RESUMO
OBJECTIVE: This study examined the association between increased early oxidative stress, measured by F2-isoprostanes (IsoPs), and respiratory morbidity at term equivalent age and neurological impairment at 12 months of corrected age (CA). STUDY DESIGN: Plasma samples were collected from 136 premature infants on days 14 and 28 after birth. All participants were infants born at ⩽28 weeks of gestational age enrolled into the Prematurity and Respiratory Outcomes Program (PROP) study. Respiratory morbidity was determined at 40 weeks of postmenstrual age (PMA) by the Respiratory Severity Index (RSI), a composite measure of oxygen and pressure support. Neurodevelopmental assessment was performed using the Developmental Assessment of Young Children (DAYC) at 12 months of CA. Multivariable logistic regression models estimated associations between IsoP change, RSI and DAYC scores. Mediation analysis was performed to determine the relationship between IsoPs and later outcomes. RESULTS: Developmental data were available for 121 patients (90% of enrolled) at 12 months. For each 50-unit increase in IsoPs, regression modeling predicted decreases in cognitive, communication and motor scores of -1.9, -1.2 and -2.4 points, respectively (P<0.001). IsoP increase was also associated with increased RSI at 40 weeks of PMA (odds ratio=1.23; P=0.01). RSI mediated 25% of the IsoP effect on DAYC motor scores (P=0.02) and had no significant impact on cognitive or communication scores. CONCLUSIONS: In the first month after birth, increases in plasma IsoPs identify preterm infants at risk for respiratory morbidity at term equivalent age and worse developmental outcomes at 12 months of CA. Poor neurodevelopment is largely independent of respiratory morbidity.
Assuntos
Displasia Broncopulmonar/sangue , Displasia Broncopulmonar/psicologia , F2-Isoprostanos/sangue , Lactente Extremamente Prematuro/sangue , Recém-Nascido de muito Baixo Peso/sangue , Desenvolvimento Infantil , Cognição , Comunicação , Feminino , Idade Gestacional , Humanos , Lactente , Lactente Extremamente Prematuro/crescimento & desenvolvimento , Recém-Nascido , Recém-Nascido de muito Baixo Peso/crescimento & desenvolvimento , Modelos Logísticos , Masculino , Destreza Motora , Análise Multivariada , Estudos Prospectivos , Índice de Gravidade de Doença , TennesseeRESUMO
While diagnoses of hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) in preterm infants may be based on criteria similar to those in term infants, management approaches often differ. In preterm infants, HRF can be classified as 'early' or 'late' based on an arbitrary threshold of 28 postnatal days. Among preterm infants with late HRF, the pulmonary vascular abnormalities associated with bronchopulmonary dysplasia (BPD) represent a therapeutic challenge for clinicians. Surfactant, inhaled nitric oxide (iNO), sildenafil, prostacyclin and endothelin receptor blockers have been used to manage infants with both early and late HRF. However, evidence is lacking for most therapies currently in use. Chronic oral sildenafil therapy for BPD-associated PH has demonstrated some preliminary efficacy. A favorable response to iNO has been documented in some preterm infants with early PH following premature prolonged rupture of membranes and oligohydramnios. Management is complicated by a lack of clear demarcation between interventions designed to manage respiratory distress syndrome, prevent BPD and treat HRF. Heterogeneity in clinical phenotype, pathobiology and genomic underpinnings of BPD pose challenges for evidence-based management recommendations. Greater insight into the spectrum of disease phenotypes represented by BPD can optimize existing therapies and promote development of new treatments. In addition, better understanding of an individual's phenotype, genotype and biomarkers may suggest targeted personalized interventions. Initiatives such as the Prematurity and Respiratory Outcomes Program provide a framework to address these challenges using genetic, environmental, physiological and clinical data as well as large repositories of patient samples.
