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Metalloelastase (MMP-12), mainly produced by macrophages, has been shown to play a key role in the pathogenesis of emphysema in animal models. Chronic cigarette smoke increases pulmonary MMP-12, which is closely correlated with an... more
Metalloelastase (MMP-12), mainly produced by macrophages, has been shown to play a key role in the pathogenesis of emphysema in animal models. Chronic cigarette smoke increases pulmonary MMP-12, which is closely correlated with an elevation of pulmonary substance P (SP). Because alveolar macrophages (AMs) contain the neurokinin-1 receptor (NK1R), we tested whether SP was able to trigger the upregulation of MMP-12 synthesis in AMs by acting on the NK1R. AMs isolated from bronchoalveolar lavage cells in C3H/HeN mice were cultured with control medium or SP that was coupled without or with NK1R antagonists (CP-99,994 or aprepitant) for 24 h. We found that SP significantly increased the mRNA of MMP-12 and NK1R by 11-fold and 82%, respectively, in AMs ( P < 0.05), and these responses were abolished by NK1R antagonists with little change in the cells' viability. Because pulmonary SP is primarily released by bronchopulmonary C-fibers (PCFs), we further asked whether destruction of PC...
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We have shown previously that epithelial cells may contribute to the inflammatory response in the lung after exposure to crystalline silica through the production of and response to specific chemokines and cytokines. However, the exact... more
We have shown previously that epithelial cells may contribute to the inflammatory response in the lung after exposure to crystalline silica through the production of and response to specific chemokines and cytokines. However, the exact cellular and molecular responses of epithelial cells to silica exposure remain unclear. We hypothesize that non-oxidant-mediated silica-cell interactions lead to the upregulation of tumor necrosis factor-α (TNF-α), whereby TNF-α-induced generation of reactive oxygen species (ROS) leads to the activation of the monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-2 genes. Using a murine alveolar type II cell line, murine lung epithelial (MLE)-15, we measured the early changes in TNF-α, MCP-1, and MIP-2 mRNA species after exposure of the cells to 18 μg/cm2silica (cristobalite) in combination with various antioxidants. Total mRNA was isolated and assayed using an RNase protection assay after 6 h of particle exposure. We found th...
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Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs... more
Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs from 3 to 14 yr of age kept under a highly regulated environment to define the effects of aging on the myocardium. Ventricular, myocardial, and myocyte function, together with anatomical and structural properties of the organ and cardiomyocytes, were evaluated. Ventricular hypertrophy was not observed with aging and the structural composition of the myocardium was modestly affected. Alterations in the myocyte compartment were identified in aged dogs, and these factors negatively interfere with the contractile reserve typical of the young heart. The duration of the action potential is prolonged in old cardiomyocytes contributing to the slower electrical recovery of the myocardium. Also, the remodeled repolarization of cardiomyocytes with aging provide...
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Evidence suggests that human milk oligosaccharides (HMOs) provide multiple benefits to infants, including prebiotic effects, gut maturation, antimicrobial activities, and immune modulation. Clinical intervention studies with HMOs are... more
Evidence suggests that human milk oligosaccharides (HMOs) provide multiple benefits to infants, including prebiotic effects, gut maturation, antimicrobial activities, and immune modulation. Clinical intervention studies with HMOs are required to confirm these benefits in infants. Our objective was to investigate the effects of feeding formulas supplemented with the HMO 2'-fucosyllactose (2'-FL) on biomarkers of immune function in healthy term infants. We performed a substudy nested within a randomized, double-blind, controlled growth and tolerance study in healthy singleton infants (birth weight ≥2490 g) who were enrolled by 5 d of life and exclusively formula-fed (n = 317) or breastfed (n = 107) from enrollment to 4 mo of age. Formula-fed infants were randomly assigned to receive 1 of 3 formulas, all containing 2.4 g total oligosaccharides/L [control: galacto-oligosaccharides (GOS) only; experimental formulas: GOS + 0.2 or 1.0 g 2'-FL/L], and compared with a breastfed r...
