RESUMEN
Recognizing immune dysregulation as a hallmark of sepsis pathophysiology, leukocytes have attracted major attention of investigation. While adult and pediatric sepsis are clinically distinct, their immunological delineation remains limited. Single cell technologies facilitated the characterization of immune signatures. We tackled to delineate immunological profiles of pediatric sepsis at a single-cell level by analyzing blood samples from six septic children, at both acute and recovery phases, and four healthy children. 16 single-cell transcriptomic datasets were analyzed and compared to adult sepsis dataset. We showed a unique shift in neutrophil subpopulations and functions between acute and recovery phases, along with the regulatory role of resistin. Neutrophil signatures were comparable between adult and pediatric sepsis. Innate-like CD4 T cells were predominantly and uniquely observed in acute phase of pediatric sepsis. Our study serves as a rich source of information about the phenotypic diversity and trajectory of circulating immune cells during pediatric sepsis.
Asunto(s)
Sepsis , Adulto , Humanos , Niño , Sepsis/genética , Linfocitos T CD4-Positivos , Transcriptoma , Perfilación de la Expresión Génica , NeutrófilosRESUMEN
Immunity at birth is considered immature. Following birth, our immune function is considered to grow and reach maturation over time. To obtain granular information of leukocyte functions and transcriptomic profiles in pediatric cohort, we examined leukocyte profiles in infants, preschool and school children using single cell RNA sequencing of their peripheral blood mononuclear cells (PBMCs). Monocytes and natural killer (NK) cells showed immaturity in infants. Their innate and adaptive immunity was developed by preschool age. Adaptive immune cells showed different maturation patterns. CD4, CD8 naïve T cells and plasma cells continued to mature untill school age. In CD8 naïve T cells, innate immunity was upregulated in infants, in support of our knowledge that they manifests more innate cell-like phenotype soon after birth. Many signaling pathways have been differentially up- and/or down-regulated in infants, preschool and school children. Their contribution to the development of the immune system needs to be delineated.
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Leucocitos Mononucleares , Transcriptoma , Lactante , Recién Nacido , Humanos , Niño , Preescolar , Leucocitos , Inmunidad Innata , Linfocitos TRESUMEN
Sedatives/anesthetics are important medical tools to facilitate medical care and increase patients' comfort. Increasingly, there is recognition that sedatives/anesthetics can modulate immune functions. Toll-like receptors (TLRs) are major pattern recognition receptors involved in the recognition of microbial components. TLR7 recognizes single-strand RNA virus such as influenza and SARS-CoV2 viruses and initiates interferon (IFN) responses. IFN production triggered by TLR7 stimulation is a critical anti-viral response. For example, patients with TLR7 variants including loss-of- function variants were associated with severe COVID-19. Taken together, it is important to determine if sedatives/anesthetics mitigate TLR7 function. We have previously showed that TLR7-mediated activation was not affected by volatile anesthetics. However, we found that propofol attenuated TLR7 activation among intravenous sedatives in the reporter assay. TLR7 agonist R837 stimulation increased TNF-α, IL-1ß, IL-6, IL-10, and IFN-ß mRNA levels in bone marrow-derived dendritic cells, while these levels were attenuated by propofol. Our murine lung slice experiments showed that propofol attenuated IFN production. R837 increased IFN-ß expression in the lungs, and propofol attenuated IFN-ß expression in an in vivo model of R837 intranasal instillation. We also found that propofol directly bound to and hindered its association of TLR7 with MyD88. Our analysis using fropofol, propofol derivative showed that the hydroxyl group in propofol was important for propofol-TLR7 interaction.
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COVID-19 , Propofol , Animales , Células Dendríticas , Humanos , Hipnóticos y Sedantes/farmacología , Imiquimod , Interferón-alfa/metabolismo , Interferón beta/metabolismo , Ratones , Propofol/análogos & derivados , Propofol/farmacología , ARN Viral/metabolismo , SARS-CoV-2 , Receptor Toll-Like 7RESUMEN
Acute lung injury is one of major complications associated with sepsis, responsible for morbidity and mortality. Patients who suffer from acute lung injury often require respiratory support under sedations, and it would be important to know the role of sedatives in lung injury. We examined volatile anesthetic isoflurane, which is commonly used in surgical setting, but also used as an alternative sedative in intensive care settings in European countries and Canada. We found that isoflurane exposure attenuated neutrophil recruitment to the lungs in mice suffering from experimental polymicrobial abdominal sepsis. We found that isoflurane attenuated one of major neutrophil chemoattractants LTB4 mediated response via its receptor BLT1 in neutrophils. Furthermore, we have shown that isoflurane directly bound to BLT1 by a competition assay using newly developed labeled BLT1 antagonist, suggesting that isoflurane would be a BLT1 antagonist.
