Biomedical subjects

Mark W Frampton

Publications and source records attributed to Mark W Frampton.

11 recordsLinked to original sources

PubMed2006

Inflammation and airborne particles.

Inflammation provides a potential mechanistic link between inhalation of particles and the diverse health effects found in epidemiologic studies. Considerable uncertainty remains as to the importance of the inflammation in mediating these effects and where that inflammation is occurring: lung, vascular endothelium, or distant organs, including the heart. This article briefly reviews the role of inflammation in pulmonary and cardiovascular disease and explores the evidence that the health effects of PM exposure are mediated, at least in part, by inflammation.

Air Pollutants↗

PubMed2006

Changes in markers of epithelial permeability and inflammation in chronic smokers switching to a nonburning tobacco device (Eclipse).

Eclipse, produced by R. J. Reynolds Tobacco Company, is a potential reduced exposure product (PREP) that heats rather than burns tobacco. We hypothesized that switching to Eclipse would result in relative normalization of pulmonary epithelial permeability, airway inflammation, and blood leukocyte activation in current smokers. We assessed 10 healthy smokers (aged 21-50 years, 19+/-8 pack-years) at baseline and after 2 and 4 weeks of switching to Eclipse, for symptoms, pulmonary function, airway inflammation, lung clearance of (99m)technicium-diethylenetriaminepentaacetic acid, and blood leukocyte activation and production of reactive oxygen species. Values were compared before and after Eclipse use and with those of healthy, lifetime nonsmokers (aged 18-53 years). Compared with baseline values before switching to Eclipse, lung permeability half-time increased from 33+/-3 to 43+/-6 min (p = .017) after 2 weeks and to 44+/-7 min (p = .10) after 4 weeks of Eclipse use. Carboxyhemoglobin levels increased from 5%+/-2% to 7%+/-2% (p<.01) at 4 weeks. Compared with smoking the usual brand of cigarettes, after smoking Eclipse the percentage of natural killer cells, the expression of intercellular adhesion molecule-1 on monocytes, and the expression of CD45RO on T cells showed significant improvement. However, expression of other surface markers, notably CD23 on monocytes, became more abnormal. Production of reactive oxygen species by smokers' neutrophils and monocytes increased further with Eclipse use. We found no significant effects on pulmonary function, cells in induced sputum, or exhaled nitric oxide. Switching to Eclipse reduces alveolar epithelial injury in some smokers but may increase carboxyhemoglobin levels and oxidative stress.

Adult↗

PubMed2006

Inhalation of ultrafine particles alters blood leukocyte expression of adhesion molecules in humans.

Ultrafine particles (UFPs; aerodynamic diameter < 100 nm) may contribute to the respiratory and cardiovascular morbidity and mortality associated with particulate air pollution. We tested the hypothesis that inhalation of carbon UFPs has vascular effects in healthy and asthmatic subjects, detectable as alterations in blood leukocyte expression of adhesion molecules. Healthy subjects inhaled filtered air and freshly generated elemental carbon particles (count median diameter approximately 25nm, geometric standard deviation approximately 1.6), for 2 hr, in three separate protocols: 10 microg/m3 at rest, 10 and 25 microg/m3 with exercise, and 50 microg/m3 with exercise. In a fourth protocol, subjects with asthma inhaled air and 10 microg/m3 UFPs with exercise. Peripheral venous blood was obtained before and at intervals after exposure, and leukocyte expression of surface markers was quantitated using multiparameter flow cytometry. In healthy subjects, particle exposure with exercise reduced expression of adhesion molecules CD54 and CD18 on monocytes and CD18 and CD49d on granulocytes. There were also concentration-related reductions in blood monocytes, basophils, and eosinophils and increased lymphocyte expression of the activation marker CD25. In subjects with asthma, exposure with exercise to 10 microg/m3 UFPs reduced expression of CD11b on monocytes and eosinophils and CD54 on granulocytes. Particle exposure also reduced the percentage of CD4+ T cells, basophils, and eosinophils. Inhalation of elemental carbon UFPs alters peripheral blood leukocyte distribution and expression of adhesion molecules, in a pattern consistent with increased retention of leukocytes in the pulmonary vascular bed.

Adult↗

PubMed2005

Comparing inhaled ultrafine versus fine zinc oxide particles in healthy adults: a human inhalation study.