Assuntos
Broncodilatadores/administração & dosagem , Óxido Nítrico/administração & dosagem , Síndrome da Persistência do Padrão de Circulação Fetal/tratamento farmacológico , Insuficiência Respiratória/tratamento farmacológico , Citrato de Sildenafila/uso terapêutico , Vasodilatadores/uso terapêutico , Administração por Inalação , Biomarcadores/sangue , Displasia Broncopulmonar/prevenção & controle , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Pulmão/fisiopatologia , Surfactantes Pulmonares/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração ArtificialRESUMO
Future priorities for the management of hypoxemic respiratory failure (HRF) and pulmonary hypertension include primary prevention of neonatal lung diseases, 'precision medicine' and translating promising clinical and preclinical research into novel therapies. Promising areas of investigation include noninvasive ventilation strategies, emerging pulmonary vasodilators (for example, cinaciguat, intravenous bosentan, rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ agonists) and hemodynamic support (arginine vasopressin). Research challenges include the optimal timing for primary prevention interventions and development of validated biomarkers that predict later disease or serve as surrogates for long-term respiratory outcomes. Differentiating respiratory disease endotypes using biomarkers and experimental therapies tailored to the underlying pathobiology are central to the concept of 'precision medicine' (that is, prevention and treatment strategies that take individual variability into account). The ideal biomarker should be expressed early in the neonatal course to offer an opportunity for effective and targeted interventions to modify outcomes. The feasibility of this approach will depend on the identification and validation of accurate, rapid and affordable point-of-care biomarker tests. Trials targeting patient-specific pathobiology may involve less risk than traditional randomized controlled trials that enroll all at-risk neonates. Such approaches would reduce trial costs, potentially with fewer negative trials and improved health outcomes. Initiatives such as the Prematurity and Respiratory Outcomes Program, supported by the National Heart, Lung, and Blood Institute, provide a framework to develop refined outcome measures and early biomarkers that will enhance our understanding of novel, mechanistic therapeutic targets that can be tested in clinical trials in neonates with HRF.
Assuntos
Hipóxia/terapia , Síndrome da Persistência do Padrão de Circulação Fetal/terapia , Insuficiência Respiratória/terapia , Vasodilatadores/uso terapêutico , Biomarcadores/análise , Humanos , Recém-Nascido , Fenótipo , Medicina de Precisão/tendências , Prevenção Primária , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração ArtificialRESUMO
Recently, we reported that reactive oxygen species (ROS) generated by NADPH oxidase (NOX) contribute to aberrant responses in pulmonary resistance arteries (PRAs) of piglets exposed to 3 days of hypoxia (Am J Physiol Lung Cell Mol Physiol 295: L881-L888, 2008). An objective of the present study was to determine whether NOX-derived ROS also contribute to altered PRA responses at a more advanced stage of pulmonary hypertension, after 10 days of hypoxia. We further wished to advance knowledge about the specific NOX and antioxidant enzymes that are altered at early and later stages of pulmonary hypertension. Piglets were raised in room air (control) or hypoxia for 3 or 10 days. Using a cannulated artery technique, we found that treatments with agents that inhibit NOX (apocynin) or remove ROS [an SOD mimetic (M40403) + polyethylene glycol-catalase] diminished responses to ACh in PRAs from piglets exposed to 10 days of hypoxia. Western blot analysis showed an increase in expression of NOX1 and the membrane fraction of p67phox. Expression of NOX4, SOD2, and catalase were unchanged, whereas expression of SOD1 was reduced, in arteries from piglets raised in hypoxia for 3 or 10 days. Markers of oxidant stress, F(2)-isoprostanes, measured by gas chromatography-mass spectrometry, were increased in PRAs from piglets raised in hypoxia for 3 days, but not 10 days. We conclude that ROS derived from some, but not all, NOX family members, as well as alterations in the antioxidant enzyme SOD1, contribute to aberrant PRA responses at an early and a more progressive stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets.