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Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/etiología , Isoflurano/farmacología , Sepsis/complicaciones , Anestésicos por Inhalación/farmacología , Animales , Quimiotaxis/efectos de los fármacos , Modelos Animales de Enfermedad , Eicosanoides/metabolismo , Isoflurano/química , Isoflurano/metabolismo , Leucotrieno B4/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , Infiltración Neutrófila/efectos de los fármacos , Receptores de Leucotrieno B4/antagonistas & inhibidores , Receptores de Leucotrieno B4/química , Receptores de Leucotrieno B4/metabolismo , Sepsis/fisiopatologíaRESUMEN
OBJECTIVES: Although neonates and infants undergoing cardiac surgery on cardiopulmonary bypass (CPB) are at high risk of developing perioperative morbidity and mortality, including lung injury, the intraoperative profile of lung injury in this cohort is not well-described. Given that the postoperative course of patients in the pediatric cardiac surgical arena has become increasingly expedited, the objective of this study was to characterize the profiles of postoperative mechanical ventilatory support in neonates and infants undergoing cardiac surgery on CPB and to examine the characteristics of lung mechanics and lung injury in this patient population who are potentially amendable to early postoperative recovery in a single tertiary pediatric institution. DESIGN: A retrospective data analysis of neonates and infants who underwent cardiac surgery on cardiopulmonary bypass. SETTING: A single-center, university teaching hospital. PARTICIPANTS: The study included 328 neonates and infants who underwent cardiac surgery on cardiopulmonary bypass. INTERVENTIONS: A subset of 128 patients were studied: 58 patients undergoing ventricular septal defect (VSD) repair, 36 patients undergoing complete atrioventricular canal (CAVC) repair, and 34 patients undergoing bidirectional Glenn (BDG) shunt surgery. MEASUREMENTS AND MAIN RESULTS: Of the entire cohort, 3.7% experienced in-hospital mortality. Among all surgical procedures, VSD repair (17.7%) was the most common, followed by CAVC repair (11.0%) and BDG shunt surgery (10.4%). Of patients who underwent VSD repair, CAVC repair, and BDG shunt surgery, 65.5%, 41.7%, and 67.6% were off mechanical ventilatory support within 24 hours postoperatively, respectively. In all three of the surgical repairs, lung compliance decreased after CPB compared to pre-CPB phase. Sixty point three percent of patients with VSD repair and 77.8% of patients with CAVC repair showed a PaO2/FIO2 (P/F) ratio of <300 after CPB. Post- CPB P/F ratios of 120 for VSD patients and 100 for CAVC patients were considered as optimal cutoff values to highly predict prolonged (>24 hours) postoperative mechanical ventilatory support. A higher volume of transfused platelets also was associated with postoperative ventilatory support ≥24 hours in patients undergoing VSD repair, CAVC repair, and BDG shunt surgery. CONCLUSIONS: There was a high incidence of lung injury after CPB in neonates and infants, even in surgeries amendable for early recovery. Given that CPB-related factors (CPB duration, crossclamp time) and volume of transfused platelet were significantly associated with prolonged postoperative ventilatory support, the underlying cause of cardiac surgery-related lung injury can be multi-factorial.
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Procedimientos Quirúrgicos Cardíacos , Defectos del Tabique Interventricular , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Puente Cardiopulmonar/efectos adversos , Niño , Defectos del Tabique Interventricular/cirugía , Humanos , Lactante , Recién Nacido , Respiración Artificial , Estudios RetrospectivosRESUMEN
A growing literature has shown that volatile anesthetics are promiscuous molecules targeting multiple molecules, some of which are critical for immunological functions. We focused on studies that delineated target molecules of volatile anesthetics on immune cells and summarized the effects of volatile anesthetics on immune functions. We also presented the perspectives of studying volatile anesthetics-mediated immunomodulation.
