RESUMEN
BACKGROUND: Propofol-based total intravenous anesthesia is gaining popularity in pediatric anesthesia. Electroencephalogram can be used to guide propofol dosing to the individual patient to mitigate against overdosing and adverse events. However, electroencephalogram interpretation and propofol pharmacokinetics are not sufficiently taught in training programs to confidently deploy electroencephalogram-guided total intravenous anesthesia. AIMS: We conducted a quality improvement project with the smart aim of increasing the percentage of electroencephalogram-guided total intravenous anesthesia cases in our main operating room from 0% to 80% over 18 months. Balancing measures were number of total intravenous anesthesia cases, emergence times, and perioperative emergency activations. METHODS: The project key drivers were education, equipment, and electronic health record modifications. Plan-Do-Study-Act cycles included: (1) providing journal articles, didactic lectures, intraoperative training, and teaching documents; (2) scheduling electroencephalogram-guided total intravenous anesthesia teachers to train faculty, staff, and fellows for specific cases and to assess case-based knowledge; (3) adding age-based propofol dosing tables and electroencephalogram parameters to the electronic health record (EPIC co, Verona, WI); (4) procuring electroencephalogram monitors (Sedline, Masimo Inc). Electroencephalogram-guided total intravenous anesthesia cases and balancing measures were identified from the electronic health record. The smart aim was evaluated by statistical process control chart. RESULTS: After the four Plan-Do-Study-Act cycles, electroencephalogram-guided total intravenous anesthesia increased from 5% to 75% and was sustained at 72% 9 months after project completion. Total intravenous anesthesia cases/mo and number of perioperative emergency activations did not change significantly from start to end of the project, while emergence time for electroencephalogram-guided total intravenous anesthesia was greater statistically but not clinically (total intravenous anesthesia without electroencephalogram [16 ± 10 min], total intravenous anesthesia with electroencephalogram [18 ± 9 min], sevoflurane [17 ± 9 min] p < .001). CONCLUSION: Quality improvement methods may be deployed to adopt electroencephalogram-guided total intravenous anesthesia in a large academic pediatric anesthesia practice. Keys to success include education, in operating room case training, scheduling teachers with learners, electronic health record modifications, and electroencephalogram devices and supplies.
Asunto(s)
Propofol , Niño , Humanos , Anestésicos Intravenosos , Hospitales Pediátricos , Mejoramiento de la Calidad , Anestesia General/métodos , Electroencefalografía , Anestesia Intravenosa/métodosRESUMEN
BACKGROUND: Propofol total intravenous anesthesia (TIVA) is increasingly popular in pediatric anesthesia, but education on its use is variable and over-dosage adverse events are not uncommon. Recent work suggests that electroencephalogram (EEG) parameters can guide propofol dosing in the pediatric population. This education quality improvement project aimed to implement a standardized EEG TIVA training program over 12 months in a large pediatric anesthesia division. METHODS: The division consisted of 63 faculty, 11 clinical fellows, 32 residents, and 28 nurse anesthetists at the Children's Hospital of Philadelphia. The program was assessed for effectiveness (a significant improvement in EEG knowledge scores), scalability (training 50% of fellows and staff), and sustainability (recurring EEG lectures for 80% of rotating residents and 100% of new fellows and staff). The key drivers included educational content development (lectures, articles, and hand-outs), training a cohort of EEG TIVA trainers, intraoperative teaching (teaching points and dosing tables), decision support tools (algorithms and anesthesia electronic record pop-ups), and knowledge tests (written exam and verbal quiz during cases). RESULTS: Over 12 months, 78.5% of the division (62/79) completed EEG training and test scores improved (mean score 38% before training vs 59% after training, p < .001). Didactic lectures were given to 100% of the fellows, 100% (11/11) of new staff, and 80% (4/5 blocks) of rotating residents. CONCLUSION: This quality improvement education project successfully trained pediatric anesthesia faculty, staff, residents, and fellows in EEG-guided TIVA. The training program was effective, scalable, and sustainable over time for newly hired faculty staff and rotating fellows and residents.
Asunto(s)
Anestesia , Anestesiología , Propofol , Anestesiología/educación , Niño , Electroencefalografía , Humanos , PhiladelphiaRESUMEN
Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd) develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs), however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical alteration at airway opening, to a greater extent than overt acinar wall destruction. Model-predicted deficits in PEEP-dependent lung recruitment correlate with altered lung lining fluid composition independent of age or genotype.