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Aerosol delivery of chemotherapeutic nanocarriers represents a promising alternative for lung cancer therapy. This study optimized gemcitabine (Gem)-loaded gelatin nanocarriers (GNCs) cross-linked with genipin (Gem-GNCs) to evaluate their... more
Aerosol delivery of chemotherapeutic nanocarriers represents a promising alternative for lung cancer therapy. This study optimized gemcitabine (Gem)-loaded gelatin nanocarriers (GNCs) cross-linked with genipin (Gem-GNCs) to evaluate their potential for nebulized lung cancer treatment. Gem-GNCs were prepared by two-step desolvation and optimized through Taguchi design and characterized for physicochemical properties. Particle size and morphology were confirmed by scanning and transmission electron microscopy. In vitro release of Gem from Gem-GNCs performed in Dulbecco's phosphate-buffered saline and simulated lung fluid was evaluated to determine release mechanisms. Particle size stability was assessed under varying pH. Differential scanning calorimetry and powder X-ray diffraction were used to determine the presence and stability of Gem-GNC components and amorphization of Gem, respectively. Gem-GNC efficacy within A549 and H460 cells was evaluated using MTT assays. Mucus rheolog...
Research Interests: Nanoparticles, Pharmaceutical Chemistry, Aerosols, Humans, Differential scanning calorimetry, and 9 moreViscosity, Drug Delivery Systems, Gelatin, X ray diffraction, Particle Size, Delayed-Action Preparations, Cardiovascular medicine and haematology, Pharmacology and pharmaceutical sciences, and lung neoplasms
Direct inhibition of smooth muscle myosin (SMM) is a potential means to treat hypercontractile smooth muscle diseases. The selective inhibitor CK-2018571 prevents strong binding to actin and promotes muscle relaxation in vitro and in... more
Direct inhibition of smooth muscle myosin (SMM) is a potential means to treat hypercontractile smooth muscle diseases. The selective inhibitor CK-2018571 prevents strong binding to actin and promotes muscle relaxation in vitro and in vivo. The crystal structure of the SMM/drug complex reveals that CK-2018571 binds to a novel allosteric pocket that opens up during the “recovery stroke” transition necessary to reprime the motor. Trapped in an intermediate of this fast transition, SMM is inhibited with high selectivity compared with skeletal muscle myosin (IC50 = 9 nM and 11,300 nM, respectively), although all of the binding site residues are identical in these motors. This structure provides a starting point from which to design highly specific myosin modulators to treat several human diseases. It further illustrates the potential of targeting transition intermediates of molecular machines to develop exquisitely selective pharmacological agents.
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Increased concentrations of airborne fine particulate matter (PM2.5; particulate matter with an aerodynamic diameter < or = 2.5 microm) are associated with increases in emergency room visits and hospitalizations of asthmatic patients.... more
Increased concentrations of airborne fine particulate matter (PM2.5; particulate matter with an aerodynamic diameter < or = 2.5 microm) are associated with increases in emergency room visits and hospitalizations of asthmatic patients. Emissions from local stationary combustion sources (e.g., coal-burning power plants) or mobile motor vehicles (e.g., diesel-powered trucks) have been identified as potential contributors to the development or exacerbation of allergic airway disease. In the present study, a rodent model of allergic airway disease was used to study the effects of concentrated ambient particles (CAPs) or diesel engine exhaust (DEE) on the development of allergic airway disease in rats sensitized to the allergen ovalbumin (OVA). The overall objective of our project was to understand the effects of PM2.5 on the development of OVA-induced allergic airway disease. Our specific aims were to test the following hypotheses: (1) exposure to CAPs during OVA challenge enhances ep...
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... Immunology 110: 493-500, 2003. Marsella et al.; Atopy patch test reactions in high-IgE beagles to different sources and concentrations of house dust mites. Veterinary Dermatology 16: 308-314, 2005. Marsella et al.; Pilot investigation... more
... Immunology 110: 493-500, 2003. Marsella et al.; Atopy patch test reactions in high-IgE beagles to different sources and concentrations of house dust mites. Veterinary Dermatology 16: 308-314, 2005. Marsella et al.; Pilot investigation ...