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Anestésicos por Inhalación/farmacología , Macrófagos/inmunología , Monocitos/inmunología , Neutrófilos/inmunología , Fagocitosis/efectos de los fármacos , Desflurano/farmacología , Humanos , Isoflurano/farmacología , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Infiltración Neutrófila/efectos de los fármacos , Infiltración Neutrófila/inmunología , Neutrófilos/efectos de los fármacos , Fagocitosis/inmunología , Sevoflurano/farmacologíaRESUMEN
Isoflurane and sevoflurane are volatile anesthetics (VA) widely used in clinical practice to provide general anesthesia. We and others have previously shown that VAs have immunomodulatory effects and may have a significant impact on the progression of disease states. Flagellin is a component of Gram negative bacteria and plays a significant role in the pathophysiology of bacterial pneumonia through its binding to Toll-like Receptor 5 (TLR5). Our results showed that VAs, not an intravenous anesthetic, significantly attenuated the activation of TLR5 and the release of the neutrophil chemoattractant IL-8 from lung epithelial cells. Furthermore, flagellin-induced lung injury was significantly attenuated by VAs by inhibiting neutrophil migration to the bronchoalveolar space. The lungs of cystic fibrosis (CF) patients are highly colonized by Pseudomonas aeruginosa, which causes inflammation. The retrospective study of oxygenation in patients with CF who had received VA versus intravenous anesthesia suggested that VAs might have the protective effect for gas exchange. To understand the interaction between VAs and TLR5, a docking simulation was performed, which indicated that isoflurane and sevoflurane docked into the binding interphase between TLR5 and flagellin.
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Anestésicos por Inhalación/farmacología , Fibrosis Quística/microbiología , Células Epiteliales/efectos de los fármacos , Flagelina/toxicidad , Inflamación/prevención & control , Pulmón/efectos de los fármacos , Infecciones por Pseudomonas/tratamiento farmacológico , Receptor Toll-Like 5/metabolismo , Anestésicos por Inhalación/química , Animales , Línea Celular Tumoral , Fibrosis Quística/complicaciones , Células Epiteliales/metabolismo , Femenino , Flagelina/química , Humanos , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-8/metabolismo , Isoflurano/química , Isoflurano/farmacología , Pulmón/metabolismo , Pulmón/microbiología , Pulmón/patología , Masculino , Ratones , Simulación del Acoplamiento Molecular , FN-kappa B/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Infecciones por Pseudomonas/complicaciones , Infecciones por Pseudomonas/metabolismo , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/inmunología , Estudios Retrospectivos , Sevoflurano/química , Sevoflurano/farmacología , Receptor Toll-Like 5/química , Receptor Toll-Like 5/genéticaRESUMEN
Toll like receptors (TLRs) are critical receptors to respond to danger signals, and their functions are relevant in the perioperative period. We previously reported that volatile anesthetics directly bound to TLR2 and TLR4 and attenuated their functions. Given that TLR9 can respond to mitochondrial DNA, a danger signal that is released upon tissue injury, we examined the role of anesthetics on TLR9 function. Our reporter assay showed that volatile anesthetics isoflurane and sevoflurane increased the activation of TLR9, while propofol attenuated it. TLR9 activation occurs via its dimerization. The dimerization is facilitated by unmethylated cytosine-phosphate-guanine (CpG) DNA as well as DNA containing cytosine at the second position from 5'-end (5'-xCx DNA). Our structural analysis using photoactivable anesthetics and rigid docking simulation showed that isoflurane and sevoflurane bound to both TLR9 dimer interface and 5'-xCx DNA binding site. Propofol bound to the TLR9 antagonist binding site. This is the first illustration that anesthetics can affect the binding of nucleic acids to their receptor. This study sets the foundation for the effect of anesthetics on TLR9 and will pave the way for future studies to determine the significance of such interactions in the clinical setting.
