RESUMEN
A well-recognized complication of the anatomic correction (arterial switch operation) of transposition of the great arteries is obstruction of the translocated coronary arteries. Myocardial reperfusion has previously been achieved by surgical revascularization or percutaneous balloon angioplasty. We report the case of a 3-month-old infant who suffered myocardial infarction 11 weeks after the arterial switch operation, in whom myocardial reperfusion was established following infusion of recombinant tissue-type plasminogen activator (Alteplase).
Asunto(s)
Isquemia Miocárdica/tratamiento farmacológico , Activadores Plasminogénicos/uso terapéutico , Activador de Tejido Plasminógeno/uso terapéutico , Angioplastia Coronaria con Balón , Cateterismo Cardíaco , Angiografía Coronaria , Ecocardiografía , Humanos , Lactante , Masculino , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/etiología , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/etiología , Transposición de los Grandes Vasos/terapia , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/etiologíaRESUMEN
OBJECTIVES: Ischemia-reperfusion injury after cardiopulmonary bypass is known to provoke an inflammatory response, which can be attenuated with steroid pretreatment. Cardiopulmonary bypass is also known to stimulate apoptosis. Induction of the cellular apoptotic cascade occurs via interaction between two membrane receptors: Fas and Fas ligand. Both molecules also exist in soluble forms, whose significance remains undetermined; however, both may have a proinflammatory role. We aimed to document the temporal profile of soluble Fas and soluble Fas ligand after cardiopulmonary bypass and to investigate whether steroid pretreatment alters this response. METHODS: The study was of a non-randomized, non-blinded, prospective nature. Twenty-seven infants were monitored prospectively, of whom 13 received dexamethasone at induction of anesthesia. Soluble Fas, soluble Fas ligand, and interleukin 6 were measured from induction of anesthesia until 24 hours after admission to the intensive care unit. Data on clinical and laboratory variables were also collected at the same time intervals. RESULTS: As expected, dexamethasone pretreatment attenuated interleukin 6 release and the clinical systemic inflammatory response after bypass. Soluble Fas showed a remarkably similar profile to interleukin 6, in terms of temporal release and attenuation with steroids. There was also a correlation between maximum soluble Fas and markers of capillary leak (colloid requirement and drain loss). Conversely, soluble Fas ligand release was unchanged by cardiopulmonary bypass and steroid administration. However, patients with higher soluble Fas ligand levels exhibited a more dramatic drop and delayed recovery in monocyte count, consistent with the role of this molecule in apoptosis. CONCLUSIONS: Release of soluble Fas and soluble Fas ligand follows a markedly different temporal profile after cardiopulmonary bypass. The similarity between soluble Fas and interleukin 6, together with the attenuation of both with steroids, may suggest a role for soluble Fas as a proinflammatory marker.
Asunto(s)
Puente Cardiopulmonar , Mediadores de Inflamación/sangre , Receptor fas/sangre , Antiinflamatorios/administración & dosificación , Apoptosis , Biomarcadores/sangre , Puente Cardiopulmonar/efectos adversos , Dexametasona/administración & dosificación , Proteína Ligando Fas , Femenino , Cardiopatías Congénitas/cirugía , Humanos , Lactante , Interleucina-6/sangre , Ligandos , Masculino , Glicoproteínas de Membrana/sangre , Estudios Prospectivos , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Síndrome de Respuesta Inflamatoria Sistémica/prevención & controlRESUMEN
Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by a deficiency in branched chain alpha-keto acid dehydrogenase that can result in neurodegenerative sequelae in human infants. In the present study, increased concentrations of MSUD metabolites, in particular alpha-keto isocaproic acid, specifically induced apoptosis in glial and neuronal cells in culture. Apoptosis was associated with a reduction in cell respiration but without impairment of respiratory chain function, without early changes in mitochondrial membrane potential and without cytochrome c release into the cytosol. Significantly, alpha-keto isocaproic acid also triggered neuronal apoptosis in vivo after intracerebral injection into the developing rat brain. These findings suggest that MSUD neurodegeneration may result, at least in part, from an accumulation of branched chain amino acids and their alpha-keto acid derivatives that trigger apoptosis through a cytochrome c-independent pathway.