Assuntos
Hipertensão Pulmonar/metabolismo , Hipóxia , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Animais Recém-Nascidos , Antioxidantes/farmacologia , Catalase/metabolismo , F2-Isoprostanos/farmacologia , Hipertensão Pulmonar/etiologia , Immunoblotting , Luminescência , Manganês , NADPH Oxidase 1 , Compostos Organometálicos/farmacologia , Fosfoproteínas/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Suínos , Resistência Vascular/efeitos dos fármacosRESUMO
Mechanistic studies on the effects of MeHg in the central nervous system (CNS) have been limited to morphology, substrate uptake and macromolecular synthesis, differentiation, and changes in gene expression during development and adulthood, but its primary site of action has yet to be identified. Proper functioning of the nitric oxide synthase (NOS)-cyclic GMP and the cyclooxygenase (COX)-prostaglandin (PG) signaling pathways in the CNS depend on post-translational modifications of key enzymes by chaperone proteins. The ability of MeHg to alter or inhibit chaperone-client protein interactions is hitherto unexplored, and potentially offers an upstream unifying mechanism for the plethora of MeHg effects, ranging from reactive species generation (ROS) generation, mitochondrial dysfunction, changes in redox potential, macromolecule synthesis, and cell swelling. In view of the prominent function of astrocytes in the maintenance of the extracellular milieu and their critical role in mediating MeHg neurotoxicity, they afford a relevant and well-established experimental model. The present review is predicated on (a) the remarkable affinity of mercurials for the anionic form of sulfhydryl (-SH) groups, (b) the essential role of thiols in protein biochemistry, and (c) the role of molecular chaperone proteins, such as heat shock protein 90 (Hsp90) in the regulation of protein redox status by facilitating the formation and breakage of disulfide bridges. We offer potential sites where MeHg may interfere with cellular homeostasis and advance a novel mechanistic model for MeHg-induced neurotoxicity.
RESUMO
OBJECTIVE: To evaluate the feasibility of conducting a prospective, randomized trial comparing early high-frequency oscillatory ventilation (HFOV) to synchronized intermittent mandatory ventilation (SIMV) in very low birth weight (VLBW) premature infants. This pilot study evaluated two ventilator management protocols to determine how well they could be implemented in a multicenter clinical trial. Although this pilot study was not powered to detect differences in outcome, we also collected outcome data. DESIGN: Prospective, multicenter, randomized pilot study. SETTING: Seven tertiary-level intensive care nurseries with previous experience with both HFOV and flow-triggered SIMV. PATIENTS: Fifty infants weighing 501 to 1200 g, less than 4 hours of age, who had received one dose of surfactant and required ventilation with mean airway pressure > or =6 cm H2O and F(I)O2 > or =0.25, and had an anticipated duration of ventilation greater than 24 hours. INTERVENTIONS: Patients were stratified by birth weight and prenatal steroid status, then randomized to either HFOV or SIMV with tidal volume monitoring. Ventilator management for patients in both study arms was strictly governed by protocols that included optimizing lung inflation and blood gases, weaning strategies, and extubation criteria. MEASUREMENTS: Data were collected using the tools planned for the larger collaborative study. Protocol compliance was closely monitored, with successive changes in the protocol made as necessary to improve clarity and increase compliance. The incidence of major neonatal adverse outcomes was recorded. MAIN RESULTS: Data are presented for 24 HFOV and 24 SIMV infants (two infants, twins, were withdrawn from the study at parent's request). Nineteen of the 24 HFOV infants and 20 of the 24 SIMV infants survived to 36 weeks corrected age. Age at final extubation for survivors was 16+/-16 (mean+/-SD) days for HFOV infants and 24+/-24 days for SIMV infants. At 36 weeks corrected age, 14 of the 19 HFOV survivors were extubated and in room air, whereas 5 required supplemental oxygen. In comparison, 6 of the 20 SIMV survivors were extubated and in room air, whereas 14 required supplemental oxygen. Grade III/IV IVH and/or periventricular leukomalacia occurred in 2 HFOV and 2 SIMV patients. Overall compliance with the ventilator protocols was 82% for the SIMV protocol, and 88% for the HFOV protocol. CONCLUSIONS: The preliminary outcome data supports conducting the large randomized trial, which began in July of 1998. The protocols for the ventilator management of VLBW infants, both with HFOV and with SIMV were easily implemented and consistently followed, and are presented here.