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Human studies suggest either a protective role or no benefit of statins against the development of Alzheimer's disease (AD). We tested the hypothesis that statin-mediated cholesterol reduction in aged dogs, which have cognitive... more
Human studies suggest either a protective role or no benefit of statins against the development of Alzheimer's disease (AD). We tested the hypothesis that statin-mediated cholesterol reduction in aged dogs, which have cognitive impairments and amyloid-β (Aβ) pathology, would improve cognition and reduce neuropathology. In a study of 12 animals, we treated dogs with 80 mg/day of atorvastatin for 14.5 months. We did not observe improvements in discrimination learning; however, there were transient impairments in reversal learning, suggesting frontal dysfunction. Spatial memory function did not change with treatment. Peripheral levels of cholesterol, LDLs, triglycerides, and HDL were significantly reduced in treated dogs. Aβ in cerebrospinal fluid and brain remained unaffected. However, β-secretase-1 (BACE1) protein levels and activity decreased and correlated with reduced brain cholesterol. Finally, lipidomic analysis revealed a significant decrease in the ratio of omega-6 to omeg...
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Sarin is an organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production, sarin is the nerve agent with a strong potential for use... more
Sarin is an organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production, sarin is the nerve agent with a strong potential for use by terrorists and rouge nations. The primary route of sarin exposure is through inhalation and, depending on the dose, sarin leads to acute respiratory failure and death. The mechanism(s) of sarin-induced respiratory failure is poorly understood. Sarin irreversibly inhibits acetylcholine esterase, leading to excessive synaptic levels of acetylcholine and, we have previously shown that sarin causes marked ventilatory changes including weakened response to hypoxia. We now show that LD50 sarin inhalation causes severe bronchoconstriction in rats, leading to airway resistance, increased hypoxia-induced factor-1α, and severe lung epithelium injury. Transferring animals into 60% oxygen chambers after sarin exposure improved the survival from about 50% to 75% at 24h; however, many animals died within hours after removal from the oxygen chambers. On the other hand, if LD50 sarin-exposed animals were administered the bronchodilator epinephrine, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;90% of the animals survived. Moreover, while both epinephrine and oxygen treatments moderated cardiorespiratory parameters, the proinflammatory cytokine surge, and elevated expression of hypoxia-induced factor-1α, only epinephrine consistently reduced the sarin-induced bronchoconstriction. These data suggest that severe bronchoconstriction is a critical factor in the mortality induced by LD50 sarin inhalation, and epinephrine may limit the ventilatory, inflammatory, and lethal effects of sarin.
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Alveolar macrophages play a key role in the development of silicosis by releasing a host of mediators, such as, cytokines and chemokines, which contribute to a complex network of interactions that result in the onset of lung injury,... more
Alveolar macrophages play a key role in the development of silicosis by releasing a host of mediators, such as, cytokines and chemokines, which contribute to a complex network of interactions that result in the onset of lung injury, inflammation, and potentially fibrosis. Using a murine macrophage cell line, RAW 264.7, we exposed the cells to cristobalite-silica (35 micrograms/cm(2)) in the presence or absence of antioxidants and various modifiers of cellular antioxidant status. Treatment with dimethyl sulfoxide, extracellular glutathione, or N-acetyl-L-cysteine (NAC) decreased cristobalite-induced tumor necrosis factor (TNF)-alpha mRNA levels by 40%, 20%, and 42%, respectively. TNF-alpha protein levels were decreased by 90%, 32%, and 53%, respectively. Cristobalite-induced macrophage inflammatory protein (MIP)-2 mRNA levels were reduced by 52%, 38%, and 57%, with DMSO, GSH, and NAC treatment, respectively. Both MIP-1alpha and MIP-1beta mRNA levels were reduced at a magnitude similar to the reduction in TNF-alpha mRNA levels, whereas monocyte chemotactic protein (MCP)-1 mRNA levels were reduced at a magnitude similar to the reduction in MIP-2 mRNA levels following antioxidant treatment. These results suggests that the macrophage response to cristobalite exposure is mediated at least in part by oxidant stress.
