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1.
Res Rep Health Eff Inst ; (197): 1-57, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31872749

RESUMO

INTRODUCTION: Many studies have established associations between exposure to air pollution, or atmospheric particulate matter (PM), and adverse health effects. An increasing array of studies have suggested oxidative stress as a possible mechanism by which PM-induced health effects arise, and as a result, many chemical and cellular assays have been developed to study PM-induced oxidant production. Although significant progress has been made in recent years, there are still many gaps in this area of research that have not been addressed. Many prior studies have focused on the aerosol of primary origin (e.g., the aerosol emitted from combustion engines) although the aerosol formed from the oxidation of volatile species, secondary organic aerosol (SOA), has been shown to be the predominant type of aerosol even in urban areas. Current SOA health studies are limited in number, and as such, the health effects of SOA are poorly characterized. Also, there is a lack of perspective in terms of the relative toxicities of different SOA systems. Additionally, although chemical assays have identified some SOA constituents associated with adverse health endpoints, the applicability of these results to cellular responses has not been well established. SPECIFIC AIMS: The overall objective of this study was to better understand the oxidative properties of different types and components of PM mixtures (especially SOA) through systematic laboratory chamber experiments and ambient field studies. The study had four specific aims.1 To develop a cellular assay optimized for measuring reactive oxygen and nitrogen species (ROS/RNS) production resulting from PM exposure and to identify a robust parameter that could represent ROS/RNS levels for comparison with different endpoints.2 To identify ambient PM components associated with ROS/RNS production and evaluate whether results from chemical assays represented cellular responses in terms of ROS/RNS production.3 To investigate and provide perspective on the relative toxicities of SOA formed from common biogenic and anthropogenic precursors under different conditions (e.g., humidity, nitrogen oxides [NOx], and redox-active metals) and identify bulk aerosol properties associated with cellular responses.4 To investigate the effects of photochemical aging on aerosol toxicity. METHODS: Ambient PM samples were collected from urban and rural sites in the greater Atlanta area as part of the Southeastern Center for Air Pollution and Epidemiology (SCAPE) study between June 2012 and October 2013. The concentrations of water-soluble species (e.g., water-soluble organic carbon [WSOC], brown carbon [Br C], and metals) were characterized using a variety of instruments. Samples for this study were chosen to span the observed range of dithiothreitol (DTT) activities.Laboratory studies were conducted in the Georgia Tech Environmental Chamber (GTEC) facility in order to generate SOA under well-controlled photooxidation conditions. Precursors of biogenic origin (isoprene, α-pinene, and ß-caryophyllene) and anthropogenic origin (pentadecane, m-xylene, and naphthalene) were oxidized under various formation conditions (dry vs. humid, NOx, and ammonium sulfate vs. iron sulfate seed particles) to produce SOA of differing chemical composition and mass loading. For the naphthalene system, a series of experiments were conducted with different initial hydrocarbon concentrations to produce aerosols with various degree of oxidation. A suite of instruments was utilized to monitor gas- and particle-phase species. Bulk aerosol properties (e.g., O:C, H:C, and N:C ratios) were measured using a high-resolution time-of-flight aerosol mass spectrometer. Filter samples were collected for chemical oxidative potential and cellular measurements. For the naphthalene system, multiple filter samples were collected over the course of a single experiment to collect aerosols of different photochemical aging.For all filter samples, chemical oxidative potentials were determined for water-soluble extracts using a semiautomated DTT assay system. Murine alveolar macrophages and neonatal rat ventricular myocytes were also exposed to PM samples extracted in cell culture medium to investigate cellular responses. ROS/RNS production was detected using the intracellular ROS/RNS probe, carboxy-2',7'-dichlorodihydrofluorescein diacetate (carboxy-H2DCFA), whereas cellular metabolic activity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Finally, cytokine production, that is, secreted levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were measured post-exposure using an enzyme-linked immunosorbent assay (ELISA). To identify PM constituents associated with oxidative properties, linear regressions between oxidative properties (cellular responses or DTT activity) and aerosol composition (metals, elemental ratios, etc.) were evaluated using Pearson's correlation coefficient, where the significance was determined using multiple imputation and evaluated using a 95% confidence interval. RESULTS: We optimized several parameters for the ROS/RNS assay, including cell density (2 × 104 cells/well for macrophages and 3.33 × 104 cells/well for cardiomyocytes), probe concentration (10 µM), and sample incubation time (24 hours). Results from both ambient and laboratory-generated aerosols demonstrate that ROS/RNS production was highly dose-dependent and nonlinear with respect to PM dose. Of the dose-response metrics investigated in this study (maximum response, dose at which the response is 10% above the baseline [threshold], dose at which 50% of the response is attained [EC50], rate at which the maximum response is attained [Hill slope], and area under the dose-response curve [AUC]), we found that the AUC was the most robust parameter whose informativeness did not depend on dose range.A positive, significant correlation was observed between ROS/RNS production as represented by AUC and chemical oxidative potential as measured by DTT for ambient samples collected in summer. Conversely, a relatively constant AUC was observed for ambient samples collected in winter regardless of the corresponding DTT activity. We also identified several PM constituents (WSOC, BrC, iron, and titanium) that were significantly correlated with AUC for summer samples. The strong correlation between organic species and ROS/RNS production highlights a need to understand the contribution of organic aerosols to PM-induced health effects. No significant correlations were observed for other ROS/RNS metrics or PM constituents, and no spatial trends were observed.For laboratory-generated aerosol, precursor identity influenced oxidative potentials significantly, with isoprene and naphthalene SOA having the lowest and highest DTT activities, respectively. Both precursor identity and formation condition significantly influenced inflammatory responses induced by SOA exposure, and several response patterns were identified for SOA precursors whose photooxidation products share similar carbon-chain length and functionalities. The presence of iron sulfate seed particles did not have an apparent effect on oxidative potentials; however, a higher level of ROS/RNS production was observed for all SOA formed in the presence of iron sulfate compared with ammonium sulfate. We also identified a significant positive correlation between ROS/RNS production and average carbon oxidation state, a bulk aerosol property. It may therefore be possible to roughly estimate ROS/RNS production using this property, which is readily obtainable. This correlation may have significant implications as aerosols have an atmospheric lifetime of a week, during which average carbon oxidation state increases because of atmospheric photochemical aging. Our results suggest that aerosols might become more toxic as they age in the atmosphere. Finally, in the context of ambient samples, laboratory-generated SOA induced comparable or higher levels of ROS/RNS. Oxidative potentials for all laboratory SOA systems, with the exception of naphthalene (which was higher), were all comparable with oxidative potentials observed in ambient samples.


