Stephan F. van Eeden

Particulate air pollution induces progression of atherosclerosis.

OBJECTIVESnWe sought to determine the effect of exposure to air pollution particulate matter <10 microm (PM(10)) on the progression of atherosclerosis in rabbits.nnnBACKGROUNDnEpidemiologic studies have associated exposure to ambient PM(10) with increased cardiovascular morbidity and mortality. We have previously shown that PM(10) exposure induces a systemic inflammatory response that includes marrow stimulation, and we hypothesized that this response accelerates atherosclerosis.nnnMETHODSnWatanabe heritable hyperlipidemic rabbits were exposed to PM(10) (n = 10) or vehicle (n = 6) for four weeks, and bone marrow stimulation was measured. Quantitative histologic methods were used to determine the morphologic features of the atherosclerotic lesions.nnnRESULTSnExposure to PM(10) caused an increase in circulating polymorphonuclear leukocytes (PMN) band cell counts (day 15: 24.6 +/- 3.0 vs. 11.5 +/- 2.7 x 10(7)/l [PM(10) vs. vehicle], p < 0.01) and an increase in the size of the bone marrow mitotic pool of PMNs. Exposure to PM(10) also caused progression of atherosclerotic lesions toward a more advanced phenotype. The volume fraction (vol/vol) of the coronary atherosclerotic lesions was increased by PM(10) exposure (33.3 +/- 4.6% vs. 19.5 +/- 3.1% [PM(10) vs. vehicle], p < 0.05). The vol/vol of atherosclerotic lesions correlated with the number of alveolar macrophages that phagocytosed PM(10) (coronary arteries: r = 0.53, p < 0.05; aorta: r = 0.51, p < 0.05). Exposure to PM(10) also caused an increase in plaque cell turnover and extracellular lipid pools in coronary and aortic lesions, as well as in the total amount of lipids in aortic lesions.nnnCONCLUSIONSnProgression of atherosclerosis and increased vulnerability to plaque rupture may underlie the relationship between particulate air pollution and excess cardiovascular death.

Chronic Obstructive Pulmonary Disease: A Chronic Systemic Inflammatory Disease

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation in both the airways causing airway obstruction and the lung tissues causing emphysema. The disease is induced by inhalation of noxious gasses and particulate matter resulting in a chronic persistent inflammatory response in the lung, and the extent of the inflammatory reaction correlates with the severity of the disease. This chronic inflammatory response in the lung is also associated with a significant systemic inflammatory response with downstream adverse clinical health effects. The systemic response in COPD is associated with mortality, specifically cardiovascular mortality. This review describes the nature of the systemic inflammatory response in COPD and the clinical manifestations associated with the systemic response, with a focus on the potential mechanisms for these adverse health effects.

Particulate Matter Induces Translocation of IL-6 from the Lung to the Systemic Circulation

The biological mechanisms responsible for an association between elevated concentrations of ambient particulate matter (PM) and increased cardiovascular morbidity and mortality remain unclear. Our laboratory showed that exposure to PM induces systemic inflammation that contributes to vascular dysfunction. This study was designed to determine whether the lung is a major source of systemic inflammatory mediators, using IL-6 as a surrogate marker. We also sought to determine the impact on vascular dysfunction after exposure to PM of less than 10 μm in diameter (PM(10)). C57BL/6 mice were intratracheally exposed to a single instillation of PM(10) (10 or 200 μg) or saline. Four hours or 24 hours after exposure, venous and arterial blood samples were simultaneously collected from the right atrium and descending aorta. Concentrations of IL-6 were measured in bronchoalveolar lavage fluid (BALF) and serum samples. Vascular functional responses to acetylcholine (ACh) and phenylephrine were measured in the abdominal aorta. Concentrations of IL-6 in BALF samples were increased at 4 and 24 hours after exposure to PM(10). At baseline, concentrations of IL-6 in venous blood were higher than those in arterial blood. Exposure to PM(10) reversed this arteriovenous gradient, 4 hours after exposure. The relaxation responses of the abdominal aorta to ACh decreased 4 hours after exposure to 200 μg PM(10). In IL-6 knockout mice, the instillation of recombinant IL-6 increased IL-6 concentrations in the blood, and exposure to PM(10) did not cause vascular dysfunction. These results support our hypothesis that exposure to PM(10) increases pulmonary inflammatory mediators that translocate to the circulation, contributing to systemic inflammation, with downstream effects such as vascular dysfunction.