Assuntos
Ventilação de Alta Frequência/métodos , Recém-Nascido de Baixo Peso , Ventilação com Pressão Positiva Intermitente/métodos , Fatores Etários , Estudos de Viabilidade , Humanos , Recém-Nascido , Projetos Piloto , Estudos ProspectivosRESUMO
We determined the expression and functional correlate of in vitro transfection with a recombinant adenoviral vector encoding the gene for bovine endothelial nitric oxide synthase (AdCMVeNOS) or Escherichia coli beta-galactosidase (AdCMVLacZ) in pulmonary endothelial cells (EC), vascular smooth muscle cells (VSMC), and pulmonary arteries (PA) from newborn piglets. AdCMVeNOS and AdCMVeLacZ vectors, grown in 293-cell monolayers, were purified by double-cesium gradient ultracentrifugation. Cell cultures and PA were incubated with increasing vector titers for 30 or 60 min, followed by incubation in fresh medium for 18 h at 37 degrees C. LacZ expression was assessed by histochemical staining; eNOS expression was evaluated by Western blot analysis. Functional eNOS expression was determined by measurement of cGMP and quantification of the relaxation response to bradykinin (BK). In PA, LacZ transgene expression was preferentially localized to the adventitia and endothelium. Increased eNOS protein expression was observed in EC and VSMC transfected with AdCMVeNOS. Functional studies revealed increased cGMP abundance in cultured cells and enhanced relaxation to BK in AdCMVeNOS-transfected PA. These studies demonstrate that gene transfer with AdCMVeNOS results in functional expression and altered vasoactive responses in the neonatal pulmonary vasculature. Gene transfer with replication-deficient adenovirus vectors is a useful tool for the study of targeted genes in vascular biology.
Assuntos
Endotélio Vascular/citologia , Endotélio Vascular/enzimologia , Músculo Liso Vascular/citologia , Músculo Liso Vascular/enzimologia , Óxido Nítrico Sintase/genética , Artéria Pulmonar/enzimologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Técnicas de Transferência de Genes , Óxido Nítrico Sintase/biossíntese , SuínosRESUMO
BACKGROUND: A retrospective medical record review of 13 consecutive, hyperglycemic, extremely low birth weight (ELBW) infants treated with continuous insulin infusions revealed a 14- to 24-hour delay (mean, 19 hours) in blood glucose normalization despite stepwise increases in insulin infusion rates. OBJECTIVE: This in vitro study examined the effects of flow rate and insulin priming on insulin recovery from polyvinyl chloride (PVC) tubing and polyethylene (PE)-lined PVC tubing infused with a standard insulin stock solution. METHODS: Stock insulin solution (0.2 U/mL) was infused through microbore PVC or PE-lined tubing at flow rates of 0.05 and 0.2 mL/h. To determine if saturation of nonspecific binding sites would alter effluent insulin concentration, we compared insulin recovery from tubing previously flushed with the stock solution and tubing primed with 5 U/mL of insulin for 20 minutes. Effluent samples, which were collected at baseline and at six time points during a 24-hour period, were immediately frozen at -20 degreesC. Insulin concentration was measured by IMx immunoassay. Data were analyzed using general linear modeling with repeated measures. RESULTS: At 0.05 mL/h flow rate, insulin recovery from unprimed PVC tubing at 1, 2, 4, and 8 hours was 17%, 11%, 27%, and 55%, respectively, with 100% recovery at 24 hours. From insulin-primed tubing, insulin recovery was approximately 70% at 1, 2, and 4 hours, and close to 100% at 8 hours. At a faster flow rate of 0.2 mL/h, insulin recovery at 1, 2, 4, and 8 hours was 22%, 38%, 67%, and 75% vs 42%, 85%, 91% and 95% from unprimed and insulin-primed PVC tubing, respectively. Similar results were obtained from unprimed and insulin-primed PE-lined tubing at 0.2 mL/h flow rate. CONCLUSIONS: Priming of microbore tubing with 5 U/mL of insulin solution for 20 minutes to block nonspecific binding sites enhances delivery of a standard insulin stock at infusion rates typically used to treat hyperglycemic ELBW infants. We conclude that priming the tubing with a higher concentration of insulin before initiation of standard insulin infusion therapy should accelerate achievement of steady-state insulin delivery and correction of hyperglycemia in ELBW infants.
