Donna M. Speers

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 ~ 25 nm, geometric standard deviation ~ 1.6), for 2 hr, in three separate protocols: 10 μg/m3 at rest, 10 and 25 μg/m3 with exercise, and 50 μg/m3 with exercise. In a fourth protocol, subjects with asthma inhaled air and 10 μg/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 μg/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.

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 μ m 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 μ g/m3, while asthmatics were exposed to 10 μ g/m3. 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 μ g/m3. However, exposing 16 normal subjects to the higher concentration of 50 μ g/m3 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.

Effect of Inhaled Carbon Ultrafine Particles on Reactive Hyperemia in Healthy Human Subjects

Background Ultrafine particles (UFP) may contribute to the cardiovascular effects of exposure to particulate air pollution, partly because of their relatively efficient alveolar deposition and potential to enter the pulmonary vascular space. Objectives This study tested the hypothesis that inhalation of elemental carbon UFP alters systemic vascular function. Methods Sixteen healthy subjects (mean age, 26.9 ± 6.5 years) inhaled air or 50 μg/m3 elemental carbon UFP by mouthpiece for 2 hr, while exercising intermittently. Measurements at preexposure baseline, 0 hr (immediately after exposure), 3.5 hr, 21 hr, and 45 hr included vital signs, venous occlusion plethysmography and reactive hyperemia of the forearm, and venous plasma nitrate and nitrite levels. Results Peak forearm blood flow after ischemia increased 3.5 hr after exposure to air but not UFP (change from preexposure baseline, air: 9.31 ± 3.41; UFP: 1.09 ± 2.55 mL/min/100 mL; t-test, p = 0.03). Blood pressure did not change, so minimal resistance after ischemia (mean blood pressure divided by forearm blood flow) decreased with air, but not UFP [change from preexposure baseline, air: −0.48 ± 0.21; UFP: 0.07 ± 0.19 mmHg/mL/min; analysis of variance (ANOVA), p = 0.024]. There was no UFP effect on pre-ischemia forearm blood flow or resistance, or on total forearm blood flow after ischemia. Venous nitrate levels were significantly lower after exposure to carbon UFP compared with air (ANOVA, p = 0.038). There were no differences in venous nitrite levels. Conclusions Inhalation of 50 μg/m3 carbon UFP during intermittent exercise impairs peak forearm blood flow during reactive hyperemia in healthy human subjects.

Amantadine effect on peripheral airways abnormalities in influenza: a study in 15 students with natural influenza A infection

Amantadine HCl administration has resulted in accelerated resolution of influenza A illness. Prolonged abnormalities in pulmonary function have been described in uncomplicated influenza A. To study the effect of amantadine on these changes, we evaluated young adults with documented natural influenza A with clear chest examinations and X rays. Subjects received placebo or amantadine in random, double-blind fashion. Physiologic studies included maximal expiratory flow volume curves with air and helium-oxygen mixtures. Air flow rates were unchanged in all subjects throughout. Initially, both groups showed comparable decreases in mean helium-oxygen maximal expiratory flow rates. The amantadine group showed accelerated physiologic improvement: significant increase in helium-oxygen flow rates occurred within 7 days (P less than 0.05). The rate of improvement in the helium-oxygen flow rates in the placebo group was not statistically significant. These studies confirm peripheral airways dysfunction after uncomplicated influenza A and suggest that amantadine is associated with accelerated resolution of this dysfunction.

Evaluation of early airway disease in smokers: cost effectiveness of pulmonary function testing.

We studied 73 young adults who were presently cigarette smokers to evaluate whether the identification of abnormalities in pulmonary function tests had a detectable influence on modification of smoking habits. Utilizing rate schedules for these tests presently applicable in Rochester, New York, we determined the potential cost to these subjects and community relative to the number of subjects who stopped smoking as a result of test findings. Subjects were evaluated by questionnaire and function testing including spirometry, flow-volume curves, body plethysmography and single breath nitrogen washout test (SBN2). Functional abnormalities were present in 75% of subjects screened. The SBN2 test was most sensitive, identifying 97% of subjects with any abnormality. The presence of common respiratory symptoms was found to be highly predictive of test abnormalities. Subjects were informed of results and counseled. At six-month follow-up, 7% of subjects with abnormal test results had stopped smoking. Utilizing even our most cost-effective test, the SBN2, it would cost

Smokers have reduced nitric oxide production by conducting airways but normal levels in the alveoli.

1,392 for each “benefit” defined as one subject not smoking for six months. Application of these screening techniques is unlikely to be effective in altering smoking habits in the absence of continued physician support.

Respiratory Syncytial Virus Infection in Adults: Clinical, Virologic, and Serial Pulmonary Function Studies

Air exhaled by cigarette smokers contains reduced amounts of nitric oxide (NO). Measurement of NO at different expiratory flow rates permits calculation of NO production by the conducting airways (VawNO) and alveolar concentration of NO (PALV). An independent measurement of diffusing capacity of the alveolar compartment (DLNO) multiplied by PALV allows calculation of NO production by the alveoli (VLNO). Twelve asymptomatic cigarette smokers and 22 age-matched nonsmokers had measurements of DLNO and expired NO at constant expiratory flow rates varying from 60 to 1500 ml/s. VawNO in smokers was only 22 ± 11 nl/min (mean ± standard deviation, SD) compared to 70 ± 37 nl/min in nonsmokers (p < .0001). In contrast, VLNO showed no significant difference (smokers: 203 ± 104 nl/min, nonsmokers: 209 ± 74 nl/min, p = .86). These data show that the diminished NO expired by smokers results from diminished NO production by the tissues of the conducting airways but normal values produced by the alveoli.