Asunto(s)
Anestésicos por Inhalación/farmacología , Isoflurano/farmacología , Sevoflurano/farmacología , Receptor Toll-Like 9/química , Anestésicos por Inhalación/química , Animales , Sitios de Unión , Células HEK293 , Caballos , Humanos , Isoflurano/química , Ratones , Simulación del Acoplamiento Molecular , Unión Proteica , Multimerización de Proteína , Sevoflurano/química , Receptor Toll-Like 9/metabolismoRESUMEN
With a significant improvement of survival in patients with congenital heart disease, we expect to encounter these patients more frequently for various medical issues. Clinical studies indicate that infection can pose higher risk in this cohort than general population. Here, with the hypothesis that more severe infection-related complications in CHD cohort may be linked to their inadequate immune response, we reviewed the current literature regarding neutrophil and T cell functions in patients with congenital heart diseases.
Asunto(s)
Cardiopatías Congénitas , Neutrófilos , Estudios de Cohortes , Humanos , Linfocitos TRESUMEN
In December 2019, a novel coronavirus, now named as SARS-CoV-2, caused a series of acute atypical respiratory diseases in Wuhan, Hubei Province, China. The disease caused by this virus was termed COVID-19. The virus is transmittable between humans and has caused pandemic worldwide. The number of death tolls continues to rise and a large number of countries have been forced to do social distancing and lockdown. Lack of targeted therapy continues to be a problem. Epidemiological studies showed that elder patients were more susceptible to severe diseases, while children tend to have milder symptoms. Here we reviewed the current knowledge about this disease and considered the potential explanation of the different symptomatology between children and adults.
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Betacoronavirus/patogenicidad , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/fisiopatología , Pandemias , Peptidil-Dipeptidasa A/genética , Neumonía Viral/epidemiología , Neumonía Viral/fisiopatología , Glicoproteína de la Espiga del Coronavirus/genética , Factores de Edad , Anciano , Enzima Convertidora de Angiotensina 2 , Animales , Betacoronavirus/inmunología , COVID-19 , Niño , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Citocinas/genética , Citocinas/inmunología , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Ratones , Peptidil-Dipeptidasa A/inmunología , Neumonía Viral/inmunología , Neumonía Viral/virología , SARS-CoV-2 , Transducción de Señal , Glicoproteína de la Espiga del Coronavirus/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/virologíaRESUMEN
Sepsis remains a significant health care burden, with high morbidities and mortalities. Patients with sepsis often require general anesthesia for procedures and imaging studies. Knowing that anesthetic drugs can pose immunomodulatory effects, it would be critical to understand the impact of anesthetics on sepsis pathophysiology. The volatile anesthetic sevoflurane is a common general anesthetic derived from ether as a prototype. Using a murine sepsis model induced by cecal ligation and puncture surgery, we examined the impact of sevoflurane on sepsis outcome. Different from volatile anesthetic isoflurane, sevoflurane exposure significantly improved the outcome of septic mice. This was associated with less apoptosis in the spleen. Because splenic apoptosis was largely attributed to the apoptosis of neutrophils, we examined the effect of sevoflurane on FasL-induced neutrophil apoptosis. Sevoflurane exposure significantly attenuated apoptosis. Sevoflurane did not affect the binding of FasL to the extracellular domain of Fas receptor. Instead, in silico analysis suggested that sevoflurane would bind to the interphase between Fas death domain (DD) and Fas-associated DD (FADD). The effect of sevoflurane on Fas DD-FADD interaction was examined using fluorescence resonance energy transfer (FRET). Sevoflurane attenuated FRET efficiency, indicating that sevoflurane hindered the interaction between Fas DD and FADD. The predicted sevoflurane binding site is known to play a significant role in Fas DD-FADD interaction, supporting our in vitro and in vivo apoptosis results.-Koutsogiannaki, S., Hou, L., Babazada, H., Okuno, T., Blazon-Brown, N., Soriano, S. G., Yokomizo, T., Yuki, K. The volatile anesthetic sevoflurane reduces neutrophil apoptosis via Fas death domain-Fas-associated death domain interaction.