Assuntos
Sistemas de Liberação de Medicamentos/instrumentação , Hiperglicemia/tratamento farmacológico , Recém-Nascido de muito Baixo Peso , Infusões Intravenosas/instrumentação , Insulina/administração & dosagem , Glicemia/análise , Desenho de Equipamento , Humanos , Recém-Nascido , Polietilenos , Cloreto de Polivinila , Estudos Retrospectivos , Fatores de TempoRESUMO
We determined whether activation of phosphatidylinositol-specific phospholipase C (PI-PLC) and a subsequent increase in cytosolic calcium concentration ([Ca2+]i) was an obligatory signaling event mediating the increase in transendothelial permeability induced by bradykinin (BK) and alpha-thrombin (alpha-T). Both BK and alpha-T (each at a concentration range of 0.01-1 microM) caused dose-dependent increases in transendothelial 125I-albumin permeability in cultured bovine pulmonary artery endothelial cell monolayers. Both agonists also produced a rise in inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] by 10 sec that was followed by a prolonged increase in [Ca2+]i. Pretreatment of endothelial cells with the PLC inhibitor, 1-(6-((17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1 H-pyrrole-2,5-dion [(U73122) at 10 microM for 15 min], prevented the increases in Ins(1,4,5)P3 and [Ca2+]i induced by both BK and alpha-T. However, inhibition of PLC with U73122 or another PLC inhibitor, neomycin, did not prevent the increase in endothelial permeability induced by either agonist. In contrast, depletion of cellular protein kinase C (PKC) with phorbol-12-myristate 13-acetate (0.01 microM for 20 hr) increased both BK- and alpha-T-induced phosphoinositide turnover but inhibited the agonist-induced increase in permeability. A PKC inhibitor, staurosporine (5 microM) likewise inhibited the BK-induced increase in endothelial cell permeability to albumin. We conclude that increases in endothelial permeability induced by the inflammatory mediators, BK and thrombin, can occur independently of PLC activation and increased [Ca2+]i but that a PKC-dependent pathway is required for the permeability response.
Assuntos
Bradicinina/farmacologia , Endotélio Vascular/fisiologia , Proteína Quinase C/metabolismo , Trombina/farmacologia , Fosfolipases Tipo C/metabolismo , Animais , Cálcio/metabolismo , Bovinos , Linhagem Celular , Endotélio Vascular/efeitos dos fármacos , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Estrenos/farmacologia , Humanos , Inositol 1,4,5-Trifosfato/metabolismo , Radioisótopos do Iodo , Cinética , Neomicina/farmacologia , Permeabilidade , Fosfatidilinositóis/metabolismo , Artéria Pulmonar , Pirrolidinonas/farmacologia , Soroalbumina Bovina/farmacocinética , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Metallothionein (MT) mRNA was determined in rat astrocyte cultures in response to ethanol (EtOH). MT-I mRNA was significantly increased after 6 h exposure to isosmotic EtOH, but not hyperosmotic EtOH. Exposure to a hyposmotic/hypotonic solution also led to a significant increase in the expression of astrocytic MT-I mRNA. The large increase in MT-I mRNA was not due to removal of extracellular NaCl, because this effect was reversed by replacement of NaCl with N-methyl D-glucamine chloride. A significant decrease in MT-I mRNA was also noted in astrocytes exposed to an EtOH-free hyperosmotic/hypertonic solution. These results suggest (1) that EtOH per se does not directly induce MT-I mRNA expression, (2) that the induction by EtOH of MT-I mRNA is secondary to hypotonicity, and (3) that hyperosmotic/hypertonic exposure is associated with reduced expression of MT-I mRNA in astrocyte cultures.
Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/fisiologia , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Metalotioneína/genética , Animais , Astrócitos/citologia , Northern Blotting , Células Cultivadas , DNA Complementar , Expressão Gênica/efeitos dos fármacos , Soluções Hipotônicas , Plasmídeos , RNA Mensageiro/metabolismo , Ratos , Cloreto de Sódio/farmacologiaRESUMO
Alteration of receptor-mediated signal transduction pathways by inorganic lead (Pb) has been postulated to contribute to the neurotoxicity of this environmental toxicant, some of these effects involving astrocytes. As Pb is known to mimic Ca2+ in various biological systems or alter Ca(2+)-mediated cellular processes, we analyzed the effect of Pb exposure on alpha 1 receptor activated astrocytic phosphoinositide metabolism and Ca2+ responses in primary astrocyte cultures prepared from cerebral cortex of 1-day-old rats. Exposure to norepinephrine (NE; 10-100 microM) resulted in a significant increase in astrocytic inositol 1,4,5-trisphosphate levels, concomitant with an increase in intracellular Ca2+ levels. Fifteen minute exposure to Pb (10 microM lead acetate) significantly increased inositol 1,4,5-trisphosphate generation compared with controls, both in the presence and absence of NE. However, the inositol 1,4,5-trisphosphate-mediated Ca2+ transients following NE stimulation was unaltered in the presence of Pb (1-100 microM). NE-evoked intracellular Ca2+ responses, both in the presence and absence of extracellular Ca2+ did not differ between control and Pb-treated astrocytes. Additional studies failed to demonstrate the occurrence of Pb influx into astrocytes within the first 12 min of exposure such that Ca2+ responses would be directly affected. It therefore appears unlikely that astrotoxic effects of Pb are mediated via direct changes in intracellular Ca2+ transients.
Assuntos
Astrócitos/efeitos dos fármacos , Cálcio/metabolismo , Córtex Cerebral/efeitos dos fármacos , Inositol 1,4,5-Trifosfato/metabolismo , Chumbo/farmacologia , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Animais , Animais Recém-Nascidos/metabolismo , Astrócitos/metabolismo , Células Cultivadas , Córtex Cerebral/metabolismo , Norepinefrina/farmacologia , RatosRESUMO
The temporal relationship between the alpha-thrombin-induced increase in transendothelial permeability and the alpha-thrombin-mediated changes in several key transmembrane signaling events was examined in confluent monolayers of bovine pulmonary artery endothelial cells (BPAEC). The time courses of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] generation, changes in cytosolic [Ca2+] ([Ca2+]i), and reorganization of cytoskeletal F-actin were determined to assess the relationship between these events and the onset of the alpha-thrombin-induced increase in endothelial permeability. alpha-Thrombin (10(-7) M) increased the transendothelial 125I-albumin clearance rate half-maximally by approximately 1 min and maximally by approximately 2 min (160% over control level). The increase in permeability occurred concomitantly with reorganization of F-actin cytoskeleton (i.e., loss of peripheral band and increased stress fiber density) and increased actin polymerization. Stimulation of fura-2-loaded BPAEC with 10(-7) M alpha-thrombin produced a typical biphasic rise in [Ca2+]i. The initial rapid increase in [Ca2+]i peaked by approximately 16 s after thrombin challenge and the [Ca2+]i response showed a slow decrease to half-maximal within 50 s. The alpha-thrombin-induced increase in permeability as well as the increase in [Ca2+]i were consistently preceded by increased Ins(1,4,5)P3 generation detectable within 10 s after thrombin challenge. These results indicate that alpha-thrombin triggers a cascade of events (i.e., Ins(1,4,5)P3 generation and the ensuing rise in [Ca2+]i), which may comprise the second messengers that mediate F-actin reorganization and the increase in endothelial permeability.
