Mark W. Frampton

Monocytes-macrophages and lymphocytes are recruited to the respiratory tract in response to influenza virus challenge and are exposed to the virus during the establishment of immune defenses. The susceptibility of human lymphocytes to infection was assessed. The presence of monocytes-macrophages was required to attain infection of both resting and proliferating lymphocytes. Lymphocyte infection occurred in the context of immune cell clusters and was blocked by the addition of anti-intercellular adhesion molecule-1 (ICAM-1) antibody to prevent cell clustering. Both peripheral blood-derived and bronchoalveolar lymphocytes were susceptible to infection. Both CD4⁺ and CD8⁺ T lymphocytes were susceptible to influenza virus infection, and the infected CD4⁺ and CD8⁺ lymphocytes served as infectious foci for other nonpermissive or even virus-permissive cells. These data show that monocytes-macrophages and both CD4⁺ and CD8⁺ lymphocytes can become infected during the course of an immune response to influenza virus challenge. The described leukocyte interactions during infection may play an important role in the development of effective anti-influenza responses.

Rationale: Acute respiratory effects of low-level ozone exposure are not well defined in older adults. Objective: The Multicenter Ozone Study in oldEr Subjects (MOSES), although primarily focused on acute cardiovascular effects, provided an opportunity to assess respiratory responses to low concentrations of ozone in older healthy adults. Methods: We performed a randomized crossover, controlled exposure study of 87 healthy adults (59.9±4.5 years old; 60% female) to 0, 70, and 120 ppb ozone for 3 hours with intermittent exercise. Outcome measures were spirometry, sputum markers of airway inflammation, and plasma club cell protein-16 (CC16), a marker of airway epithelial injury. The effects of ozone exposure on these outcomes were evaluated with mixed effect linear models. A p-value 1 and FVC increased from pre-exposure values by 2.7% (2.0, 3.4) and 2.1% (1.3, 2.9), respectively, 15 min post-exposure to filtered air (0 ppb). Exposure to ozone reduced these increases in a concentration-dependent manner. After 120 ppb exposure, FEV₁ and FVC decreased by 1.7% (1.1, 2.3) and 0.8% (0.3, 1.3), respectively. A similar concentration-dependent pattern was still discernible 22 h post-exposure. At 4 h post-exposure, plasma CC16 increased from pre-exposure levels in an ozone-concentration-dependent manner. Sputum neutrophils obtained 22 h post-exposure showed a marginally significant increase in a concentration-dependent manner (p=0.012), but pro-inflammatory cytokines (IL-6, IL-8, TNFα) were not significantly affected. Conclusions: Exposure to ozone at near ambient levels induced lung function effects, airway injury, and airway inflammation in older healthy adults. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01487005

Context: Exposure to ozone has acute respiratory effects, but few human clinical studies have evaluated cardiovascular effects. Objective: We hypothesized that ozone exposure alters pulmonary and systemic vascular function, and cardiac function, with more pronounced effects in subjects with impaired antioxidant defense from deletion of the glutathione-S-transferase M1 gene (GSTM1 null). Methods: Twenty-four young, healthy never-smoker subjects (12 GSTM1 null) inhaled filtered air, 100 ppb ozone and 200 ppb ozone for 3 h, with intermittent exercise, in a double-blind, randomized, crossover fashion. Exposures were separated by at least 2 weeks. Vital signs, spirometry, arterial and venous blood nitrite levels, impedance cardiography, peripheral arterial tonometry, estimation of pulmonary capillary blood volume (Vc), and blood microparticles and platelet activation were measured at baseline and during 4 h after each exposure. Results: Ozone inhalation decreased lung function immediately after exposure (mean ± standard error change in FEV₁, air: −0.03 ± 0.04 L; 200 ppb ozone: −0.30 ± 0.07 L; p < 0.001). The immediate post-exposure increase in blood pressure, caused by the final 15-min exercise period, was blunted by 200 ppb ozone exposure (mean ± standard error change for air: 16.7 ± 2.6 mmHg; 100 ppb ozone: 14.5 ± 2.4 mmHg; 200 ppb ozone: 8.5 ± 2.5 mmHg; p = 0.02). We found no consistent effects of ozone on any other measure of cardiac or vascular function. All results were independent of the GSTM1 genotype. Conclusions: We did not find convincing evidence for early acute adverse cardiovascular consequences of ozone exposure in young healthy adults. The ozone-associated blunting of the blood pressure response to exercise is of unclear clinical significance.