Research Interests: Cytokines, Oxidative Stress, Macrophages, Antioxidants, Cell line, and 15 moreIn Vitro, Mice, Animals, Complex network, Male, Cell Death, Glutathione, Chemokine, Lung Injury, Chemokines, Enzyme Linked Immunosorbent Assay, Alveolar Macrophage, Ribonucleases, Antidotes, and Pharmacology and pharmaceutical sciences
There is a growing concern about whether the myriad of culture conditions, cell lines, and doses of nonfibrous and fibrous particles used in vitro are truly representative of the complex environment of the in vivo particle exposure... more
There is a growing concern about whether the myriad of culture conditions, cell lines, and doses of nonfibrous and fibrous particles used in vitro are truly representative of the complex environment of the in vivo particle exposure situation. The use of serum as a supplement to the growth medium of cultured cells is a widely accepted practice. However, little is known about whether the various serum proteins may interact with the surfaces of particles, consequently altering their toxicity, inflammatory properties, or fibrogenicity, etc. observed in vivo. Using a murine alveolar type II cell line, MLE-15, we measured the early changes in various chemokine mRNA species following exposure of the cells to silica (cristobalite) in the presence or absence of serum. Total mRNA was isolated and assayed using an RNase protection assay after 6 h of particle exposure. We observed that the addition of serum to the culture media reduced the in vitro silica-induced chemokine response (i.e., shift in the dose-response curve) in MLE-15 cells. Further, using Western blot analysis and protein sequencing techniques, we have identified a specific serum component, apolipoprotein-A1 (apo-A1), as a protein in serum that binds selectively to silica, thus leading to the altered chemokine response. We also found that apo-A1 not only binds to silica but also binds to other nonfibrous and fibrous particles such as titanium dioxide and asbestos. These results demonstrate the importance of culture conditions for modifying the outcome of an experiment when performing in vitro particle exposure studies.
Research Interests: Western blotting, Cell line, Mice, Silica, Animals, and 13 moreParticles, Titanium dioxide, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, apolipoprotein A-I, Protein Sequence Analysis, Western blot, Chemokines, Culture Media, Silicon Dioxide, Blood Proteins, Serum albumin, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
Research Interests: Animal Behavior, Cognition, Aging, Memory, Dogs, and 15 moreBrain, Discrimination Learning, Female, Animals, Male, Immunization, Longitudinal Studies, Analysis of Variance, Cognitive Function, Neurofibrillary Tangles, Enzyme Linked Immunosorbent Assay, Choice Behavior, Neuropsychological Tests, Immunization Schedule, and Medical and Health Sciences
Research Interests: Immune response, Asthma, Antibodies, Pregnancy, Allergy, and 15 moreHumans, Female, Animals, Natriuretic Peptides, Mothers, Allergens, Clinical Sciences, Breast feeding, Immune, Risk Factors, Genetic Predisposition, immunoglobulin G, Pregnancy complications, Pharmacology and pharmaceutical sciences, and In Utero
Research Interests: Mass Spectrometry, Scanning Electron Microscopy, Drug delivery, Pharmaceutical Chemistry, Adsorption, and 15 moreDogs, Differential scanning calorimetry, Lasers, Pharmaceutical, Animals, Male, Desiccation, High Pressure Liquid Chromatography, Glass Transition Temperature, Particle Size, Powders, Fine Particles, Airway resistance, Albuterol, and Pharmacology and pharmaceutical sciences
Previously we showed that anti-Abeta peptide immunotherapy significantly attenuated... more
Previously we showed that anti-Abeta peptide immunotherapy significantly attenuated Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s-like amyloid deposition in the central nervous system of aged canines. In this report we have characterized the changes that occurred in the humoral immune response over 2.4years in canines immunized repeatedly with aggregated Abeta(1-42) (AN1792) formulated in alum adjuvant. We observed a rapid and robust induction of anti-Abeta antibody titers, which were associated with an anti-inflammatory T helper type 2 (Th2) response. The initial antibody response was against dominant linear epitope at the N-terminus region of the Abeta(1-42) peptide, which is identical to the one in humans and vervet monkeys. After multiple immunizations the antibody response drifted toward the elevation of antibodies that recognized conformational epitopes of assembled forms of Abeta and other types of amyloid. Our findings indicate that prolonged immunization results in distinctive temporal changes in antibody profiles, which may be important for other experimental and clinical settings.