Assuntos
Cálcio/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Endotélio Vascular/metabolismo , Fosfatos de Inositol/metabolismo , Trombina/farmacologia , Actinas/metabolismo , Animais , Células Cultivadas , Cromatografia em Gel , Citoesqueleto/metabolismo , Endotélio Vascular/citologia , Albumina Sérica/farmacocinética , Fatores de Tempo , Distribuição TecidualRESUMO
Many of the neurotoxic aspects of organotin exposure have been described. Organotin exposure culminates in its accumulation in the CNS and PNS. The clinical picture is dominated by neurological disturbances; yet, the primary basis for their neurotoxicity is unknown. Trimethyltin (TMT) is primarily a CNS neurotoxin affecting neurons within the hippocampal pyramidal band and the fascia dentata. Triethyltin (TET) is a neurotoxin that produces a pathological picture dominated by brain and spinal cord edema. The first part of this review summarizes the current understanding of the interaction of TMT and TET with biologically active sites in the induction of neurotoxicity. In the second part, several hypotheses for the differential neurotoxic effects of these organotins and their shortcomings are discussed.
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Doenças do Sistema Nervoso/induzido quimicamente , Compostos Orgânicos de Estanho/toxicidade , Compostos de Trietilestanho/toxicidade , Compostos de Trimetilestanho/toxicidade , Animais , Humanos , Doenças do Sistema Nervoso/fisiopatologiaRESUMO
The observations by Couper in 1837 are acknowledged as the earliest description of the toxic syndrome associated with chronic manganese (Mn) exposure. Since that time, many of the neurotoxic aspects of manganism have been described, yet, the primary basis for its neurotoxicity remains unknown. Recent evidence corroborates the original hypothesis by Maynard and Cotzias (82) which invokes the mitochondrion as the target organelle for Mn cytotoxicity which is primarily expressed as a perturbation in Ca2+ homeostasis. Despite recognition that excessive Mn exposure culminates in Mn accumulation in the CNS and a clinical picture dominated by neurological disturbances, the role of the blood-brain barrier in the CNS uptake of Mn has received little attention. Accordingly, the first part of this review summarizes the current understanding of the interaction of Mn with biologically active sites in the induction of Mn cytotoxicity. The second part of this review summarizes what is known about Mn transport across the blood-brain barrier, a major regulator of the CNS milieu, with the contention that the rate and extent of Mn transport across the blood-brain barrier modulates its neurotoxicity.
Assuntos
Barreira Hematoencefálica/fisiologia , Intoxicação por Manganês , Doenças do Sistema Nervoso/induzido quimicamente , Animais , Humanos , Manganês/metabolismo , Sistema Nervoso/citologia , Doenças do Sistema Nervoso/fisiopatologiaRESUMO
alpha-Thrombin causes a dose-dependent increase in endothelial permeability as measured by the clearance rate of 125I-albumin across a monolayer of bovine pulmonary artery endothelial cells. We determined if an active catalytic site is necessary for the thrombin-mediated increase in endothelial permeability. alpha-Thrombin was reacted with 10-fold excess D-phenylalanyl-prolyl-arginine chloromethyl ketone (PPACK), an irreversible inhibitor that forms a covalent bond with thrombin's active site, producing an enzymatically inactive thrombin. PPACK completely inhibited the alpha-thrombin-mediated increase in 125I-albumin permeability. Similar results were obtained with gamma-thrombin, an enzymatically active alpha-thrombin form with an altered fibrinogen recognition domain. PPACK alone and the active site-inhibited PPACK-alpha-thrombin had no effect on permeability. Diisopropylphospho (DIP)-alpha-thrombin was effective only in very high concentrations (10(-6)M), and this effect was abolished by the addition of PPACK. These studies demonstrate that binding alone is insufficient for the thrombin-mediated increase in endothelial monolayer permeability. Thrombin's active catalytic site is a requirement for the increase in transendothelial albumin permeability.