RATIONALE: Zinc oxide is a common, biologically active constituent of particulate air pollution as well as a workplace toxin. Ultrafine particles (< 0.1 microm diameter) are believed to be more potent than an equal mass of inhaled accumulation mode particles (0.1-1.0 microm diameter). OBJECTIVES: We compared exposure-response relationships for respiratory, hematologic, and cardiovascular endpoints between ultrafine and accumulation mode zinc oxide particles. METHODS: In a human inhalation study, 12 healthy adults inhaled 500 microg/m3 of ultrafine zinc oxide, the same mass of fine zinc oxide, and filtered air while at rest for 2 hours. MEASUREMENTS AND MAIN RESULTS: Preexposure and follow-up studies of symptoms, leukocyte surface markers, hemostasis, and cardiac electrophysiology were conducted to 24 hours post-exposure. Induced sputum was sampled 24 hours after exposure. No differences were detected between any of the three exposure conditions at this level of exposure. CONCLUSIONS: Freshly generated zinc oxide in the fine or ultrafine fractions inhaled by healthy subjects at rest at a concentration of 500 microg/m3 for 2 hours is below the threshold for acute systemic effects as detected by these endpoints.

Administration, Inhalation↗

PubMed2004

Pulmonary function, diffusing capacity, and inflammation in healthy and asthmatic subjects exposed to ultrafine particles.

Particulate air pollution is associated with asthma exacerbations and increased morbidity and mortality from respiratory causes. Ultrafine particles (particles less than 0.1 microm in diameter) may contribute to these adverse effects because they have a higher predicted pulmonary deposition, greater potential to induce pulmonary inflammation, larger surface area, and enhanced oxidant capacity when compared with larger particles on a mass basis. We hypothesized that ultrafine particle exposure would induce airway inflammation in susceptible humans. This hypothesis was tested in a series of randomized, double-blind studies by exposing healthy subjects and mild asthmatic subjects to carbon ultrafine particles versus filtered air. Both exposures were delivered via a mouthpiece system during rest and moderate exercise. Healthy subjects were exposed to particle concentrations of 10, 25, and 50 microg/m(3), while asthmatics were exposed to 10 microg/m(3). Lung function and airway inflammation were assessed by symptom scores, pulmonary function tests, and airway nitric oxide parameters. Airway inflammatory cells were measured via induced sputum analysis in several of the protocols. There were no differences in any of these measurements in normal or asthmatic subjects when exposed to ultrafine particles at concentrations of 10 or 25 microg/m(3). However, exposing 16 normal subjects to the higher concentration of 50 microg/m(3) caused a reduction in maximal midexpiratory flow rate (-4.34 +/- 1.78% [ultrafine particles] vs. +1.08 +/- 1.86% [air], p =.042) and carbon monoxide diffusing capacity (-1.76 +/- 0.66 ml/min/mm Hg [ultrafine particles] vs. -0.18 +/- 0.41 ml/min/mm Hg [air], p =.040) at 21 h after exposure. There were no consistent differences in symptoms, induced sputum, or exhaled nitric oxide parameters in any of these studies. These results suggest that exposure to carbon ultrafine particles results in mild small-airways dysfunction together with impaired alveolar gas exchange in normal subjects. These effects do not appear related to airway inflammation. Additional studies are required to confirm these findings in normal subjects, compare them with additional susceptible patient populations, and determine their pathophysiologic mechanisms.

Adult↗

PubMed2004

Ultrafine particle deposition in subjects with asthma.

Ambient air particles in the ultrafine size range (diameter < 100 nm) may contribute to the health effects of particulate matter. However, there are few data on ultrafine particle deposition during spontaneous breathing, and none in people with asthma. Sixteen subjects with mild to moderate asthma were exposed for 2 hr, by mouthpiece, to ultrafine carbon particles with a count median diameter (CMD) of 23 nm and a geometric standard deviation of 1.6. Deposition was measured during spontaneous breathing at rest (minute ventilation, 13.3 +/- 2.0 L/min) and exercise (minute ventilation, 41.9 +/- 9.0 L/min). The mean +/- SD fractional deposition was 0.76 +/- 0.05 by particle number and 0.69 +/- 0.07 by particle mass concentration. The number deposition fraction increased as particle size decreased, reaching 0.84 +/- 0.03 for the smallest particles (midpoint CMD = 8.7 nm). No differences between sexes were observed. The deposition fraction increased during exercise to 0.86 +/- 0.04 and 0.79 +/- 0.05 by particle number and mass concentration, respectively, and reached 0.93 +/- 0.02 for the smallest particles. Experimental deposition data exceeded model predictions during exercise. The deposition at rest was greater in these subjects with asthma than in previously studied healthy subjects (0.76 +/- 0.05 vs. 0.65 +/- 0.10, p < 0.001). The efficient respiratory deposition of ultrafine particles increases further in subjects with asthma. Key words: air pollution, asthma, deposition, dosimetry, inhalation, ultrafine particles.

Adult↗

PubMed2004

Effects of exposure to ultrafine carbon particles in healthy subjects and subjects with asthma.