Asunto(s)
Envejecimiento , Inflamación , Enfermedades Pulmonares , Pulmón , Modelos Biológicos , Envejecimiento/metabolismo , Envejecimiento/patología , Envejecimiento/fisiología , Animales , Enfermedad Crónica , Biología Computacional , Inflamación/metabolismo , Inflamación/patología , Inflamación/fisiopatología , Pulmón/anatomía & histología , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Enfermedades Pulmonares/metabolismo , Enfermedades Pulmonares/patología , Enfermedades Pulmonares/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Exposure to World Trade Center (WTC) dust has been linked to respiratory disease in humans. In the present studies we developed a rodent model of WTC dust exposure to analyze lung oxidative stress and inflammation, with the goal of elucidating potential epigenetic mechanisms underlying these responses. Exposure of mice to WTC dust (20µg, i.t.) was associated with upregulation of heme oxygenase-1 and cyclooxygenase-2 within 3days, a response which persisted for at least 21days. Whereas matrix metalloproteinase was upregulated 7days post-WTC dust exposure, IL-6RA1 was increased at 21days; conversely, expression of mannose receptor, a scavenger receptor important in particle clearance, decreased. After WTC dust exposure, increases in methylation of histone H3 lysine K4 at 3days, lysine K27 at 7days and lysine K36, were observed in the lung, along with hypermethylation of Line-1 element at 21days. Alterations in pulmonary mechanics were also observed following WTC dust exposure. Thus, 3days post-exposure, lung resistance and tissue damping were decreased. In contrast at 21days, lung resistance, central airway resistance, tissue damping and tissue elastance were increased. These data demonstrate that WTC dust-induced inflammation and oxidative stress are associated with epigenetic modifications in the lung and altered pulmonary mechanics. These changes may contribute to the development of WTC dust pathologies.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Polvo , Epigénesis Genética , Inflamación/diagnóstico , Estrés Oxidativo , Animales , Western Blotting , Ciclooxigenasa 2/metabolismo , Citocinas/genética , Metilación de ADN/efectos de los fármacos , Femenino , Expresión Génica/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Histonas/metabolismo , Humanos , Inmunohistoquímica , Inflamación/etiología , Inflamación/genética , Exposición por Inhalación , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/fisiopatología , Lisina/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Metilación/efectos de los fármacos , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ataques Terroristas del 11 de Septiembre , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Surfactant protein D (SP-D) modulates the lung's immune system. Its absence leads to NOS2-independent alveolar lipoproteinosis and NOS2-dependent chronic inflammation, which is critical for early emphysematous remodeling. With aging, SP-D knockout mice develop an additional interstitial fibrotic component. We hypothesize that this age-related interstitial septal wall remodeling is mediated by NOS2. Using invasive pulmonary function testing such as the forced oscillation technique and quasistatic pressure-volume perturbation and design-based stereology, we compared 29-wk-old SP-D knockout (Sftpd(-/-)) mice, SP-D/NOS2 double-knockout (DiNOS) mice, and wild-type mice (WT). Structural changes, including alveolar epithelial surface area, distribution of septal wall thickness, and volumes of septal wall components (alveolar epithelium, interstitial tissue, and endothelium) were quantified. Twenty-nine-week-old Sftpd(-/-) mice had preserved lung mechanics at the organ level, whereas elastance was increased in DiNOS. Airspace enlargement and loss of surface area of alveolar epithelium coexist with increased septal wall thickness in Sftpd(-/-) mice. These changes were reduced in DiNOS, and compared with Sftpd(-/-) mice a decrease in volumes of interstitial tissue and alveolar epithelium was found. To understand the effects of lung pathology on measured lung mechanics, structural data were used to inform a computational model, simulating lung mechanics as a function of airspace derecruitment, septal wall destruction (loss of surface area), and septal wall thickening. In conclusion, NOS2 mediates remodeling of septal walls, resulting in deposition of interstitial tissue in Sftpd(-/-). Forward modeling linking structure and lung mechanics describes the complex mechanical properties by parenchymatous destruction (emphysema), interstitial remodeling (septal wall thickening), and altered recruitability of acinar airspaces.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Modelos Biológicos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Alveolos Pulmonares/metabolismo , Proteína D Asociada a Surfactante Pulmonar/deficiencia , Mecánica Respiratoria , Animales , Ratones , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo II/genética , Alveolos Pulmonares/patología , Proteína D Asociada a Surfactante Pulmonar/metabolismoRESUMEN
Acute Cl2 exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl2 inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60ppm-hour Cl2 dose, and were euthanized 3, 24 and 48h later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24h, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24h. Cl2 exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO3(-) or NO2(-). Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl2 exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48h, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl2 inhalation.
