, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12478405

RESUMO

Currently, xenogeneic extracorporeal liver perfusion is used in the treatment of acute liver failure. In order to determine whether transgeneity for human regulatory proteins could improve the functional outcome of the ex-vivo liver in relation to the histopathological changes, we studied the effect of the humoral mechanism in xenogeneic isolated rat liver perfusion in normal and transgenic rat livers. Isolated rat liver perfusion was performed for 2 h in normal rat livers with Krebs Henseleit (KH) and human serum (HS), and in livers transgenic for human decay accelerating factor (hDAF; Tg HS). Function of the liver was established by measurement of liver enzymes and bile production, and clearance of bromosulphophthalein (BSP). Tissue specimens taken after perfusion were analysed by routine histology and immunofluorescence staining for C3c deposition. No change in release of liver enzymes could be established throughout the perfusion period. In the 2nd hour, a higher level of bile production was seen for the transgenic group than for the HS group. The transgenic rat livers outperformed the normal livers perfused with HS, when BSP concentration in the bile was measured; however, clearance of BSP from the perfusate was not significantly different. Haematoxylin-eosin (HE) staining of the liver tissue showed evidence of hyperacute rejection in the HS group. There was only mild tissue injury in the transgenic liver. High-intensity fluorescent staining for C3c deposition was seen in the normal livers perfused with HS, and significantly less in the transgenic livers. Although histologically less tissue damage and less C3c deposition was shown, no significantly improved function of the livers transgenic for hDAF was established. These results suggest that for short-term extracorporeal liver perfusion transgenesis offers no functional benefit.


Assuntos
Antígenos CD55/genética , Fígado/fisiologia , Animais , Animais Geneticamente Modificados , Antígenos CD/genética , Fenômenos Fisiológicos Sanguíneos , Transfusão de Sangue , Humanos , Fígado/patologia , Masculino , Perfusão/efeitos adversos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Transplante Heterólogo
6.
Ann Surg ; 237(1): 123-8, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12496539

RESUMO

OBJECTIVE: To assess whether use of antiadhesive liquids or coatings could prevent adhesion formation to prosthetic mesh. SUMMARY BACKGROUND DATA: Incisional hernia repair frequently involves the use of prosthetic mesh. However, concern exists about development of adhesions between viscera and the mesh, predisposing to intestinal obstruction or enterocutaneous fistulas. METHODS: In 91 rats, a defect in the muscular abdominal wall was created, and mesh was fixed intraperitoneally to cover the defect. Rats were divided in five groups: polypropylene mesh only (control group), addition of Sepracoat or Icodextrin solution to polypropylene mesh, Sepramesh (polypropylene mesh with Seprafilm coating), and Parietex composite mesh (polyester mesh with collagen coating). Seven and 30 days postoperatively, adhesions were assessed and wound healing was studied by microscopy. RESULTS: Intraperitoneal placement of polypropylene mesh was followed by bowel adhesions to the mesh in 50% of the cases. A mean of 74% of the mesh surface was covered by adhesions after 7 days, and 48% after 30 days. Administration of Sepracoat or Icodextrin solution had no influence on adhesion formation. Coated meshes (Sepramesh and Parietex composite mesh) had no bowel adhesions. Sepramesh was associated with a significant reduction of the mesh surface covered by adhesions after 7 and 30 days. Infection was more prevalent with Parietex composite mesh, with concurrent increased mesh surface covered by adhesions after 30 days (78%). CONCLUSIONS: Sepramesh significantly reduced mesh surface covered by adhesions and prevented bowel adhesion to the mesh. Parietex composite mesh prevented bowel adhesions as well but increased infection rates in the current model.


Assuntos
Materiais Biocompatíveis/farmacologia , Glucanos/farmacologia , Glucose/farmacologia , Hérnia Ventral/cirurgia , Telas Cirúrgicas , Aderências Teciduais/prevenção & controle , Animais , Materiais Revestidos Biocompatíveis , Modelos Animais de Doenças , Ácido Hialurônico , Icodextrina , Intestino Grosso/patologia , Intestino Delgado/patologia , Masculino , Polipropilenos , Complicações Pós-Operatórias/prevenção & controle , Probabilidade , Ratos , Ratos Wistar , Valores de Referência , Sensibilidade e Especificidade , Resultado do Tratamento
7.
Ann Surg ; 237(3): 351-7, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12616118

RESUMO

OBJECTIVE: To investigate the long-term impact of pneumoperitoneum used for laparoscopic donor nephrectomy on renal function and histomorphology in donor and recipient. SUMMARY BACKGROUND DATA: Laparoscopic donor nephrectomy has the potential to increase the number of living kidney donations by reducing donor morbidity. However, function of laparoscopically procured kidneys might be at risk due to ischemia as a consequence of elevated intra-abdominal pressure during laparoscopy. METHODS: In experiment 1, 30 Brown Norway rats were randomized to three procedures: 2 hours of CO2 insufflation, 2 hours of helium insufflation, and 2 hours of gasless laparoscopy. After this, a unilateral nephrectomy was performed in all animals. Another six rats were used as controls. In experiment 2, 36 donor Brown Norway rats were subjected to a similar insufflation protocol, but after nephrectomy a syngeneic renal transplantation was performed. All rats had a follow-up period of 12 months. Urine and blood samples were collected each month for determination of renal function. After 1 year, donor and recipient kidneys were removed for histomorphologic and immunohistochemical analysis. RESULTS: In donors as well as in recipients, no significant changes in serum creatinine, proteinuria, or glomerular filtration rate were detected between the CO2, the helium, and the gasless control group after 1 year. No histologic abnormalities due to abdominal gas insufflation were found. Immunohistochemical analysis did not show significant differences in the number of infiltrating cells (CD4, CD8, ED1, OX62, and OX6) and adhesion molecule expression (ICAM-1) between the three groups. CONCLUSIONS: Abdominal gas insufflation does not impair renal function in the donor 1 year after LDN. One year after transplantation, no differences in renal function or histomorphology were detected between kidney grafts exposed to either pneumoperitoneum or a gasless procedure.


Assuntos
Transplante de Rim/fisiologia , Rim/fisiologia , Laparoscopia , Nefrectomia , Pneumoperitônio Artificial , Coleta de Tecidos e Órgãos , Animais , Dióxido de Carbono , Creatinina/sangue , Hélio , Imuno-Histoquímica , Molécula 1 de Adesão Intercelular/análise , Rim/química , Rim/citologia , Masculino , Tamanho do Órgão , Proteinúria , Ratos , Ratos Endogâmicos BN , Doadores de Tecidos , Urina
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