Research Interests: Neurobiology Of Disease, Neurobiology, Western blotting, Dogs, Animals, and 13 moreCentral Nervous System, Animal Model, Vaccination, Amyloid Beta, Clinical Sciences, Longitudinal Studies, Analysis of Variance, Alzheimer Disease, Epitopes, Neurosciences, Enzyme Linked Immunosorbent Assay, Temporal Change, and Antibody Response
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Coal-fired power plant emissions can contribute a significant portion of the ambient air pollution in many parts of the world. We hypothesized that exposure to simulated downwind coal combustion emissions (SDCCE) may exacerbate... more
Coal-fired power plant emissions can contribute a significant portion of the ambient air pollution in many parts of the world. We hypothesized that exposure to simulated downwind coal combustion emissions (SDCCE) may exacerbate pre-existing allergic airway responses. Mice were sensitized and challenged with ovalbumin (OVA). Parallel groups were sham-sensitized with saline. Mice were exposed 6 h/day for 3 days to air (control, C) or SDCCE containing particulate matter (PM) at low (L; 100 μg/m³), medium (M; 300 μg/m³), or high (H; 1000 μg/m³) concentrations, or to the H level with PM removed by filtration (high-filtered, HF). Immediately after SDCCE exposure, mice received another OVA challenge (pre-OVA protocol). In a second (post-OVA) protocol, mice were similarly sensitized but only challenged to OVA before air/SDCCE. Measurement of airway hyperresponsiveness (AHR), bronchoalveolar lavage (BAL), and blood collection were performed ~24 h after the last exposure. SDCCE significantly increased BAL macrophages and eosinophils in OVA-sensitized mice from the post-OVA protocol. However, there was no effect of SDCCE on BAL macrophages or eosinophils in OVA-sensitized mice from the pre-OVA protocol. BAL neutrophils were elevated following SDCCE in both protocols in nonsensitized mice. These changes were not altered by filtering out the PM. In the post-OVA protocol, SDCCE decreased OVA-specific IgG₁ in OVA-sensitized mice but increased levels of total IgE, OVA-specific IgE and OVA-specific IgG₁ and IgG(2a) in non-sensitized animals. In the pre-OVA protocol, SDCCE increased OVA-specific IgE in both sensitized and non-sensitized animals. Additionally, BAL IL-4, IL-13, and IFN-γ levels were elevated in sensitized mice. These results suggest that acute exposure to either the particulate or gaseous phase of SDCCE can exacerbate various features of allergic airway responses depending on the timing of exposure in relation to allergen challenge.
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Gasoline-powered vehicle emissions contribute significantly to ambient air pollution. We hypothesized that exposure to gasoline engine emissions (GEE) may exacerbate preexisting allergic airway responses. Male BALB/c mice were sensitized... more
Gasoline-powered vehicle emissions contribute significantly to ambient air pollution. We hypothesized that exposure to gasoline engine emissions (GEE) may exacerbate preexisting allergic airway responses. Male BALB/c mice were sensitized by injection with ovalbumin (OVA) and then received a 10-min aerosolized OVA challenge. Parallel groups were sham-sensitized with saline. Mice were exposed 6 h/day to air (control, C) or GEE containing particulate matter (PM) at low (L), medium (M), or high (H) concentrations, or to the H level with PM removed by filtration (high-filtered, HF). Immediately after GEE exposure mice received another 10-min aerosol OVA challenge (pre-OVA protocol). In a second (post-OVA) protocol, mice were similarly sensitized but only challenged to OVA before air or GEE exposure. Measurements of airway hyperresponsiveness (AHR), bronchoalveolar lavage (BAL), and blood collection were performed approximately 24 h after the last exposure. In both protocols, M, H, and HF GEE exposure significantly decreased BAL neutrophils from nonsensitized mice but had no significant effect on BAL cells from OVA-sensitized mice. In the pre-OVA protocol, GEE exposure increased OVA-specific IgG(1) but had no effect on BAL interleukin (IL)-2, IL-4, IL-13, or interferon (IFN)-gamma in OVA-sensitized mice. Nonsensitized GEE-exposed mice had increased OVA-specific IgG(2a), IgE, and IL-2, but decreased total IgE. In the post-OVA protocol, GEE exposure reduced BAL IL-4, IL-5, and IFN-gamma in nonsensitized mice but had no effect on sensitized mice. These results suggest acute exposure to the gas-vapor phase of GEE suppressed inflammatory cells and cytokines from nonsensitized mice but did not substantially exacerbate allergic responses.