Assuntos
Aerossóis/metabolismo , Aerossóis/farmacologia , Bioensaio , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/metabolismo , Material Particulado/farmacologia , Humanos , Laboratórios , Material Particulado/análise
2.
Biomater Sci ; 3(6): 787-99, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26221839

RESUMO

Therapeutic proteins can face substantial challenges to their activity, requiring protein modification or use of a delivery vehicle. Nanoparticles can significantly enhance delivery of encapsulated cargo, but traditional small molecule carriers have some limitations in their use for protein delivery. Nanoparticles made from protein have been proposed as alternative carriers and have benefits specific to therapeutic protein delivery. This review describes protein nanoparticles made by self-assembly, including protein cages, protein polymers, and charged or amphipathic peptides, and by desolvation. It presents particle fabrication and delivery characterization for a variety of therapeutic and model proteins, as well as comparison of the features of different protein nanoparticles.


Assuntos
Portadores de Fármacos/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Peptídeos/administração & dosagem , Proteínas/química , Sistemas de Liberação de Medicamentos , Humanos , Peptídeos/química
3.
Am J Obstet Gynecol ; 149(4): 426-34, 1984 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-6731521

RESUMO

A study was made of the effects of maternal exercise on fetal plasma concentrations of catecholamines in nine ewes with chronically catheterized singleton fetuses at 125 to 137 days' gestation. The ewes were subjected to acute treadmill exercise of 2.5 mph for 45 minutes with continuous recording of maternal and fetal blood pressures. Samples of arterial blood were obtained for measurement of catecholamines, glucose, and blood gases. Changes in blood flow in fetal organs in response to maternal exercise were assessed by injection of radioactive microspheres. The maternal plasma catecholamine responses were related to the severity of the exercise stress as indicated by the index of cardiac effort. The fetal responses did not correlate with maternal cardiac effort. A significant decrease in fetal Po2 with a moderate alkalosis occurred, accompanied by a significant elevation in circulating levels of norepinephrine. At the peak of exercise, there was an increase in fetal renal, adrenal, and placental blood flows, as compared to the control period.


Assuntos
Dopamina/sangue , Epinefrina/sangue , Sangue Fetal/fisiologia , Norepinefrina/sangue , Esforço Físico , Animais , Circulação Sanguínea , Gasometria , Glicemia , Pressão Sanguínea , Feminino , Microesferas , Gravidez , Ovinos
4.
Brain Res Bull ; 12(6): 735-40, 1984 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-6206931

RESUMO

Using the fluorescent tracer dyes bisbenzimide, nuclear yellow and fast blue, the possibility of differential innervation of various regions of the bladder and urethra was tested in cats. The dyes were injected into the lateral detrusor, bladder base, and urethra. Fluorescent cell bodies were counted in serial 48 micron sections of dorsal root, inferior mesenteric, sympathetic chain and pelvic plexus ganglia. Several dorsal root ganglia, primarily S2, were the principal source of afferent innervation to all locations injected. The bladder and urethra received significant efferent innervation from both the inferior mesenteric ganglia and sympathetic chain ganglia (particularly L7 to S2) however, pelvic plexus ganglia made only small contribution to the innervation of these areas. The sympathetic chain and inferior mesenteric ganglia contributed equally to the innervation of the detrusor and bladder base but the sympathetic chain made double the contribution of the inferior mesenteric ganglia to the innervation of the urethra. There was a very low incidence (less than 1%) of neurons which projected to more than one injection site.


Assuntos
Vias Aferentes/análise , Vias Eferentes/anatomia & histologia , Medula Espinal/anatomia & histologia , Uretra/inervação , Bexiga Urinária/inervação , Animais , Transporte Axonal , Gatos , Corantes , Masculino , Microscopia de Fluorescência
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