Asunto(s)
Aminoácidos de Cadena Ramificada/metabolismo , Grupo Citocromo c/metabolismo , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Mitocondrias/metabolismo , Neuronas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Caspasa 3 , Caspasas/metabolismo , Respiración de la Célula/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Fragmentación del ADN , Activación Enzimática , Humanos , Membranas Intracelulares/metabolismo , Cetoácidos/metabolismo , Cetoácidos/farmacología , Leucina/metabolismo , Leucina/farmacología , Potenciales de la Membrana/efectos de los fármacos , Ratones , Neuroglía/citología , Neuroglía/efectos de los fármacos , Neuronas/patología , Ratas , Ratas WistarRESUMEN
Fas/CD95/Apo-1 is a cell surface receptor that transduces apoptotic death signals following activation and has been implicated in triggering apoptosis in infected or damaged cells in disease states. Apoptosis is a major mechanism of neuronal loss following hypoxic-ischemic injury to the developing brain, although the role of Fas in this process has not been studied in detail. In the present study, we have investigated the expression and function of Fas in neuronal cells in vitro and in vivo. Fas was found to be expressed in the 14 day old rat brain, with strongest expression in the cortex, hippocampus and cerebellum. Cross-linking of Fas induced neuronal apoptosis both in neuronal PC12 cells in culture and following intracerebral injection in vivo, indicating that neuronal Fas was functional as a death receptor. This death was shown to be caspase dependent in primary neuronal cultures and was blocked by the selective caspase 8 inhibitor IETD. Finally, cerebral hypoxia-ischemia resulted in a strong lateralised upregulation of Fas in the hippocampus, that peaked six to twelve hours after the insult and was greater on the side of injury. These results suggest that Fas may be involved in neuronal apoptosis following hypoxic-ischemic injury to the developing brain.
Asunto(s)
Apoptosis/inmunología , Encéfalo/fisiopatología , Hipoxia-Isquemia Encefálica/fisiopatología , Neuronas/inmunología , Neuronas/patología , Regulación hacia Arriba/inmunología , Receptor fas/inmunología , Receptor fas/metabolismo , Animales , Animales Recién Nacidos , Encéfalo/inmunología , Encéfalo/patología , Caspasas/inmunología , Corteza Cerebral/inmunología , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Hipocampo/inmunología , Hipocampo/patología , Hipocampo/fisiopatología , Hipoxia-Isquemia Encefálica/inmunología , Inmunoglobulina M/inmunología , Inmunoglobulina M/farmacología , Células PC12 , Ratas , Ratas WistarRESUMEN
Transient unilateral forebrain hypoxia-ischaemia (HI) in 14-day-old rats produces infarction and delayed neuronal death in the frontal cortex. Cell death can also be observed in regions distant from the primary injury, a phenomenon known as diaschisis. While apoptosis is involved in selective neuronal death, its role in infarction and diaschisis remains poorly understood. Here, we have investigated the proteolytic cleavage of poly(ADP ribose) polymerase (PARP) and the occurrence of apoptosis in the hippocampus and the cerebellum following either HI or traumatic brain injury. We demonstrate that: (i) in vitro, PARP is cleaved during apoptosis but not necrosis in cultured neuronal (N1E) cells and Swiss 3T3 fibroblasts; (ii) following HI, apoptotic cells can be detected by 4 h after injury in the hippocampus; (iii) in the ipsilateral hippocampus the appearance of cells with apoptotic morphology is preceded by a dramatic increase in PARP cleavage in the same region, starting immediately following HI and persisting for 24 h; (iv) HI also induces apoptosis in the cerebellum and, as in the hippocampus, the appearance of cells with apoptotic morphology is preceded by PARP cleavage that is greater on the side ipsilateral to forebrain injury; and (v) similarly, traumatic brain injury to the forebrain leads to PARP cleavage and apoptosis in the cerebellum. We conclude that HI injury or traumatic injury to the developing rat forebrain leads to PARP cleavage in directly affected areas and in sites distant from the primary injury that precedes the appearance of cells with apoptotic morphology. Our results are consistent with a role for apoptotic cell death in infarction and in diaschisis resulting from forebrain injury to the developing brain.