Asunto(s)
Cloro/toxicidad , Pulmón/efectos de los fármacos , Neumonía/inducido químicamente , Proteínas Asociadas a Surfactante Pulmonar/metabolismo , Resistencia de las Vías Respiratorias , Animales , Biomarcadores/metabolismo , Elasticidad , Exposición a Riesgos Ambientales , Gases , Regulación de la Expresión Génica , Inmunidad Innata/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Rendimiento Pulmonar , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Permeabilidad , Neumonía/genética , Neumonía/inmunología , Neumonía/metabolismo , Neumonía/patología , Neumonía/fisiopatología , Respiración con Presión Positiva , ARN Mensajero/metabolismo , Pruebas de Función Respiratoria , Factores de TiempoRESUMEN
Nitrogen mustard (NM) is a toxic alkylating agent that causes damage to the respiratory tract. Evidence suggests that macrophages and inflammatory mediators including tumor necrosis factor (TNF)α contribute to pulmonary injury. Pentoxifylline is a TNFα inhibitor known to suppress inflammation. In these studies, we analyzed the ability of pentoxifylline to mitigate NM-induced lung injury and inflammation. Exposure of male Wistar rats (150-174 g; 8-10 weeks) to NM (0.125 mg/kg, i.t.) resulted in severe histopathological changes in the lung within 3d of exposure, along with increases in bronchoalveolar lavage (BAL) cell number and protein, indicating inflammation and alveolar-epithelial barrier dysfunction. This was associated with increases in oxidative stress proteins including lipocalin (Lcn)2 and heme oxygenase (HO)-1 in the lung, along with pro-inflammatory/cytotoxic (COX-2(+) and MMP-9(+)), and anti-inflammatory/wound repair (CD163+ and Gal-3(+)) macrophages. Treatment of rats with pentoxifylline (46.7 mg/kg, i.p.) daily for 3d beginning 15 min after NM significantly reduced NM-induced lung injury, inflammation, and oxidative stress, as measured histologically and by decreases in BAL cell and protein content, and levels of HO-1 and Lcn2. Macrophages expressing COX-2 and MMP-9 also decreased after pentoxifylline, while CD163+ and Gal-3(+) macrophages increased. This was correlated with persistent upregulation of markers of wound repair including pro-surfactant protein-C and proliferating nuclear cell antigen by Type II cells. NM-induced lung injury and inflammation were associated with alterations in the elastic properties of the lung, however these were largely unaltered by pentoxifylline. These data suggest that pentoxifylline may be useful in treating acute lung injury, inflammation and oxidative stress induced by vesicants.
Asunto(s)
Lesión Pulmonar Aguda/patología , Mecloretamina/toxicidad , Estrés Oxidativo/efectos de los fármacos , Pentoxifilina/farmacología , Neumonía/inducido químicamente , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Sustancias para la Guerra Química/toxicidad , Ciclooxigenasa 2/metabolismo , Hemo-Oxigenasa 1/metabolismo , Irritantes/toxicidad , Lipocalina 2 , Lipocalinas/metabolismo , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Neumonía/tratamiento farmacológico , Ratas , Ratas Wistar , Receptores CXCR3/metabolismoRESUMEN
In these studies we determined whether progressive pulmonary inflammation associated with aging in surfactant protein D (Sftpd)-/- mice leads to an exacerbated response to ozone. In Sftpd-/- mice, but not wild-type (WT) mice, age-related increases in numbers of enlarged vacuolated macrophages were observed in the lung, along with alveolar wall rupture, type 2 cell hyperplasia, and increased bronchoalveolar lavage protein and cell content. Numbers of heme oxygenase+ macrophages also increased with age in Sftpd-/- mice, together with classically (iNOS+) and alternatively (mannose receptor+, YM-1+, or galectin-3+) activated macrophages. In both WT and Sftpd-/- mice, increasing age from 8 to 27 wk was associated with reduced lung stiffness, as reflected by decreases in resistance and elastance spectra; however, this response was reversed in 80-wk-old Sftpd-/- mice. Ozone exposure (0.8 ppm, 3 h) caused increases in lung pathology, alveolar epithelial barrier dysfunction, and numbers of iNOS+ macrophages in 8- and 27-wk-old Sftpd-/-, but not WT mice at 72 h postexposure. Conversely, increases in alternatively activated macrophages were observed in 8-wk-old WT mice following ozone exposure, but not in Sftpd-/- mice. Ozone also caused alterations in both airway and tissue mechanics in Sftpd-/- mice at 8 and 27 wk, but not at 80 wk. These data demonstrate that mild to moderate pulmonary inflammation results in increased sensitivity to ozone; however, in senescent mice, these responses are overwhelmed by the larger effects of age-related increases in baseline inflammation and lung injury.