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Apoptosis/efectos de los fármacos , Proteína de Dominio de Muerte Asociada a Fas , Neutrófilos/metabolismo , Receptor fas , Animales , Sitios de Unión , Proteína de Dominio de Muerte Asociada a Fas/química , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Ratones , Neutrófilos/citología , Sevoflurano/química , Sevoflurano/farmacología , Receptor fas/química , Receptor fas/metabolismoRESUMEN
General anesthesia has been the requisite component of surgical procedures for over 150 yr. Although immunomodulatory effects of volatile anesthetics have been growingly appreciated, the molecular mechanism has not been understood. In septic mice, the commonly used volatile anesthetic isoflurane attenuated the production of 5-lipoxygenase products and IL-10 and reduced CD11b and intercellular adhesion molecule-1 expression on neutrophils, suggesting the attenuation of TLR4 signaling. We confirmed the attenuation of TLR4 signaling in vitro and their direct binding to TLR4-myeloid differentiation-2 (MD-2) complex by photolabeling experiments. The binding sites of volatile anesthetics isoflurane and sevoflurane were located near critical residues for TLR4-MD-2 complex formation and TLR4-MD-2-LPS dimerization. Additionally, TLR4 activation was not attenuated by intravenous anesthetics, except for a high concentration of propofol. Considering the important role of TLR4 system in the perioperative settings, these findings suggest the possibility that anesthetic choice may modulate the outcome in patients or surgical cases in which TLR4 activation is expected.-Okuno, T., Koutsogiannaki, S., Hou, L., Bu, W., Ohto, U., Eckenhoff, R. G., Yokomizo, T., Yuki, K. Volatile anesthetics isoflurane and sevoflurane directly target and attenuate Toll-like receptor 4 system.
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Anestésicos por Inhalación/farmacología , Isoflurano/farmacología , Sevoflurano/farmacología , Receptor Toll-Like 4/metabolismo , Animales , Sitios de Unión , Células Cultivadas , Antígeno 96 de los Linfocitos/química , Antígeno 96 de los Linfocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Unión Proteica , Multimerización de Proteína , Receptor Toll-Like 4/químicaRESUMEN
BACKGROUND: Previously we have shown that volatile anesthetic isoflurane attenuated neutrophil recruitment and phagocytosis in mouse sepsis and skin inflammation models. The objectives of this study were to test ex vivo function of neutrophils in patients who underwent cardiac catheterization under volatile anesthesia versus intravenous anesthesia (IA), and also to assess the effect of anesthesia on surgical site infections (SSIs) using mouse model to understand the clinical relevance of anesthesia-induced immunomodulation. METHODS: Whole blood from patients who underwent cardiac catheterization procedures either by volatile anesthesia or IA was collected and subjected to phagocytosis assay and a lipopolysaccharide-induced tumor necrosis factor-α assay. Mouse SSI with Staphylococcus aureus USA300 was created, and the effect of isoflurane and propofol exposure (short or long exposure) on bacterial loads was tested. RESULTS: Neutrophil phagocytosis was significantly attenuated after the induction of volatile anesthesia in patients, but not by IA. Monocyte phagocytosis was not affected by the anesthesia regimen. Bacterial loads following SSIs were significantly higher in mice receiving long, but not short, isoflurane exposure. Propofol exposure did not affect bacterial loads. DISCUSSION: Neutrophil phagocytosis can be affected by the type of anesthesia, and preclinical model of SSIs showed potential clinical relevance. The effects of anesthesia regimen on SSIs in patients needs to be studied extensively in the future.
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Anestésicos por Inhalación/efectos adversos , Carga Bacteriana/inmunología , Neutrófilos/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Infección de la Herida Quirúrgica/inmunología , Adolescente , Adulto , Anestésicos por Inhalación/administración & dosificación , Anestésicos Intravenosos/administración & dosificación , Anestésicos Intravenosos/efectos adversos , Animales , Carga Bacteriana/efectos de los fármacos , Cateterismo Cardíaco/efectos adversos , Niño , Preescolar , Modelos Animales de Enfermedad , Escherichia coli/inmunología , Femenino , Humanos , Isoflurano/administración & dosificación , Isoflurano/efectos adversos , Masculino , Ratones , Neutrófilos/inmunología , Propofol/administración & dosificación , Propofol/efectos adversos , Staphylococcus aureus/inmunología , Staphylococcus aureus/aislamiento & purificación , Infección de la Herida Quirúrgica/microbiología , Infección de la Herida Quirúrgica/prevención & control , Adulto JovenRESUMEN
Complement-mediated opsonization, phagocytosis, and immune stimulation are critical processes in host defense and homeostasis, with the complement activation fragment iC3b playing a key effector role. To date, however, there is no high-resolution structure of iC3b, and some aspects of its structure-activity profile remain controversial. Here, we employed hydrogen-deuterium exchange mass spectrometry to describe the structure and dynamics of iC3b at a peptide resolution level in direct comparison with its parent protein C3b. In our hydrogen-deuterium exchange mass spectrometry study, 264 peptides were analyzed for their deuterium content, providing almost complete sequence coverage for this 173-kDa protein. Several peptides in iC3b showed significantly higher deuterium uptake when compared with C3b, revealing more dynamic, solvent-exposed regions. Most of them resided in the CUB domain, which contains the heptadecapeptide C3f that is liberated during the conversion of C3b to iC3b. Our data suggest a highly disordered CUB, which has acquired a state similar to that of intrinsically disordered proteins, resulting in a predominant form of iC3b that features high structural flexibility. The structure was further validated using an anti-iC3b mAb that was shown to target an epitope in the CUB region. The information obtained in this work allows us to elucidate determinants of iC3b specificity and activity and provide functional insights into the protein's recognition pattern with respect to regulators and receptors of the complement system.