Diabetes may confer an increased risk for the cardiovascular health effects of particulate air pollution, but few human clinical studies of air pollution have included people with diabetes. Ultrafine particles (UFP, ≤100 nm in diameter) have been hypothesized to be an important component of particulate air pollution with regard to cardiovascular health effects.

We and others have shown that increases in particulate air pollutant (PM) concentrations in the previous hours and days have been associated with increased risks of myocardial infarction, but little is known about the relationships between air pollution and specific subsets of myocardial infarction, such as ST-elevation myocardial infarction (STEMI) and non ST-elevation myocardial infarction (NSTEMI).

Exposure to air pollution is associated with increased morbidity and mortality from cardiovascular disease. We hypothesized that increases in exposure to ambient air pollution are associated with platelet activation and formation of circulating tissue factor-expressing microparticles. We studied 19 subjects with type 2 diabetes, without clinical evidence of cardiovascular disease, who had previously participated in a human clinical study of exposure to ultrafine particles (UFP). Blood was obtained for measurements of platelet activation following an overnight stay in the Clinical Research Center, prior to each of their two pre-exposure visits. Air pollution and meteorological data, including UFP counts, were analyzed for the 5 days prior to the subjects’ arrival at the Clinical Research Center. Contrary to expectations, increases in UFP were associated with decreases in surface expression of platelet activation markers. The number of platelet-leukocyte conjugates decreased by −80 (95% confidence interval (CI) −123 to −37, p = 0.001) on the first lag day (20–44 h prior to the blood draw) and by −85 (CI −139 to −31, p = 0.005) on combined lag days 1 to 5, per interquartile range (IQR) increase in UFP particle number (2482). However, levels of soluble CD40L increased 104 (CI 3 to 205, p = 0.04) pg/ml per IQR increase in UFP on lag day 1, a finding consistent with prior platelet activation. We speculate that, in people with diabetes, exposure to UFP activates circulating platelets within hours of exposure, followed by an increase in soluble CD40L and a rebound reduction in circulating platelet surface markers.

Introduction: Ultrasound measurements of brachial artery reactivity in response to stagnant ischemia provide estimates of microvascular function and conduit artery endothelial function. We hypothesized that brachial artery reactivity would independently predict severe sepsis and severe sepsis mortality. Methods: This was a combined case-control and prospective cohort study. We measured brachial artery reactivity in 95 severe sepsis patients admitted to the medical and surgical intensive care units of an academic medical center and in 52 control subjects without acute illness. Measurements were compared in severe sepsis patients versus control subjects and in severe sepsis survivors versus nonsurvivors. Multivariable analyses were also conducted. Results: Hyperemic velocity (centimeters per cardiac cycle) and flow-mediated dilation (percentage) were significantly lower in severe sepsis patients versus control subjects (hyperemic velocity: severe sepsis = 34 (25 to 48) versus controls = 63 (52 to 81), P < 0.001; flow-mediated dilation: severe sepsis = 2.65 (0.81 to 4.79) versus controls = 4.11 (3.06 to 6.78), P < 0.001; values expressed as median (interquartile range)). Hyperemic velocity, but not flow-mediated dilation, was significantly lower in hospital nonsurvivors versus survivors (hyperemic velocity: nonsurvivors = 25 (16 to 28) versus survivors = 39 (30 to 50), P < 0.001; flow-mediated dilation: nonsurvivors = 1.90 (0.68 to 3.41) versus survivors = 2.96 (0.91 to 4.86), P = 0.12). Lower hyperemic velocity was independently associated with hospital mortality in multivariable analysis (odds ratio = 1.11 (95% confidence interval = 1.04 to 1.19) per 1 cm/cardiac cycle decrease in hyperemic velocity; P = 0.003). Conclusions: Brachial artery hyperemic blood velocity is a noninvasive index of microvascular function that independently predicts mortality in severe sepsis. In contrast, brachial artery flow-mediated dilation, reflecting conduit artery endothelial function, was not associated with mortality in our severe sepsis cohort. Brachial artery hyperemic velocity may be a useful measurement to identify patients who could benefit from novel therapies designed to reverse microvascular dysfunction in severe sepsis and to assess the physiologic efficacy of these treatments.