Increased levels of particulate air pollution are associated with increased respiratory and cardiovascular mortality and morbidity as well as worsening of asthma. Ultrafine particles (UFP; less than 0.1 microm in aerodynamic diameter) may contribute to the health effects of particulate matter (PM) for a number of reasons. Compared with larger particles on a mass basis, UFP have a higher predicted pulmonary deposition, greater potential to induce pulmonary inflammation, larger surface area, and enhanced oxidant capacity. UFP also have the potential to cross the epithelium and enter the systemic circulation. We hypothesized that exposure to UFP causes airway inflammation in susceptible humans with activation of circulating leukocytes and vascular endothelium, a systemic acute phase response, and transient hypercoagulability. We further hypothesized that in people with asthma, UFP deposition would be increased and underlying airway inflammation enhanced. Our objectives were: to develop a system for controlled exposures of humans to UFP; to measure the pulmonary fractional deposition of UFP; to assess the effects of UFP exposure on blood leukocyte and endothelial adhesion molecule expression and activation, on airway nitric oxide (NO) production, on the systemic acute phase response, on blood coagulability, and on cardiac electrical activity and repolarization; and to evaluate these responses in both healthy subjects and people with asthma. We developed and validated a mouthpiece exposure system for human studies of carbon UFP and then conducted three clinical exposure studies: healthy subjects breathing filtered air and UFP (10 microg/m3) at rest (UPREST); healthy subjects breathing air and UFP (10 and 25 microg/m3) with intermittent exercise (UPDOSE); and subjects with mild asthma breathing air and UFP (10 microg/m3) with intermittent exercise (UPASTHMA). All exposures were for 2 hours on the mouthpiece system. Exposures were separated by at least 2 (UPREST and UPDOSE) or 3 (UPASTHMA) weeks. Prior to and at intervals after each exposure, we assessed symptoms, pulmonary function, blood markers of inflammation and coagulation, and airway NO production. Sputum inflammatory cells were assessed 21 hours after exposure. Continuous 12-lead electrocardiography (ECG) recordings were analyzed for changes in heart rate variability, repolarization, and arrhythmias. For healthy subjects, the fractional deposition of UFP at rest was 0.66 +/- 0.11 (mean +/- SD) by particle number, confirming the high deposition for UFP predicted by models. Deposition further increased during exercise (0.83 +/- 0.04). Asthmatic subjects showed higher UFP deposition than did healthy subjects when breathing at rest (0.76 +/- 0.05). During the UPREST protocol, there were no convincing effects for any outcome measures. Breathing 25 microg/m3 UFP with exercise (UPDOSE) was associated with reductions in blood monocytes and activation of T lymphocytes in healthy females. In asthmatic subjects (UPASTHMA), breathing 10 microg/m3 UFP was associated with reduced numbers of blood eosinophils and CD4+ T lymphocytes. In the UPDOSE group, monocyte expression of intercellular adhesion molecule-1 (ICAM-1) was reduced in a concentration-related manner (P = 0.001). In the UPASTHMA group, CD11b expression was reduced on monocytes and eosinophils, and ICAM-1 expression was reduced on polymorphonuclear leukocytes (PMNs). ECG analyses of UPDOSE subjects showed transient reductions in parasympathetic influence on heart rate variability and a reduced repolarization (QT) interval. In UPASTHMA subjects, ECG analyses showed decreased QT variability, but no effect on the QT interval. There were no significant effects in any of the studies on symptoms, pulmonary function, or markers of airway inflammation. We found no increases in soluble markers of systemic inflammation or coagulation. Our hypothesis that inhalation of carbon UFP causes pulmonary inflammation and an acute phase response was not confirmed. However, the observed subtle changes in leukocyte subsets and adhesion molecule expression are consistent with effects on vascular endothelial function. We also found effects on heart rate variability and on cardiac repolarization in healthy subjects. If confirmed, the finding that very low mass concentrations of particles have cardiovascular effects would have important implications for future PM regulatory strategies.

Adult↗

PubMed2003

Alveolar epithelial cell-macrophage interactions affect oxygen-stimulated interleukin-8 release.

Interactions of alveolar macrophages with respiratory epithelium may play a key role in hyperoxia-induced lung inflammation. We studied the effect of cell-cell contact with epithelial cells in hyperoxia on macrophages' secretion of interleukin-8 (IL-8). A549 pulmonary epithelial cells and THP-1 monocyte/macrophage cells were cultured either singly, in contact coculture, or prevented from contact by a porous membrane, and exposed to oxygen or room air. Phorbol-12-myristate-13-acetate-(PMA)-treated THP-1 cells were exposed to the same conditions. Neither cell line cultured alone produced appreciable amounts of IL-8 in hyperoxia. Contact cocultures exposed to hyperoxia produced increased IL-8, while in the noncontact coculture it was attenuated. Both cell-cell contact and PMA increased THP-1 cell CD54 expression. Intracellular IL-8 production was increased in contact cocultured, hyperoxia exposed THP-1 cells, while the A549 sample showed no change. Increased IL-8 mRNA expression was not demonstrated in cocultured, hyperoxic exposed THP-1 cells, suggesting nontranscriptional regulation of IL-8 protein levels. Contact with epithelial cells appears to potentiate macrophage responses to hyperoxia.