Asunto(s)
Complemento C3b/química , Medición de Intercambio de Deuterio/métodos , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Humanos , Espectrometría de Masas , Estructura Cuaternaria de Proteína , Resonancia por Plasmón de SuperficieRESUMEN
The central component of the complement cascade, C3, is involved in various biological functions, including opsonization of foreign bodies, clearance of waste material, activation of immune cells, and triggering of pathways controlling development. Given its broad role in immune responses, particularly in phagocytosis and the clearance of microbes, a deficiency in complement C3 in humans is often associated with multiple bacterial infections. Interestingly, an increased susceptibility to infections appears to occur mainly in the first two years of life and then wanes throughout adulthood. In view of the well-established connection between C3 deficiency and infections, therapeutic inhibition of complement at the level of C3 is often considered with caution or disregarded. We therefore set out to investigate the immune and biochemical profile of non-human primates under prolonged treatment with the C3 inhibitor compstatin (Cp40 analog). Cynomolgus monkeys were dosed subcutaneously with Cp40, resulting in systemic inhibition of C3, for 1â¯week, 2â¯weeks, or 3â¯months. Plasma concentrations of both C3 and Cp40 were measured periodically and complete saturation of plasma C3 was confirmed. No differences in hematological, biochemical, or immunological parameters were identified in the blood or tissues of animals treated with Cp40 when compared to those injected with vehicle alone. Further, skin wounds showed no signs of infection in those treated with Cp40. In fact, Cp40 treatment was associated with a trend toward accelerated wound healing when compared with the control group. In addition, a biodistribution study in a rhesus monkey indicated that the distribution of Cp40 in the body is associated with the presence of C3, concentrating in organs that accumulate blood and produce C3. Overall, our data suggest that systemic C3 inhibition in healthy adult non-human primates is not associated with a weakened immune system or susceptibility to infections.
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Complemento C3/antagonistas & inhibidores , Inactivadores del Complemento/toxicidad , Péptidos Cíclicos/toxicidad , Cicatrización de Heridas/inmunología , Infección de Heridas/epidemiología , Animales , Complemento C3/inmunología , Complemento C3/metabolismo , Inactivadores del Complemento/farmacocinética , Macaca fascicularis , Macaca mulatta , Péptidos Cíclicos/farmacocinética , Factores de Tiempo , Distribución Tisular , Heridas y Lesiones/inmunologíaRESUMEN
Propofol is an intravenous anesthetic that produces its anesthetic effect, largely via the GABAA receptor in the CNS, and also reduces the N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophil respiratory burst. Because fMLP-stimulated neutrophils produce leukotriene (LT)B4, we examined the effect of propofol on LTB4 production in vivo and in vitro Cecal ligation and puncture surgery was performed in mice, with or without exposure to propofol. Propofol attenuated the production of 5-lipoxygenase (5-LOX)-related arachidonic acid (AA) derivatives in the peritoneal fluid. Also, in the in vitro experiments on fMLP-stimulated neutrophils and 5-LOX-transfected human embryonic kidney cells, propofol attenuated the production of 5-LOX-related AA derivatives. Based on these results, we hypothesized that propofol would directly affect 5-LOX function. Using meta-azi-propofol (AziPm), we photolabeled stable 5-LOX protein, which had been used to solve the X-ray crystallographic structure of 5-LOX, and examined the binding site(s) of propofol on 5-LOX. Two propofol binding pockets were identified near the active site of 5-LOX. Alanine scanning mutagenesis was performed for the residues of 5-LOX in the vicinity of propofol, and we evaluated the functional role of these pockets in LTB4 production. We demonstrated that these pockets were functionally important for 5-LOX activity. These two pockets can be used to explore a novel 5-LOX inhibitor in the future.-Okuno, T., Koutsogiannaki, S., Ohba, M., Chamberlain, M., Bu, W., Lin, F.-Y., Eckenhoff, R. G., Yokomizo T., Yuki, K. Intravenous anesthetic propofol binds to 5-lipoxygenase and attenuates leukotriene B4 production.