Asunto(s)
Envejecimiento , Lesión Pulmonar , Oxidantes Fotoquímicos/efectos adversos , Ozono/efectos adversos , Neumonía , Mecánica Respiratoria/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Envejecimiento/genética , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/genética , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Lesión Pulmonar/fisiopatología , Activación de Macrófagos/efectos de los fármacos , Activación de Macrófagos/genética , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Ratones , Ratones Noqueados , Oxidantes Fotoquímicos/farmacología , Ozono/farmacología , Neumonía/inducido químicamente , Neumonía/genética , Neumonía/metabolismo , Neumonía/patología , Neumonía/fisiopatología , Proteína D Asociada a Surfactante Pulmonar/genética , Proteína D Asociada a Surfactante Pulmonar/metabolismo , Mecánica Respiratoria/genética , Factores de TiempoRESUMEN
Surfactant protein-D (Sftpd) is a pulmonary collectin important in down-regulating macrophage inflammatory responses. In these experiments, we analyzed the effects of chronic macrophage inflammation attributable to loss of Sftpd on the persistence of ozone-induced injury, macrophage activation, and altered functioning in the lung. Wild-type (Sftpd(+/+)) and Sftpd(-/-) mice (aged 8 wk) were exposed to air or ozone (0.8 parts per million, 3 h). Bronchoalveolar lavage (BAL) fluid and tissue were collected 72 hours later. In Sftpd(-/-) mice, but not Sftpd(+/+) mice, increased BAL protein and nitrogen oxides were observed after ozone inhalation, indicating prolonged lung injury and oxidative stress. Increased numbers of macrophages were also present in BAL fluid and in histologic sections from Sftpd(-/-) mice. These cells were enlarged and foamy, suggesting that they were activated. This conclusion was supported by findings of increased BAL chemotactic activity, and increased expression of inducible nitric oxide synthase in lung macrophages. In both Sftpd(+/+) and Sftpd(-/-) mice, inhalation of ozone was associated with functional alterations in the lung. Although these alterations were limited to central airway mechanics in Sftpd(+/+) mice, both central airway and parenchymal mechanics were modified by ozone exposure in Sftpd(-/-) mice. The most notable changes were evident in resistance and elastance spectra and baseline lung function, and in lung responsiveness to changes in positive end-expiratory pressure. These data demonstrate that a loss of Sftpd is associated with prolonged lung injury, oxidative stress, and macrophage accumulation and activation in response to ozone, and with more extensive functional changes consistent with the loss of parenchymal integrity.
Asunto(s)
Contaminantes Atmosféricos/efectos adversos , Lesión Pulmonar/inmunología , Ozono/efectos adversos , Neumonía/inmunología , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Elasticidad , Exposición por Inhalación , Pulmón/inmunología , Pulmón/patología , Pulmón/fisiopatología , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/metabolismo , Activación de Macrófagos , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxidos de Nitrógeno/metabolismo , Neumonía/inducido químicamente , Neumonía/metabolismo , Proteína D Asociada a Surfactante Pulmonar/genética , Proteína D Asociada a Surfactante Pulmonar/metabolismo , Pruebas de Función RespiratoriaRESUMEN
On March 20, 2021, the Columbia University Department of Anesthesiology hosted the Papper virtual event dedicated to an academic discussion of various aspects of coronavirus disease-2019. Dr. Eva Cheung, a pediatric intensivist and pediatric cardiologist, spoke about the clinical challenges associated with tackling multisystem inflammatory syndrome in children, a novel clinical entity in pediatric patients related to coronavirus disease-2019, and the experience with confronting multisystem inflammatory syndrome in children in New York.