Asunto(s)
Isquemia Encefálica/metabolismo , Hipocampo/lesiones , Neuronas/citología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Prosencéfalo/lesiones , Células 3T3 , Factores de Edad , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Western Blotting , Caspasas/metabolismo , Cerebelo/citología , Cerebelo/metabolismo , Fragmentación del ADN , Inhibidores Enzimáticos/farmacología , Hipocampo/irrigación sanguínea , Hipocampo/citología , Ratones , Necrosis , Agujas , Neuroblastoma , Neuronas/enzimología , Neuronas/patología , Poli Adenosina Difosfato Ribosa/metabolismo , Poli(ADP-Ribosa) Polimerasas/análisis , Prosencéfalo/irrigación sanguínea , Prosencéfalo/citología , Ratas , Ratas Wistar , Azida Sódica/farmacología , Estaurosporina/farmacología , Azul de Tripano , Células Tumorales Cultivadas , Heridas Punzantes/metabolismoRESUMEN
Perinatal hypoxic ischaemic brain injury (HII) is a major cause of neonatal mortality and long-term neurological morbidity. An understanding of the molecular events which follow HII may lead to novel treatments to improve the final outcome for affected infants. The beta-amyloid precursor protein (beta-APP) is a widely expressed transmembrane protein whose proposed functions include stabilization of neuronal calcium fluxes, inhibition of the clotting cascade and cell-cell or cell-matrix adhesion. Normally present at low levels in neurons its expression is induced as part of the acute response of the adult brain to HII. This study aimed to determine whether beta-APP is also part of the acute adaptive response of the infant brain to HII. Immunohistochemistry and Western blotting were used to assess cerebral beta-APP expression in 14-day-old rat pups subjected to unilateral HII, and in 10 term human infants, who died between 12 h and 16 months after severe perinatal HII. In the rat pups beta-APP expression was increased by 2 h post-injury, peaked, fourfold above control levels, at 24 h and gradually declined over the following 4 days. Expression was induced bilaterally, but was greater on the side of injury. In the human infants, increased, predominantly neuronal expression of beta-APP, was detectable immunohistochemically within 24 h of injury and was greatest in those infants dying within 3 days. Expression was particularly strong in the areas showing histological evidence of injury, but was also seen in apparently undamaged areas. We conclude that beta-APP induction is part of the the acute adaptive response of the neonatal brain to HII.
Asunto(s)
Precursor de Proteína beta-Amiloide/análisis , Precursor de Proteína beta-Amiloide/biosíntesis , Química Encefálica/fisiología , Isquemia Encefálica/metabolismo , Hipoxia Encefálica/metabolismo , Animales , Animales Recién Nacidos , Western Blotting , Modelos Animales de Enfermedad , Humanos , Inmunohistoquímica , RatasAsunto(s)
Apoptosis , Grupo Citocromo c/metabolismo , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Potenciales de la Membrana , Mitocondrias/fisiología , Neuronas/patología , Humanos , Enfermedad de la Orina de Jarabe de Arce/enzimología , Enfermedad de la Orina de Jarabe de Arce/patología , Mitocondrias/enzimologíaRESUMEN
We have investigated the effect of nitric oxide (NO) on apoptosis in Swiss 3T3 fibroblasts and compared it to the effect of the nitrosonium cation (NO+). Both species induced apoptosis, confirmed by electron microscopy, propidium iodide staining, DNA laddering and activation of caspases. The kinetics of triggering apoptosis were different for the two redox species: NO+ required only a 2 hour exposure, whereas NO required 24 hours. Three sources of NO were used: aqueous solutions of NO and two NO donors, S-nitrosoglutathione and S-nitroso-N-acetylpenicillamine. The time course of apoptosis induced by these two S-nitrosothiols correlated with their rate of decomposition to NO. The apoptotic effect of NO was reduced in the presence of the NO scavenger oxyhaemoglobin, or the antioxidants N-acetylcysteine and ascorbic acid, whereas in the case of NO+ these antioxidants potentiated apoptosis. Glutathione also had a potentiating effect on the cytotoxicity of NO+. This suggests that cellular antioxidants may play a role in protecting the cell from NO-induced apoptosis while NO+ may trigger apoptosis independently of oxidative stress mechanisms.