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Anestésicos Intravenosos/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , Propofol/farmacología , Animales , Araquidonato 5-Lipooxigenasa/química , Araquidonato 5-Lipooxigenasa/genética , Ácidos Araquidónicos/metabolismo , Sitios de Unión , Células Cultivadas , Células HEK293 , Humanos , Leucotrieno B4/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Unión ProteicaRESUMEN
BACKGROUND: While mortality and adverse perioperative events after noncardiac surgery in children with a broad range of congenital cardiac lesions have been investigated using large multiinstitutional databases, to date single-center studies addressing adverse outcomes in children with congenital heart disease (CHD) undergoing noncardiac surgery have only included small numbers of patients with significant heart disease. The primary objective of this study was to determine the incidences of perioperative cardiovascular and respiratory events in a large cohort of patients from a single institution with a broad range of congenital cardiac lesions undergoing noncardiac procedures and to determine risk factors for these events. METHODS: We identified 3010 CHD patients presenting for noncardiac procedures in our institution over a 5-year period. We collected demographic information, including procedure performed, cardiac diagnosis, ventricular function as assessed by echocardiogram within 6 months of the procedure, and classification of CHD into 3 groups (minor, major, or severe CHD) based on residual lesion burden and cardiovascular functional status. Characteristics related to conduct of anesthesia care were also collected. The primary outcome variables for our analysis were the incidences of intraoperative cardiovascular and respiratory events. Univariable and multivariable logistic regressions were used to determine risk factors for these 2 outcomes. RESULTS: The incidence of cardiovascular events was 11.5% and of respiratory events was 4.7%. Univariate analysis and multivariable analysis demonstrated that American Society of Anesthesiologists (≥3), emergency cases, major and severe CHD, single-ventricle physiology, ventricular dysfunction, orthopedic surgery, general surgery, neurosurgery, and pulmonary procedures were associated with perioperative cardiovascular events. Respiratory events were associated with American Society of Anesthesiologists (≥4) and otolaryngology, gastrointestinal, general surgery, and maxillofacial procedures. CONCLUSIONS: Intraoperative cardiovascular events and respiratory events in patients with CHD were relatively common. While cardiovascular events were highly associated with cardiovascular status, respiratory events were not associated with cardiovascular status.