Asunto(s)
COVID-19 , COVID-19/complicaciones , Niño , Humanos , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria SistémicaRESUMEN
Mutations in the alveolar epithelial-specific gene encoding for surfactant protein C (SP-C) are linked to pulmonary disease. Ozone (O3) is a ubiquitous pollutant known to exacerbate stress through oxidative injury and inflammation. To comprehend the structural, functional, and immunological impact of single and repeated O3 exposure, SP-CWT and surfactant protein-C I73T mutant (SP-CI73T) mice were exposed to air or O3 (0.8 ppm, 3 h, up to ×4 consecutive days). O3 was associated with mitochondrial and autophagic activation (PINK1, LC3B, and p62), focal remodeling, and inflammation localized at the terminal bronchiole-to-alveolar junctions. Histological damage was exacerbated by repeated exposure. Single O3 challenge resulted in transient elastin fiber loss, whereas repeated exposure resulted in marked increases in elastance in SP-CI73T mice. Flow cytometric analysis revealed increases in classical monocyte and monocyte-derived macrophages recruitment in conditions of repeated exposure, which peaked earlier (24 h) in SP-CI73T mice. Immunohistochemical analysis also showed clustering of Arg-1+ and CD206+ activated cells within regions of remodeled lung. Lymphoid cell analysis identified CX3CR1-B220+ B cells accumulating after single (24/72 h). Repeated exposure produces a switch in the phenotype of these B cells CX3CR1+ (72 h) only in SP-CWT mice. SP-CI73T mutants also displayed depletion in NK1.1+ NKp46+ natural killer cells in lung, as well as bone marrow, blood, and spleen. These results illustrate the cumulative impact of O3 on lung structure and function in healthy lung, and aberrant myeloid and lymphoid recruitment in SP-C mutants responding to challenge. Together, this work highlights the significance of modeling environmental exposure across the spectrum of genetic susceptibility, consistent with human disease.
Asunto(s)
Pulmón , Ozono , Animales , Humanos , Inflamación/patología , Pulmón/patología , Macrófagos , Ratones , Ozono/toxicidad , TensoactivosRESUMEN
The modification of protein cysteine residues underlies some of the diverse biological functions of nitric oxide (NO) in physiology and disease. The formation of stable nitrosothiols occurs under biologically relevant conditions and time scales. However, the factors that determine the selective nature of this modification remain poorly understood, making it difficult to predict thiol targets and thus construct informatics networks. In this review, the biological chemistry of NO will be considered within the context of nitrosothiol formation and degradation whilst considering how specificity is achieved in this important post-translational modification. Since nitrosothiol formation requires a formal one-electron oxidation, a classification of reaction mechanisms is proposed regarding which species undergoes electron abstraction: NO, thiol or S-NO radical intermediate. Relevant kinetic, thermodynamic and mechanistic considerations will be examined and the impact of sources of NO and the chemical nature of potential reaction targets is also discussed.
RESUMEN
Inflammatory changes caused by viruses, bacteria, exposure to toxins, commonly used drugs and even surgical intervention have the potential of causing abnormal epithelial permeability, which is manifest as infiltrative processes on computed tomography (CT), including the widespread infiltrates seen in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS). We utilized a previously published mouse model of ARDS, intranasal delivery of LPS, to induce the alveolar-capillary barrier permeability seen in lung disease. We intravenously injected mice with Cy7 or 68-Gallium (68Ga) labeled mouse albumin and imaged using optical imaging (OI)/CT and PET. We observed significantly increased lung levels of Cy7-albumin on 3D OI/CT, which matched the abnormal appearance on microCT. This uptake correlated with fluorescence seen on sectioned lungs. To examine the translational potential of these findings, we radiolabeled albumin with 68Ga. We found that in mice with LPS-induced lung injury, 68Ga-albumin PET correlated with our optical imaging findings and demonstrated abnormal activity in the lung fields, indicative of abnormal epithelial permeability. These findings indicate 68Ga-albumin can be utilized as a sensitive translational radiotracer for quantifying the abnormal epithelial permeability that is seen in various lung pathologies, including COVID-19 induced pneumonia and ARDS. The ability to use Cy7-albumin 3D OI/CT imaging as a preclinical translational surrogate for 68Ga-albumin offers an accessible high throughput means to rapidly screen potential therapeutics against lung diseases that clinically manifest with endothelial permeability.
