RESUMO
PURPOSE: Hematopoietic progenitor cell transplantation (HSCT) is a procedure used in different hematological diseases as part of the curative treatment, so the investigators propose a system of conditioning of reduced intensity based on total lymphoid irradiation (TLI) as an alternative to the classic total body irradiation (TBI) followed by haploidentical transplantation in patients compatible with a single HLA haplotype, as an alternative to patients who do not have an HLA compatible donor. MATERIALS AND METHODS: A cohort of 25 patients with hematological disease underwent haploidentical HSCT from February 2015 to May 2018, conditioned with TLI from day - 10 (2-4 days of treatment) followed by thiotepa (5 mg/kg/12 h) and melphalan (70 mg/m2/day) prior to HSCT and prophylaxis with ciclosporin (1.5 mg/kg/12 h). 2 Gy/fraction was administered to complete 8 Gy with IMRT and VMAT technique. RESULTS: 12% rejection of the transplant was obtained with acute GVHD < II (48%) and chronic GVHD 12%. No acute toxicity was recorded in irradiated patients and 56% survival of patients at the end of follow-up. CONCLUSION: Conditioning the haploidentical transplant with TLI, IMRT, and VMAT techniques compared with TBI and RT3D-C techniques is a feasible technique that helps inducing the necessary immunosuppression in patients with a high risk of graft rejection, minimal adverse effects, low incidence of GVHD, and high survival rate.
Assuntos
Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Irradiação Linfática , Condicionamento Pré-Transplante , Adolescente , Antibioticoprofilaxia , Criança , Pré-Escolar , Ciclosporina/uso terapêutico , Fracionamento da Dose de Radiação , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doenças Hematológicas/radioterapia , Humanos , Masculino , Agonistas Mieloablativos/uso terapêutico , Transplante Haploidêntico , Resultado do TratamentoRESUMO
Previous studies have shown that cyclic peptides corresponding to residues 35 to 52 of the Limulus antilipopolysaccharide (anti-LPS) factor (LALF) bind and neutralize LPS-mediated in vitro and in vivo activities. Therapeutic approaches based on agents which bind and neutralize LPS activities are particularly attractive because these substances directly block the primary stimulus for the entire proinflammatory cytokine cascade. Here we describe new activities of the LALF(31-52) peptide, other than its LPS binding ability. Surprisingly, supernatants from human mononuclear cells stimulated with the LALF peptide are able to induce in vitro antiviral effects on the Hep-2 cell line mediated by gamma interferon (IFN-gamma) and IFN-alpha. Analysis of the effect of LALF(31-52) on tumor necrosis factor (TNF) and nitric oxide (NO) production by LPS-stimulated peritoneal macrophages revealed that a pretreatment with the peptide decreased LPS-induced TNF production but did not affect NO generation. This indicates that the LALF peptide modifies the LPS-induced response. In a model in mice with peritoneal fulminating sepsis, LALF(31-52) protected the mice when administered prophylactically, and this effect is related to reduced systemic TNF-alpha levels. This study demonstrates, for the first time, the anti-inflammatory properties of the LALF-derived peptide. These properties widen the spectrum of the therapeutic potential for this LALF-derived peptide and the molecules derived from it. These agents may be useful in the prophylaxis and therapy of viral and bacterial infectious diseases, as well as for septic shock.
Assuntos
Anti-Infecciosos/imunologia , Caranguejos Ferradura/imunologia , Hormônios de Invertebrado/imunologia , Lipopolissacarídeos/imunologia , Peptídeos/imunologia , Animais , Anti-Infecciosos/química , Peptídeos Catiônicos Antimicrobianos , Proteínas de Artrópodes , Humanos , Hormônios de Invertebrado/química , CamundongosRESUMO
BACKGROUND: Heparin and heparin derivatives with low anticoagulant activity exhibit a wide spectrum of biological functions affecting adhesion, activation and trafficking of leukocytes. METHODS: We investigated the in vitro effect of heparin and a low molecular weight heparin derivative (LMWH) on nitric oxide (NO) production by human polymorphonuclear leukocytes (PMN). RESULTS: N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated NO production was significantly decreased by heparin at doses of 0.5 and 5 micrograms/mL, while LMWH was only effective at doses of 50 and 200 micrograms/mL by means of a mechanism not related to NO synthase (NOS) activity. CONCLUSIONS: These results support the hypothesis that heparin and LMWH derivatives may offer therapeutic benefit for inflammatory diseases where NO plays a protagonic role.