Assuntos
Permeabilidade da Membrana Celular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Trombina/farmacologia , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Linhagem Celular , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Humanos , Relação Estrutura-AtividadeRESUMO
The binding characteristics of manganese (Mn) to transferrin (Tf) were examined on G-75 Sephadex gel columns. When 54MnCl2 was combined with Tf and immediately fractionated on the Sephadex column, 49% of 54Mn was found to Tf. The fraction of 54Mn which was Tf-bound was dependent upon the incubation period, and increased in a time-dependent fashion. In vivo, 6 hr of intravenous administration of ferric-hydroxide dextran complex significantly inhibited (p less than 0.05) 54Mn brain uptake as compared to its uptake in iron-free dextran-treated rats. These results suggest that iron (Fe) homeostasis may play an important role in the regulation of Mn transport across the blood-brain barrier (BBB).
Assuntos
Barreira Hematoencefálica , Homeostase , Ferro/metabolismo , Manganês/farmacocinética , Animais , Feminino , RatosRESUMO
Mercury exists in a wide variety of physical and chemical states, each of which has unique characteristics of target organ toxicity. The classic symptoms associated with exposure to elemental mercury vapor (Hg0) and methylmercury (CH3Hg+; MeHg) involve the central nervous system (CNS), while the kidney is the target organ for the mono- and divalent salts of mercury (Hg+ and Hg++, respectively). Physical properties and redox potentials determine the qualitative and quantitative differences in toxicity among inorganic mercury compounds, while the ability of MeHg to cross the blood-brain barrier accounts for its accumulation in the CNS and a clinical picture that is dominated by neurological disturbances. This review gives an up-to-date account of mercury's physical and chemical properties and its interaction with biologically active sites pertinent to transport across the blood-brain barrier, a major regulator of the CNS millieu.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Mercúrio/farmacocinética , Animais , Transporte Biológico Ativo/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Humanos , Mercúrio/toxicidade , Compostos de Metilmercúrio/farmacocinéticaRESUMO
A randomized trial of surfactant replacement therapy at birth was conducted at the University of Rochester between June 1983 and November 1985. Thirty-four premature infants, 25 to 29 weeks' gestational age, received a preventilatory dose of a calf lung surfactant extract in saline prepared at the University of Rochester. A control group of 31 infants received a preventilatory dose of saline alone. The major finding of this trial is that a single preventilatory dose of calf lung surfactant extract reduces the severity of the respiratory distress syndrome during the first 24 hours of life. The beneficial effects, however, are not sustained in many infants and diminish after 24 hours of life. The survival rate was 71% in both the control and surfactant-treated groups. There was a lower incidence of pneumothorax in the surfactant-treated group. There were no differences in the incidence of bronchopulmonary dysplasia, patent ductus arteriosus, and intraventricular hemorrhage. No adverse effects of surfactant replacement therapy were identified. Results of this study suggest that multiple postventilatory doses of surfactant will be required for optimal therapy.
Assuntos
Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Ensaios Clínicos como Assunto , Método Duplo-Cego , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Pneumotórax/etiologia , Distribuição Aleatória , Respiração Artificial , Síndrome do Desconforto Respiratório do Recém-Nascido/complicaçõesRESUMO
Spontaneous, focal gastrointestinal perforation occurred in six very low birth weight infants. The first recognized clinical sign of perforation in five of the six infants was striking blue-black discoloration of the abdominal wall. In all cases the clinical and radiographic presentations, as well as the histologic findings, were distinct from those associated with necrotizing enterocolitis. All 4 infants who underwent exploratory laparotomy and repair had excellent surgical outcomes.