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Gasoline engine emissions are a ubiquitous source of exposure to complex mixtures of particulate matter (PM) and non-PM pollutants; yet their health hazards have received little study in comparison with those of diesel emissions. As a... more
Gasoline engine emissions are a ubiquitous source of exposure to complex mixtures of particulate matter (PM) and non-PM pollutants; yet their health hazards have received little study in comparison with those of diesel emissions. As a component of the National Environmental Respiratory Center (NERC) multipollutant research program, F344 and SHR rats and A/J, C57BL/6, and BALBc mice were exposed 6 h/day, 7 days/week for 1 week to 6 months to exhaust from 1996 General Motors 4.3-L engines burning national average fuel on a simulated urban operating cycle. Exposure groups included whole exhaust diluted 1:10, 1:15, or 1:90, filtered exhaust at the 1:10 dilution, or clean air controls. Evaluations included organ weight, histopathology, hematology, serum chemistry, bronchoalveolar lavage, cardiac electrophysiology, micronuclei in circulating cells, DNA methylation and oxidative injury, clearance of Pseudomonas aeruginosa from the lung, and development of respiratory allergic responses to ovalbumin. Among the 120 outcome variables, only 20 demonstrated significant exposure effects. Several statistically significant effects appeared isolated and were not supported by related variables. The most coherent and consistent effects were those related to increased red blood cells, interpreted as likely to have resulted from exposure to 13-107 ppm carbon monoxide. Other effects supported by multiple variables included mild lung irritation and depression of oxidant production by alveolar macrophages. The lowest exposure level caused no significant effects. Because only 6 of the 20 significant effects appeared to be substantially reversed by PM filtration, the majority of effects were apparently caused by non-PM components of exhaust.
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Despite their prevalence in the environment, and the myriad studies that have shown associations between morbidity or mortality with proximity to roadways (proxy for motor vehicle exposures), relatively little is known about the toxicity... more
Despite their prevalence in the environment, and the myriad studies that have shown associations between morbidity or mortality with proximity to roadways (proxy for motor vehicle exposures), relatively little is known about the toxicity of gasoline engine emissions (GEE). We review the studies conducted on GEE to date, and summarize the findings from each of these studies. While there have been several studies, most of the studies were conducted prior to 1980 and thus were not conducted with contemporary engines, fuels, and driving cycles. In addition, many of the biological assays conducted during those studies did not include many of the assays that are conducted on contemporary inhalation exposures to air pollutants, including cardiovascular responses and others. None of the exposures from these earlier studies were characterized at the level of detail that would be considered adequate today. A recent GEE study was conducted as part of the National Environmental Respiratory Center (www.nercenter.org). In this study several in-use mid-mileage General Motors (Chevrolet S-10) vehicles were purchased and utilized for inhalation exposures. An exposure protocol was developed where engines were operated with a repeating California Unified Driving Cycle with one cold start per day. Two separate engines were used to provide two cold starts over a 6-h inhalation period. The exposure atmospheres were characterized in detail, including detailed chemical and physical analysis of the gas, vapor, and particle phase. Multiple rodent biological models were studied, including general toxicity and inflammation (e.g., serum chemistry, lung lavage cell counts/differentials, cytokine/chemokine analysis, histopathology), asthma (adult and in utero exposures with pulmonary function and biochemical analysis), cardiovascular effects (biochemical and electrocardiograph changes in susceptible rodent models), and susceptibility to infection (Pseudomonas bacteria challenge). GEE resulted in significant biological effects for upregulation of MIP-2, clearance of Pseudomonas bacteria, development of allergic response after in utero exposure, and cardiovascular indicators of vasoconstriction, oxidant stress, and damage.