Cell Communication↗

PubMed2003

Ultrafine particle deposition in humans during rest and exercise.

Ultrafine particles (diameter < 100 nm) may be important in the health effects of air pollution, in part because of their predicted high respiratory deposition. However, there are few measurements of ultrafine particle deposition during spontaneous breathing. The fractional deposition for the total respiratory tract of ultrafine carbon particles (count median diameter = 26 nm, geometric standard deviation = 1.6) was measured in 12 healthy subjects (6 female, 6 male) at rest (minute ventilation 9.0 +/- 1.3 L/min) using a mouthpiece exposure system. The mean +/- SD fractional deposition was 0.66 +/- 0.11 by particle number and 0.58 +/- 0.13 by particle mass concentration, similar to model predictions. The number deposition fraction increased as particle size decreased, reaching 0.80 +/- 0.09 for the smallest particles (midpoint count median diameter = 8.7 nm). No gender differences were observed. In an additional 7 subjects (2 female, 5 male) alternating rest with moderate exercise (minute ventilation 38.1 +/- 9.5 L/min), the deposition fraction during exercise increased to 0.83 +/- 0.04 and 0.76 +/- 0.06 by particle number and mass concentration, respectively, and reached 0.94 +/- 0.02 for the smallest particles. Experimental deposition data exceeded model predictions during exercise. The total number of deposited particles was more than 4.5-fold higher during exercise than at rest because of the combined increase in deposition fraction and minute ventilation. Fractional deposition of ultrafine particles during mouth breathing is high in healthy subjects, and increases further with exercise.

Adolescent↗

PubMed2002

Cardiovascular effects associated with air pollution: potential mechanisms and methods of testing.

A recent series of epidemiologic reports have shown associations between fine particulate matter (PM) levels and increased cardiovascular morbidity and mortality. Elevated PM levels have been linked with cardiac events, including serious ventricular arrhythmias and myocardial infarction. A workshop brought together epidemiologists, cardiologists, and toxicologists from academia, government, and industry to examine plausible mechanisms that could be responsible for such effects, and to consider the armamentarium of noninvasive tests available to examine these relationships. Possible mechanisms considered by the participants include: (a) effects on the autonomic nervous system; (b) alterations on ion channel function in myocardial cells; (c) ischemic responses in the myocardium; and (d) inflammatory responses triggering endothelial dysfunction, atherosclerosis, and thrombosis. A large number of tests were identified to assess specific mechanistic pathways underlying the cardiovascular effects of air pollution and include: (a) autonomic control of the cardiovascular system assessed primarily by heart-rate variability; (b) myocardial substrate and vulnerability assessed by the electrocardiogram and estimations of ejection fraction and wall motion abnormalities in imaging studies; and (c) endothelial function, atherosclerosis, and thrombosis assessed by clotting parameters, cytokines, lipid profiles, and forearm blood flow. A variety of approaches ranging from molecular and genetic investigations to human clinical studies were recommended to further investigate the important epidemiologic associations.

Air Pollutants↗

PubMed2002

Nitrogen dioxide exposure: effects on airway and blood cells.

This study examined the effects of nitrogen dioxide (NO(2)) exposure on airway inflammation, blood cells, and antiviral respiratory defense. Twenty-one healthy volunteers were exposed on separate occasions to air and 0.6 and 1.5 ppm NO(2) for 3 h with intermittent moderate exercise. Phlebotomy and bronchoscopy were performed 3.5 h after each exposure, and recovered cells were challenged with respiratory viruses in vitro. Blood studies revealed a 4.1% NO(2) dose-related decrease in hematocrit (P = 0.003). Circulating total lymphocytes (P = 0.024) and T lymphocytes (P = 0.049) decreased with NO(2) exposure. Exposure to NO(2) increased the blood lymphocyte CD4(+)-to-CD8(+) ratio from 1.74 +/- 0.11 to 1.85 +/- 0.12 in males but decreased it from 1.88 +/- 0.19 to 1.78 +/- 0.19 in females (P < 0.001 for gender difference). Polymorphonuclear leukocytes in bronchial lavage increased with NO(2) exposure (P = 0.003). Bronchial epithelial cells obtained after exposure to 1.5 ppm NO(2) released 40% more lactate dehydrogenase after challenge with respiratory syncytial virus than with air exposure (P = 0.024). In healthy subjects, exposures to NO(2) at levels found indoors cause mild airway inflammation, effects on blood cells, and increased susceptibility of airway epithelial cells to injury from respiratory viruses.

Adult↗