A peer-reviewed open access journal published by the National Institute of Environmental Health Sciences

Background: Growing evidence indicates that ambient air pollution is associated with exacerbation of chronic diseases like chronic pulmonary disease. A prospective panel study was conducted to investigate short-term changes of blood markers of inflammation and coagulation in response to daily changes in air pollution in Erfurt, Germany. 12 clinical visits were scheduled and blood parameters were measured in 38 male patients with chronic pulmonary disease during winter 2001/2002. Additive mixed models with random patient intercept were applied, adjusting for trend, weekday, and meteorological parameters. Hourly data on ultrafine particles (UFP, 0.01-0.1 μm), accumulation mode particles (ACP, 0.1-1.0 μm), PM₁₀ (particulate matter 2], carbon monoxide [CO], and sulphur dioxide [SO₂]) were collected at a central monitoring site and meteorological data were received from an official network. For each person and visit the individual 24-hour average of pollutants immediately preceding the blood withdrawal (lag 0) up to day 5 (lag1-4) and 5-day running means were calculated. Results: Increased levels of fibrinogen were observed for an increase in one interquartile range of UFP, PM₁₀, EC, OC, CO, and NO revealing the strongest effect for lag 3. E-selectin increased in association with ACP and PM₁₀ with a delay of one day. The ACP effect was also seen with the 5-day-mean. The pattern found for D-dimer was inconsistent. Prothrombin fragment 1+2 decreased with lag 4 consistently for all particulate pollutants. Von Willebrand factor antigen (vWF) showed a consistent decrease in association with almost all air pollutants with all lags except for lag 0. No associations were found for C-reactive protein, soluble intercellular adhesion molecule 1, serum amyloid A and factor VII. Conclusion: These results suggest that elevated concentrations of air pollution are associated with changes in some blood markers of inflammation and coagulation in patients with chronic pulmonary disease. The clinical implications of these findings need further investigation.

The mechanisms underlying the association between air pollution and cardiovascular morbidity and mortality are unknown. This study aimed to determine whether controlled exposure to elemental carbon ultrafine particles (UFP) affects electrocardiogram (ECG) parameters describing heart rate variability; repolarization duration, morphology, and variability; and changes in the ST segment. Two separate controlled studies (12 subjects each) were performed using a crossover design, in which each subject was exposed to filtered air and carbon UFP for 2 hours. The first protocol involved 2 exposures to air and 10 μg/m³ (∼ 2× 10⁶ particles/cm³, count median diameter ∼25 nm, geometric standard deviation ∼1.6), at rest. The second protocol included 3 exposures to air, 10, and 25 μg/m³ UFP (∼ 7× 10⁶ particles/cm³), with repeated exercise. Each subject underwent a continuous digital 12-lead ECG Holter recording to analyze the above ECG parameters. Repeated measures analysis of variance (ANOVA) was used to compare tested parameters between exposures. The observed responses to UFP exposure were small and generally not significant, although there were trends indicating an increase in parasympathetic tone, which is most likely also responsible for trends toward ST elevation, blunted QTc shortening, and increased variability of T-wave complexity after exposure to UFP. Recovery from exercise showed a blunted response of the parasympathetic system after exposure to UFP in comparison to air exposure. In conclusion, transient exposure to 10–25 μ g/m³ ultrafine carbon particles does not cause marked changes in ECG-derived parameters in young healthy subjects. However, trends are observed indicating that some subjects might be susceptible to air pollution, with a response involving autonomic modulation of the heart and repolarization of the ventricular myocardium.