RESUMO
BACKGROUND: alpha-Melanocyte stimulating hormone (alpha-MSH) is an endogenous peptide that has remarkable anti-inflammatory and antimicrobial effects. These activities have been traced to the C-terminal tripeptide Lys-Pro-Val (KPV). A dimer composed of two KPV sequences connected with a Cys-Cys linker, (CKPV)2, is currently under clinical investigation for antimicrobial use. The present research was designed to evaluate effects of (CKPV)(2) on endotoxin-induced host reactions in vitro and in vivo. MATERIALS AND METHODS: Effects of (CKPV)2, KPV, and [Nle4-dPhe7]-alpha-MSH (NDP-alpha-MSH) on tumor necrosis factor alpha (TNF-alpha) production were determined: 1) in human peripheral blood mononuclear cells (PBMC) stimulated with lipopolysaccharide (LPS) in vitro, and 2) in rats injected with LPS i.v. and sacrificed at 1 h. In additional experiments, dialysis peritonitis was induced in rats by adding LPS to dialysis fluid. Net ultrafiltrate was calculated and concentrations of nitrite (NO2-) and TNF-alpha were measured in blood and peritoneal fluid at 7 h. RESULTS: (CKPV)2 inhibited TNF-alpha production by LPS-stimulated human PBMC. This small peptide was as effective as NDP-alpha-MSH and more potent than KPV. Similar effectiveness was observed in vivo: 1 h after LPS injection, the large increase in circulating TNF-alpha was markedly reduced by (CKPV)2 treatment. In LPS-induced peritonitis, (CKPV)2 restored net ultrafiltrate to control values and significantly inhibited concentrations of TNF-alpha and NO2- both in plasma and in dialysate. CONCLUSIONS: The remarkable capacity of (CKPV)2 to inhibit endotoxin-induced host reactions suggests that it may be useful in treatment of inflammatory disorders.
Assuntos
Lipopolissacarídeos/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , alfa-MSH/fisiologia , Animais , Técnicas de Cultura de Células , Leucócitos Mononucleares , Óxido Nítrico/análise , Fragmentos de Peptídeos/fisiologia , Diálise Peritoneal , Ratos , Ratos Wistar , alfa-MSH/análogos & derivadosRESUMO
Novel therapies are sought to increase efficiency and survival of transplanted organs. Previous research on experimental heart transplantation showed that treatment with the anti-inflammatory peptide alpha-melanocyte-stimulating hormone (alpha-MSH) prolongs allograft survival. The aim of the present research was to determine the molecular mechanism of this protective activity. Gene expression profile was examined in heart grafts removed on postoperative days 1 and 4 from rats treated with saline or the synthetic alpha-MSH analog Nle4DPhe7 (NDP)-alpha-MSH. On postoperative day 1, the peptide induced expression of cytoskeleton proteins, intracellular kinases, transcription regulators, metallopeptidases, and protease inhibitors. Conversely, NDP-alpha-MSH repressed immune, inflammatory, cell cycle, and protein turnover mediators. Later effects of alpha-MSH treatment included down-regulation of oxidative stress response and up-regulation of ion channels, calcium regulation proteins, phosphatidylinositol signaling system, and glycolipidic metabolism. NDP-alpha-MSH exerted its effects on both Ag-dependent and -independent injury. The results indicate that NDP-alpha-MSH preserves heart function through a broad effect on multiple pathways and suggest that the peptide could improve the outcome of organ transplantation in combination with immunosuppressive treatments.
Assuntos
Perfilação da Expressão Gênica , Transplante de Coração , Miocárdio/metabolismo , alfa-MSH/análogos & derivados , Animais , Cálcio/metabolismo , Masculino , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Homólogo , alfa-MSH/uso terapêuticoRESUMO
A retrospective data analysis on liver transplantation for Wilson's disease (WD) was performed among Italian Liver Transplant Centers. Thirty-seven cases were identified. The main indication for liver transplantation was chronic advanced liver disease in 78% of patients. Mixed hepatic and neuropsychiatric symptoms were recorded in 32.3%. Eight patients presented with fulminant liver failure; 44.8% were on medical treatment. Patient and graft survival at 3 months, 12 months, 3 years, 5 years, and 10 years after transplantation were, respectively, 91.8%, 89.1%, 82.9%, 75.6%, and 58.8%, and 85.3%, 83.0%, 77.1%, 70.3%, and 47.2%. Neurological symptoms significantly improved after orthotopic liver transplantation (OLT), but the survival of patients with mixed hepatic and neuropsychiatric involvement was significantly lower than in patients with liver disease alone (P = 0.04). WD characterized by hepatic involvement alone is a rare but good indication for liver transplantation when specific medical therapy fails. Patients with neuropsychiatric signs have a significantly shorter survival even though liver transplantation has a positive impact on neurological symptoms. In conclusion, a combination of hepatic and neuropsychiatric conditions deserves careful neurological evaluation, which should contraindicate OLT in case of severe neurological impairment.
