RESUMO
BACKGROUND: Ischemia/reperfusion injury may have deleterious short- and long-term consequences for cardiac allografts. The underlying mechanisms involve microvascular dysfunction that may culminate in primary graft failure or untreatable chronic rejection. METHODS AND RESULTS: Here, we report that rat cardiac allograft ischemia/reperfusion injury resulted in profound microvascular dysfunction that was prevented by donor treatment with peroral single-dose simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase and Rho GTPase inhibitor, 2 hours before graft procurement. During allograft preservation, donor simvastatin treatment inhibited microvascular endothelial cell and pericyte RhoA/Rho-associated protein kinase activation and endothelial cell-endothelial cell gap formation; decreased intragraft mRNA levels of hypoxia-inducible factor-1α, inducible nitric oxide synthase, and endothelin-1; and increased heme oxygenase-1. Donor, but not recipient, simvastatin treatment prevented ischemia/reperfusion injury-induced vascular leakage, leukocyte infiltration, the no-reflow phenomenon, and myocardial injury. The beneficial effects of simvastatin on vascular stability and the no-reflow phenomenon were abolished by concomitant nitric oxide synthase inhibition with N-nitro-l-arginine methyl ester and RhoA activation by geranylgeranyl pyrophosphate supplementation, respectively. In the chronic rejection model, donor simvastatin treatment inhibited cardiac allograft inflammation, transforming growth factor-ß1 signaling, and myocardial fibrosis. In vitro, simvastatin inhibited transforming growth factor-ß1-induced microvascular endothelial-to-mesenchymal transition. CONCLUSIONS: Our results demonstrate that donor simvastatin treatment prevents microvascular endothelial cell and pericyte dysfunction, ischemia/reperfusion injury, and chronic rejection and suggest a novel, clinically feasible strategy to protect cardiac allografts.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Microvasos/efeitos dos fármacos , Disfunção Primária do Enxerto/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Sinvastatina/uso terapêutico , Animais , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/enzimologia , Endotelina-1/biossíntese , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/enzimologia , Heme Oxigenase-1/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Complexo Principal de Histocompatibilidade/efeitos dos fármacos , Masculino , Microvasos/enzimologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/biossíntese , Fenômeno de não Refluxo/prevenção & controle , Fosfatos de Poli-Isoprenil/farmacologia , Disfunção Primária do Enxerto/enzimologia , Ratos , Ratos Endogâmicos WF , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
BACKGROUND: Morbidity and mortality rates in orthotopic liver transplantation have decreased in the past few years. Risk factors related to severe postoperative complications, such as primary graft dysfunction, still need to be analyzed. We evaluated the influence of the hypnotic agent used during anesthesia on primary graft dysfunction. METHODS: We performed a retrospective analysis of 419 consecutive patients who received a liver transplant between 2005 and 2013 in a single center. We analyzed the incidence of primary graft dysfunction (defined as alanine aminotransferase or aspartate aminotransferase levels higher than 1500 IU/L on the first 3 days after surgery) and if the hypnotic agent was associated with this event. RESULTS: The incidence of primary graft dysfunction was 42.2% (114 patients), similar in both groups (propofol group, 89 patients, 43.2% and sevoflurane group, 25 patients, 39.1%). In the multivariate analysis, we did not find any relationship between the hypnotic agent (propofol or sevoflurane) and early graft dysfunction. CONCLUSIONS: In our patients, we found no differences in the incidence of liver graft dysfunction according to the hypnotic used during transplantation. We can suggest that both drugs (sevoflurane and propofol) are equally safe in orthotopic liver transplantation.
Assuntos
Anestesia/métodos , Hipnóticos e Sedativos/administração & dosagem , Transplante de Fígado , Éteres Metílicos/administração & dosagem , Disfunção Primária do Enxerto/tratamento farmacológico , Propofol/administração & dosagem , Idoso , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Incidência , Masculino , Éteres Metílicos/efeitos adversos , Pessoa de Meia-Idade , Análise Multivariada , Disfunção Primária do Enxerto/enzimologia , Disfunção Primária do Enxerto/etiologia , Propofol/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Sevoflurano , Fatores de TempoRESUMO
OBJECTIVES: Accepting organs donated after cardiac death (DCD) is an effective approach to the donor shortage. However, lung transplantations from DCD donors show severe rapid pulmonary graft dysfunction (PGD) followed by warm ischemia-reperfusion injury (IRI). This study sought to clarify the molecular mediators in warm IRI, including activation of mitogen-activated protein kinase (MAPK) and the downstream cascades. METHODS: We performed single left lung transplantation using organs from male Sprague-Dawley rats after 0 (CIT group), 30 (30WIT group), or 180 (180WIT group) minutes of warm ischemia time. Pulmonary graft functions were estimated by blood gas analysis. At 1 hour after reperfusion, the phosphorylation status of MAPKs (ERK, p38, and JNK) and the gene expression levels of transcription factors (Egr-1 and ATF-3) and immune mediators (MCP-1, MIP-2, PAI-1, ICAM-1, TNF-α, IL-1ß, IL-6, and COX-2) in the grafts were examined using Western blotting and real-time polymerase chain reaction assays. RESULTS: Severe PGD was observed in the 180WIT group compared with transplanted lungs in the other groups, which exhibited good pulmonary graft function. ERK and JNK activations, as well as mRNA levels of transcription factors (Egr-1 and ATF3) significantly increased with greater warm ischemic times. The pattern of JNK activation correlated with the severity of PGD. MCP-1, ICAM-1, IL-1ß, IL-6, and COX-2 were also up-regulated among the 180WIT group, although MIP-2 and PAI-1 showed no significant differences among the groups. CONCLUSIONS: We suggest that the ERK and JNK pathways may play important roles to induce the injury caused by prolonged warm ischemia followed by reperfusion in the setting of lung transplantation from DCD donors.