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Hardwood smoke (HWS) from wood burning stoves and fireplaces can be a significant contributor to the composition of ambient air pollution. We hypothesize that the inhalation of HWS by ovalbumin (OVA)-sensitized mice with preexisting lung... more
Hardwood smoke (HWS) from wood burning stoves and fireplaces can be a significant contributor to the composition of ambient air pollution. We hypothesize that the inhalation of HWS by ovalbumin (OVA)-sensitized mice with preexisting lung inflammation leads to the exacerbation of allergic airway responses. Two different models were employed to characterize the effects of inhaled wood smoke on allergic airway inflammation. In both models, male BALB/c mice were sensitized by injection with OVA and alum. In one model, mice were challenged by inhalation with OVA 1 day prior to exposure to HWS (30, 100, 300, or 1000 microg particulate matter [PM]/m(3)) for 6 h/day on 3 consecutive days. In the other model, mice were exposed by inhalation to OVA, rested for 11 days, were exposed to HWS for 3 consecutive days, and then were exposed to OVA immediately after the final HWS exposure. Bronchoalveolar lavage (BAL), and blood collection were performed approximately 18 h after the last HWS or OVA exposure. HWS exposure after the final allergen challenge (first model) led to a significant increase in BAL eosinophils only at the 300 microg/m(3) level. In contrast, changes in BAL cells did not reach statistical significance in the second model. There were no HWS-induced changes in BAL interleukin (IL)-2, IL-4, IL-13, and interferon (IFN)gamma levels in either model following OVA challenge. These results suggest that acute HWS exposure can minimally exacerbate some indices of allergic airway inflammation when a final OVA challenge precedes HWS exposure, but does not alter Th1/Th2 cytokine levels.
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Episodic increases in air pollution have been associated with the exacerbation of asthma symptoms. Ultrafine particles are a component of air pollution and may be involved in causing the adverse health effects associated with high air... more
Episodic increases in air pollution have been associated with the exacerbation of asthma symptoms. Ultrafine particles are a component of air pollution and may be involved in causing the adverse health effects associated with high air pollution. We evaluated the effects of ultrafine particle inhalation on immune and airway responses in a beagle dog model of allergic asthma. Six allergic (ragweed sensitive) and six nonallergic dogs were exposed to ultrafine carbon particles (232.3 +/- 2.5 microg/m(3), 35.2 +/- 0.3 nm) for 1 h, followed by a challenge with vehicle (water) as a negative control. Airway resistance was measured during particle exposure and after vehicle challenge. Immune responses 3 days before and after (1 h and 1, 4, 7, and 11 days) particle exposure were assessed by measuring total immunoglobulin E (IgE) and ragweed-specific IgE and IgG in serum and bronchoalveolar lavage fluid (BALF), and cell differentials in BALF. Each dog was exposed a second time to ultrafine carbon particles (251.4 +/- 5.3 microg/m(3), 34.9 +/- 0.5 nm) for 1 h followed by a challenge with ragweed and the same measurements. Airway resistance did not change during particle exposure in any of the dogs, and ragweed-induced airway reactivity was not altered by particle exposure. Total and ragweed-specific serum IgE and total IgE in BALF were higher in allergic dogs at all time points. Particle exposure did not affect antibody levels in serum or BALF in allergic dogs. Nonallergic dogs developed specific IgG in response to multiple inhalation exposures to ragweed, but this was not associated with particle exposure. Neutrophils were elevated in BALF for all groups 1 day after particle exposure. In conclusion, despite the induction of low level inflammation in the lungs of allergic and nonallergic dogs, exposure to ultrafine carbon particles did not alter airway reactivity or immune responses.
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Research Interests: Immunology, Asthma, Histamine, Dogs, Pregnancy, and 15 moreFemale, Animals, Immunization, Allergens, Immunoglobulin E, Risk factors, Phenotype, Eosinophils, Risk Factors, Maternal-fetal exchange, immunoglobulin G, Bronchoalveolar lavage, Airway resistance, Paediatrics and reproductive medicine, and leukocyte Count
We describe a study testing fibrillar β-amyloid1–42 (Aβ42) vaccination in dogs. Three young beagles (4.6 years) were immunized twice with Aβ42 and a Th1 adjuvant (TiterMax Gold). Animals generated primarily IgG2 and IgM antibody... more
We describe a study testing fibrillar β-amyloid1–42 (Aβ42) vaccination in dogs. Three young beagles (4.6 years) were immunized twice with Aβ42 and a Th1 adjuvant (TiterMax Gold). Animals generated primarily IgG2 and IgM antibody responses, which were specific for the Aβ11–30 region of Aβ1–42. Next, 3 aged beagles (8.9–13.8 years) were immunized 4 times with Aβ42 and a Th2 adjuvant