Assuntos
Degeneração Hepatolenticular/cirurgia , Transplante de Fígado , Transtornos Mentais/etiologia , Doenças do Sistema Nervoso/etiologia , Adulto , Feminino , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/mortalidade , Humanos , Transplante de Fígado/mortalidade , Masculino , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
Recurrence of hepatitis B impairs the outcome of liver transplantation (OLT). In serum hepatitis B virus (HBV)-DNA-positive recipients, prophylaxis using lamivudine and immunoglobulins (HBIg) reduces the risk of recurrence, but it is undefined whether this regimen also protects candidates with YMDD mutants. Seventeen OLT viraemic candidates received pre-emptive lamivudine followed by post-OLT prophylaxis with lamivudine and HBIg. Both sera and liver biopsies were prospectively collected and high-sensitive polymerase chain reaction (PCR) assay was applied for HBV-DNA detection. Finally, the presence of YMDD mutants was explored in all PCR-positive samples. All patients remained hepatitis B recurrence-free after a mean follow up of 32 months. By PCR, serum HBV-DNA was detectable in 64.3% of cases at OLT-baseline, in 64.7% under combined prophylaxis and in 58.8% in patients (70.5% of the total) with a minimum follow up of 24 months. At OLT-baseline, YMDD mutants were found in 44.4% of patients. After OLT, mutants were present in 50% of patients but only in 16.6% of cases in the long period. Although 41% of the native livers and 42.8% of the analysed grafts harboured HBV-DNA, YMDD mutants were detected in 57% of the native positive livers. YMDD mutants were largely detected both at OLT-baseline and post-OLT, but their presence decreased over time. Regardless of the presence of YMDD mutants, no hepatitis B recurrence was observed in our OLT recipients using pre-emptive lamivudine followed by continuous prophylaxis with lamivudine and HBIg.
Assuntos
Antivirais/administração & dosagem , Hepatite B/prevenção & controle , Transplante de Fígado/efeitos adversos , Adulto , DNA Viral/sangue , DNA Viral/genética , Farmacorresistência Viral/genética , Quimioterapia Combinada , Hepatite B/etiologia , Hepatite B/virologia , Anticorpos Anti-Hepatite B/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Humanos , Imunossupressores/uso terapêutico , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , RecidivaAssuntos
Colangite Esclerosante/complicações , Histiocitose de Células de Langerhans/complicações , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/cirurgia , Transplante de Fígado/métodos , Adulto , Biópsia por Agulha , Colangite Esclerosante/patologia , Colangite Esclerosante/cirurgia , Feminino , Seguimentos , Histiocitose de Células de Langerhans/patologia , Humanos , Imuno-Histoquímica , Falência Hepática Aguda/patologia , Medição de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION: Hemolytic-uremic syndrome (HUS) is a rare complication in organ transplantation, characterized by hemolytic microangiopathic anemia, thrombocytopenia, and severe renal failure. The syndrome is a well-recognized complication in bone marrow transplantation, and has been likewise described in several cases of solid organs transplantation, but never in patients receiving combined liver and kidney transplantation. CASE REPORT: We describe a case of HUS in a 59-year-old woman who underwent combined liver-kidney transplantation for hepato-renal polycystic disease. Clinical and laboratory manifestations of the syndrome were severe and included renal failure, hemolytic anemia, severe thrombocytopenia, hypertension, and neurological damage. The initial treatment consisted of withdrawal of cyclosporine, introduction of low-dose tacrolimus, and administration of fresh frozen plasma (FFP) transfusion and heparin. Since there was no improvement in clinical or biochemical features, plasmapheresis with FFP replacement (2000 mL/day) followed by intravenous immunoglobulin (0.4 mg/Kg/day) was started. A rapid improvement in renal function, platelet count, and hemolytic anemia was observed. CONCLUSIONS: Based on the good response observed in our patient, we feel that an aggressive treatment with plasmapheresis and intravenous immunoglobulin should be offered to organ transplant recipients with severe HUS.
Assuntos
Síndrome Hemolítico-Urêmica/terapia , Imunoglobulinas Intravenosas/administração & dosagem , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Plasmaferese/métodos , Terapia Combinada , Feminino , Seguimentos , Síndrome Hemolítico-Urêmica/etiologia , Humanos , Testes de Função Renal , Transplante de Rim/métodos , Transplante de Fígado/métodos , Pessoa de Meia-Idade , Medição de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: With the increasing need for organ transplantation and the use of "marginal" organs, novel approaches are sought to increase the efficiency and survival of transplanted tissue. We tested the idea that treatment with the anti-inflammatory peptide, alpha-melanocyte-stimulating hormone (alpha-MSH), an endogenous hormone that does not cause marked immunosuppression but does reduce reperfusion injury, may protect allografts and prolong their survival. METHODS: Donor cardiac grafts (Brown Norway) were transplanted heterotopically into the abdomen of recipient (Lewis) rats. Treatments consisted of intraperitoneal injections of Nle DPhe -alpha-MSH (NDP-alpha-MSH) or saline from the time of transplantation until sacrifice or spontaneous rejection. Allografts were removed on day 1, day 4, or at the time of rejection and examined for histopathology and expression of molecules prominent in reperfusion injury, transplant rejection, and apoptosis. RESULTS: NDP-alpha-MSH treatment caused a significant increase in allograft survival and a marked decrease in leukocyte infiltration. Expression of molecules such as endothelin 1, chemokines, and adhesion molecules, which are involved in allograft rejection, was significantly inhibited in NDP-alpha-MSH-treated rats. CONCLUSIONS: The results indicate that protection of the allograft from early injury with alpha-MSH can postpone rejection. Addition of this early protection with the peptide to usual treatment with immunosuppressive agents may, therefore, improve success of organ transplants.