Asunto(s)
Enfermedades Cardiovasculares/epidemiología , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/cirugía , Complicaciones Posoperatorias/epidemiología , Trastornos Respiratorios/epidemiología , Enfermedades Cardiovasculares/diagnóstico , Niño , Preescolar , Estudios de Cohortes , Bases de Datos Factuales/tendencias , Femenino , Cardiopatías Congénitas/diagnóstico , Humanos , Incidencia , Lactante , Masculino , Complicaciones Posoperatorias/diagnóstico , Trastornos Respiratorios/diagnóstico , Factores de RiesgoRESUMEN
OBJECTIVES: A mathematical model of the oxygen delivery kinetics of the bidirectional Glenn (BDG) shunt circulation incorporating aortopulmonary collateral (APC) flow was created. The model was used to characterize oxygen delivery and compare modeled data to actual patient data obtained using cardiac magnetic resonance imaging (MRI) and catheterization. In addition, cardiac MRI and catheterization assessment of pulmonary blood flow in the presence of APC flow were compared. DESIGN: Mathematical model and retrospective data analysis of patients who underwent cardiac MRI and catheterization. The mathematical model is based on the concept that APC flow to the lungs is recirculated pulmonary venous blood flow, which does not contribute to systemic oxygen delivery. SETTING: Single-center, university teaching hospital. PARTICIPANTS: The study included 98 patients with BDG shunt undergoing cardiac MRI and cardiac catheterization. MEASUREMENTS AND MAIN RESULTS: In the absence of APC flow, the pulmonary blood flow to systemic blood flow ratio (Qp/Qs) calculated using cardiac catheterization data closely matched that obtained with cardiac MRI. In the presence of APC flow, Qp/Qs calculated using cardiac catheterization data systematically underestimated values obtained with cardiac MRI. A mathematical model of BDG shunt oxygen delivery incorporating variable APC flow was created. The model provided reasonable prediction of actual patient data for arterial blood oxygen, superior vena cava oxygen saturation, and oxygen delivery obtained at the time of cardiac catheterization in patients. CONCLUSION: The oxygen delivery kinetics of a BDG shunt incorporating variable APC flow can be modeled mathematically. Model output can be used to predict blood oxygen saturation after coil embolization of APC flow in the cardiac catheterization laboratory.
Asunto(s)
Cateterismo Cardíaco , Circulación Colateral/fisiología , Procedimiento de Fontan , Modelos Teóricos , Oxígeno/metabolismo , Circulación Pulmonar/fisiología , Niño , Preescolar , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND: An increasing number of surgical and nonsurgical procedures are being performed on an ambulatory basis in children. Analysis of a large group of pediatric patients with congenital heart disease undergoing ambulatory procedures has not been undertaken. AIMS: The objective of this study was to characterize the profile of children with congenital heart disease who underwent noncardiac procedures on an ambulatory basis at our institution, to determine the incidence of adverse cardiovascular and respiratory adverse events, and to determine the risk factors for unscheduled hospital admission. METHODS: This is a retrospective study of children with congenital heart disease who underwent noncardiac procedures on an ambulatory basis in a single center. Using the electronic preoperative anesthesia evaluation form, we identified 3010 patients with congenital heart disease who underwent noncardiac procedures of which 1028 (34.1%) were scheduled to occur on an ambulatory basis. Demographic, echocardiographic and functional status data, cardiovascular and respiratory adverse events, and reasons for postprocedure admission were recorded. Univariable analysis was conducted. RESULTS: The unplanned hospital admission was 2.7% and univariable analysis demonstrated that performance of an echocardiogram within 6 mo of the procedure and procedures performed in radiology were associated with postoperative admission. Cardiovascular adverse event incidence was 3.9%. Respiratory adverse event incidence was 1.8%. CONCLUSION: Ambulatory, noncomplex procedures can be performed in pediatric patients with congenital heart disease and good functional status with a relatively low unanticipated hospital admission rate.
Asunto(s)
Procedimientos Quirúrgicos Ambulatorios/estadística & datos numéricos , Cardiopatías Congénitas/epidemiología , Hospitalización/estadística & datos numéricos , Complicaciones Posoperatorias/epidemiología , Boston/epidemiología , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The clinical management of paroxysmal nocturnal hemoglobinuria (PNH), a rare but life-threatening hematologic disease, has fundamentally improved with the introduction of a therapeutic that prevents complement-mediated intravascular hemolysis. However, a considerable fraction of PNH patients show insufficient treatment response and remain transfusion dependent. Because the current treatment only prevents C5-induced lysis but not upstream C3 activation, it has been speculated that ongoing opsonization with C3 fragments leads to recognition and phagocytosis of PNH erythrocytes by immune cells. Here, for the first time, we provide experimental evidence for such extravascular hemolysis and demonstrate that PNH erythrocytes from anti-C5-treated patients are phagocytosed by activated monocytes in vitro. Importantly, we show that this uptake can be mediated by the end-stage opsonin C3dg, which is not traditionally considered a phagocytic marker, via interaction with complement receptor 3 (CR3). Interaction studies confirmed that C3dg itself can act as a ligand for the binding domain of CR3. The degree of C3dg-mediated erythrophagocytosis in samples from different PNH patients correlated well with the individual level of C3dg opsonization. This finding may guide future treatment options for PNH but also has potential implications for the description and management of other complement-mediated diseases.