Patterns of Retention of Particulate Matter in Lung Tissues of Patients With COPD: Potential Role in Disease Progression

BACKGROUNDnParticulate matter (PM) is present in lung tissues of smokers and urban dwellers. This study was designed to quantify the burden of PM in different lung tissues of subjects with COPD and determine its relationship to disease severity.nnnMETHODSnSurgical lung tissue samples from nonsmokers (control subjects) were compared with those from smokers with normal spirometry and subjects in the four other categories of the GOLD (Global Initiative for Obstructive Lung Disease) classification of COPD severity using quantitative histologic techniques.nnnRESULTSnPM was present in the lung parenchyma, blood vessel walls, airways, lymphoid follicles, and alveolar macrophages. The total burden of PM (volume fraction [Vv]) in all tissues of the lung was higher in smokers than nonsmokers (P < .001) and also in smokers with airflow obstruction compared with the smokers with normal spirometry (P < .01). There was an incremental increase in total PM burden with increased COPD severity that peaked in GOLD II and then trended downward in GOLD III and IV COPD. This same pattern of PM retention was also observed in alveolar walls. The total burden of PM in lung tissues correlated with a decline in FEV(1)/FVC as well as pack-years smoking. mRNA expression of fibrinogen (γ chain) correlated with total lung burden of PM and burden of PM in lung parenchyma (r(2) = 0.22, P < .001).nnnCONCLUSIONSnWe conclude that retained PM is widely distributed in lung tissues of subjects with COPD and that cigarette smoke exposure and airflow obstruction are associated with retention of PM in lung tissues. We attribute the downward trend in PM burden in severe COPD to either less deposition and retention or selective removal of PM containing tissues by emphysematous destruction.

Circulating white blood cells affect red cell pulmonary transit times in endurance athletes during intense exercise

PURPOSEnThe aim of this study was to determine the relationship between the right-to-left ventricular red cell pulmonary transit times (PTT) during intense exercise and circulating white blood cell (WBC) counts in highly trained endurance athletes. We postulated that high levels of WBCs preexercise would slow PTT. Eleven endurance-trained athletes (VO2max = 69.6 +/- 7.7 mL.kg-1.min-1; weight = 75.0 +/- 6.2 kg; height = 181.0 +/- 7.1 cm) performed 6.5 min constant-load, near-maximal cycling exercise (approximately 92% VO2max) on two different days. Preexercise WBC counts were measured in arterial blood drawn from the radial artery 30 min before exercise. PTT was measured during the 3rd min of exercise by first-pass radionuclide cardiography using centroid and deconvolution analysis, whereas cardiac output (Q) was measured during the last 2.5 min of exercise via a count-based ratio method from the MUGA technique.nnnRESULTSnCombined mean PTT from both deconvolution and centroid analysis at minute three of exercise was 2.45 +/- 0.21 s, whereas the preexercise WBC count was 5.3 +/- 1.6 x 109.L-1. Cardiopulmonary blood volume at minute three of exercise was 1.22 +/- 0.13 L, VO2 was 4.58 +/- 0.44 L.min-1, and Q was 30.2 +/- 4.2 L.min-1. We found that PTT was negatively correlated with circulating WBC (r = -0.61; adjusted r2 = 0.30; P = 0.04; N = 11) but not with the dispersion (spread) of transit times around the mean (r = 0.19; P = 0.57).nnnCONCLUSIONnThis suggests that athletes with higher circulating numbers of WBCs preexercise have faster (shorter) red cell transit times through the lung during intense exercise.