RESUMEN
Lung recruitment and derecruitment contribute significantly to variations in the elastance of the respiratory system during mechanical ventilation. However, the decreases in elastance that occur with deep inflation are transient, especially in acute lung injury. Bates and Irvin (8) proposed a model of the lung that recreates time-varying changes in elastance as a result of progressive recruitment and derecruitment of lung units. The model is characterized by distributions of critical opening and closing pressures throughout the lung and by distributions of speeds with which the processes of opening and closing take place once the critical pressures have been achieved. In the present study, we adapted this model to represent a mechanically ventilated mouse. We fit the model to data collected in a previous study from control mice and mice in various stages of acid-induced acute lung injury (3). Excellent fits to the data were obtained when the normally distributed critical opening pressures were about 5 cmH(2)O above the closing pressures and when the hyperbolically distributed opening velocities were about an order of magnitude greater than the closing velocities. We also found that, compared with controls, the injured mice had markedly increased opening and closing pressures but no change in the velocities, suggesting that the key biophysical change wrought by acid injury is dysfunction of surface tension at the air-liquid interface. Our computational model of lung recruitment and derecruitment dynamics is thus capable of accurately mimicking data from mice with acute lung injury and may provide insight into the altered biophysics of the injured lung.
Asunto(s)
Enfermedades Pulmonares/fisiopatología , Pulmón/fisiopatología , Reclutamiento Neurofisiológico/fisiología , Presión del Aire , Algoritmos , Animales , Fenómenos Biomecánicos , Simulación por Computador , Elasticidad , Ácido Clorhídrico , Enfermedades Pulmonares/inducido químicamente , Ratones , Modelos Estadísticos , Respiración con Presión Positiva , Alveolos Pulmonares/fisiología , Respiración ArtificialRESUMEN
Here we examine the organ level toxicology of both carbon black (CB) and silver nanoparticles (AgNP). We aim to determine metal-specific effects to respiratory function, inflammation and potential interactions with lung lining fluid (LLF). C57Bl6/J male mice were intratracheally instilled with saline (control), low (0.05 µg/g) or high (0.5 µg/g) doses of either AgNP or CB 15 nm nanospheres. Lung histology, cytology, surfactant composition and function, inflammatory gene expression, and pulmonary function were measured at 1, 3, and 7 days post-exposure. Acutely, high dose CB resulted in an inflammatory response, increased neutrophilia and cytokine production, without alteration in surfactant composition or respiratory mechanics. Low dose CB had no effect. Neither low nor high dose AgNPs resulted in an acute inflammatory response, but there was an increase in work of breathing. Three days post-exposure with CB, a persistent neutrophilia was noted. High dose AgNP resulted in an elevated number of macrophages and invasion of lymphocytes. Additionally, AgNP treated mice displayed increased expression of IL1B, IL6, CCL2, and IL10. However, there were no significant changes in respiratory mechanics. At day 7, inflammation had resolved in AgNP-treated mice, but tissue stiffness and resistance were significantly decreased, which was accompanied by an increase in surfactant protein D (SP-D) content. These data demonstrate that the presence of metal alters the response of the lung to nanoparticle exposure. AgNP-surfactant interactions may alter respiratory function and result in a delayed immune response, potentially due to modified airway epithelial cell function.
RESUMEN
Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05 µg/g body weight) 20 and 110 nm diameter in size, and functionalized with citrate or polyvinylpyrrolidone. Both size and functionalization were significant factors in particle aggregation and lipid interaction in vitro. One day post-intratracheal instillation lung function was assessed, and bronchoalveolar lavage (BAL) and lung tissue collected. There were no signs of overt inflammation. There was no change in surfactant protein-B content in the BAL but there was loss of surfactant protein-D with polyvinylpyrrolidone (PVP)-stabilized particles. Mechanical impedance data demonstrated a significant increase in pulmonary elastance as compared to control, greatest with 110 nm PVP-stabilized particles. Seven days post-instillation of PVP-stabilized particles increased BAL cell counts, and reduced lung function was observed. These changes resolved by 21 days. Hence, AgNP-mediated alterations in the lung lining and mechanical function resolve by 21 days. Larger particles and PVP stabilization produce the largest disruptions. These studies demonstrate that low dose AgNPs elicit deficits in both mechanical and innate immune defense function, suggesting that organ level toxicity should be considered.