Assuntos
Heparina de Baixo Peso Molecular/farmacologia , Heparina/farmacologia , Neutrófilos/metabolismo , Óxido Nítrico/biossíntese , Humanos , Metemoglobina/metabolismo , N-Formilmetionina Leucil-Fenilalanina/farmacologiaRESUMO
We studied the role of advanced glycosylation end products on the induction of nitric oxide synthase in peritoneal mouse macrophages previously exposed to modified BSA. A dose-dependent increment in the nitric oxide production induced by LPS and IFN-gamma was observed when cell cultures were pretreated with modified BSA for 48 hours. In addition, the up regulation of nitric oxide production was also time-dependent, being maximal at 24-48 hours. Experiments carried out in the presence of neutralizing antibodies to IL-1 and TNF-alpha, suggested that up regulation was not due to the capacity of modified BSA to induce both proinflammatory signals. The up regulation of nitric oxide production was paralleled with an increase in iNOS mRNA.
Assuntos
Produtos Finais de Glicação Avançada/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Óxido Nítrico Sintase/biossíntese , Animais , Indução Enzimática , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/enzimologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: Because surgery involving cardiopulmonary bypass induces a systemic inflammatory response, the effect of cardiopulmonary bypass on nitric oxide (NO) generation was investigated in human lung tissue. METHODS: Nitric oxide synthase (NOS) activity was measured by the conversion of 14C-L-arginine to 14C-L-citrulline in tissue biopsy samples obtained before and after cardiopulmonary bypass. RESULTS: The Ca(2+)-independent production of NO found before cardiopulmonary bypass was extremely low (1.5 (0.5) pmol citrulline/mg/min), but was increased after the bypass operation (23.6 (11) pmol/mg/min). CONCLUSIONS: Ca(2+)-independent NOS activity was detected in human lung after cardiopulmonary bypass. This finding may provide an important insight into the pathogenesis of the tissue damage and acute phase response observed after such surgery.
Assuntos
Aminoácido Oxirredutases/análise , Ponte Cardiopulmonar , Pulmão/enzimologia , Aminoácido Oxirredutases/biossíntese , Arginina/metabolismo , Cálcio/metabolismo , Citrulina/metabolismo , Cardiopatias/enzimologia , Cardiopatias/cirurgia , Humanos , Óxido Nítrico Sintase , Período Pós-OperatórioRESUMO
We evaluated the effect of monocyte chemotactic protein-1 (MCP-1) on the induction of nitric oxide synthase activity in J774 cells. MCP-1 was able to inhibit the production of nitric oxide induced by LPS and IFN-gamma in a dose-dependent manner. Moreover, the inhibition was only achieved when the cells were pretreated with MCP-1. No inhibition was observed when MCP-1 was added after stimulation with LPS and IFN-gamma. These results demonstrate that MCP-1 is able to inhibit the induction of nitric oxide synthesis.
Assuntos
Aminoácido Oxirredutases/biossíntese , Fatores Quimiotáticos/farmacologia , Citocinas/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Animais , Quimiocina CCL2 , Relação Dose-Resposta a Droga , Indução Enzimática/efeitos dos fármacos , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase , Fatores de Tempo , Células Tumorais CultivadasRESUMO
The effects of chlorpromazine on either the activity of mouse brain nitric oxide synthase or the induction of lung nitric oxide synthase in mice and rats were studied. Chlorpromazine inhibited the nitric oxide synthase activity in mouse brain cytosol. This effect could be reversed by adding an excess of calmodulin. In addition, chlorpromazine was able to inhibit the induction of lung nitric oxide synthase, in both species, after LPS administration. Furthermore, chlorpromazine also inhibited arginase activity in mouse lung cytosol.