Asunto(s)
Inmunidad Innata/efectos de los fármacos , Nanopartículas del Metal/toxicidad , Mecánica Respiratoria/efectos de los fármacos , Plata/toxicidad , Animales , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Tamaño de la Partícula , Respiración con Presión Positiva , Povidona/farmacologíaRESUMEN
In these studies, we analyzed the effects of ozone on bronchiolar epithelium. Exposure of rats to ozone (2 ppm, 3 h) resulted in rapid (within 3 h) and persistent (up to 72 h) histological changes in the bronchiolar epithelium, including hypercellularity, loss of cilia, and necrotizing bronchiolitis. Perivascular edema and vascular congestion were also evident, along with a decrease in Clara cell secretory protein in bronchoalveolar lavage, which was maximal 24 h post-exposure. Ozone also induced the appearance of 8-hydroxy-2'-deoxyguanosine, Ym1, and heme oxygenase-1 in the bronchiolar epithelium. This was associated with increased expression of cleaved caspase-9 and beclin-1, indicating initiation of apoptosis and autophagy. A rapid and persistent increase in galectin-3, a regulator of epithelial cell apoptosis, was also observed. Following ozone exposure (3-24 h), increased expression of cyclooxygenase-2, inducible nitric oxide synthase, and arginase-1 was noted in bronchiolar epithelium. Ozone-induced injury and oxidative stress in bronchiolar epithelium were linked to methacholine-induced alterations in pulmonary mechanics. Thus, significant increases in lung resistance and elastance, along with decreases in lung compliance and end tidal volume, were observed at higher doses of methacholine. This indicates that ozone causes an increase in effective stiffness of the lung as a consequence of changes in the conducting airways. Collectively, these studies demonstrate that bronchiolar epithelium is highly susceptible to injury and oxidative stress induced by acute exposure to ozone; moreover, this is accompanied by altered lung functioning.
Asunto(s)
Lesión Pulmonar Aguda/inducido químicamente , Pulmón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ozono/toxicidad , Mucosa Respiratoria/efectos de los fármacos , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/fisiopatología , Animales , Bronquiolos/efectos de los fármacos , Bronquiolos/metabolismo , Modelos Animales de Enfermedad , Femenino , Pulmón/metabolismo , Pulmón/fisiopatología , Ratas , Ratas Wistar , Pruebas de Función Respiratoria , Mucosa Respiratoria/metabolismoRESUMEN
Heterogeneity of regional lung mechanics is an important determinant of the work of breathing and may be a risk factor for ventilator associated lung injury. The ability to accurately assess heterogeneity may have important implications for monitoring disease progression and optimizing ventilator settings. Inverse modeling approaches, when applied to dynamic pulmonary impedance data (Z(L)), are thought to be sensitive to the detection of mechanical heterogeneity with the ability to characterize global lung function using a minimal number of free parameters. However, the reliability and bias associated with such model-based estimates of heterogeneity are unknown. We simulated Z(L) spectra from healthy, emphysematous, and acutely injured lungs using a computer-generated anatomic canine structure with asymmetric Horsfield branching and various predefined distributions of stochastic lung tissue heterogeneity. Various inverse models with distinct topologies incorporating linear resistive and inertial airways with parallel tissue viscoelasticity were then fitted to these Z(L) spectra and evaluated in terms of their quality of fit as well as the accuracy and reliability of their respective model parameters. While all model topologies detected appropriate changes in tissue heterogeneity, only a topology consisting of lumped airway properties with distributed tissue properties yielded accurate estimates of both mean lung tissue stiffness and the spread of regional elastances. These data demonstrate that inverse modeling approaches applied to noninvasive measures of Z(L) may provide reliable and accurate assessments of lung tissue heterogeneity as well as insight into distributed lung mechanical properties.