Ambient Particulate Matter,C-Reactive Protein,and Coronary Artery Disease

Abstract

This article is a review of the scientific literature with respect to fine particulate matter (PM), 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, and coronary artery disease (CAD). The association between air pollution and respiratory diseases has been extensively investigated for decades; however, the role of air pollution in exacerbating heart disease has only recently become a focus of attention. It has been shown that for every 10-μg/m³ increase in fine PM in the air, there appears to be a 2.1% increase in the number of deaths related to ischemic heart disease. PM has been linked to increased levels of systemic inflammation biomarkers such as C-reactive proteins (CRP). Daily variation of ambient pollution is correlated with rises and falls in CRP levels. Increased CRP levels have been associated with increased morbidity and mortality in individuals with CAD. Seventy-five percent of patients with elevated CRP levels have reportedly experienced a major cardiac event despite low-density lipoproteins (LDL) levels that were below the threshold recommended for pharmacological intervention. HMG CoA reductase inhibitors (statins) have been shown to cause a reduction in coronary events by lowering LDL levels. However, recently it has been shown that statins have the effect of lowering CRP levels. This may explain why individuals with normal lipid levels may benefit from statin therapy. Ambient PM exposure levels and its effects on CRP are risk factors associated with coronary events and should be considered as a target for the treatment of CAD.     

Acute Functional Enhancement of Circulatory Neutrophils After Intratracheal Instillation with Diesel Exhaust Particles in Rats

Abstract

We have previously demonstrated that intratracheal instillation (IT) with diesel exhaust particles (DEP) exacerbates myocardial ischemia/reperfusion-induced arrhythmia in rats. Since activated neutrophils play a pivotal role in ischemia/reperfusion arrhythmia, in the present study we investigated the effects of DEP on peripheral neutrophil count and on the oxyradical production (ORP) of neutrophils in rats. We also determined the production of cytokines for better understanding of the relationship between pulmonary inflammation and neutrophil function. Instillation with 5 mg DEP elevated circulatory neutrophil counts (CNC) at 12 and 24 h post-instillation to levels approximately 2.1- and 2.3-fold those in the vehicle-treated animals, respectively. On the other hand, 1-mg DEP caused an approximately 0.4-fold increase in CNC at 6 h. 12-O-Tetradecanoylphorbol 13-acetate-induced ORP in the isolated neutrophil was enhanced at 12 and 24 h after instillation with 5 mg DEP. Cytokine-induced neutrophil chemoattractant-1 (CINC-1), tumor necrosis factor-α (TNFα) and macrophage inflammatory protein-2 (MIP-2) levels were increased in the bronchoalveolar lavage fluid (BALF) collected from animals that received 5 mg DEP. In serum, a marked elevation of CINC-1 and a slight elevation of MIP-2 were also observed, while TNFα was not detected. Granulocyte–macrophage colony-stimulating factor (GM-CSF) was detected in neither BALF nor serum for 24 h after the instillation. These results suggest that IT instillation of DEP enhances systemic oxidative stress by increasing neutrophil count and ORP in the acute period.     

Ambient Particulate Matter Affects Cardiac Recovery in a Langendorff Ischemia Model

Exposure to ambient particulate matter (PM) is associated with increased mortality and morbidity among subjects with cardiovascular impairment. We hypothesized that exposure of spontaneously hypertensive (SH) rats to PM impairs the recovery of cardiovascular performance after coronary occlusion and reperfusion-ischemia. SH rats were exposed by intratracheal instillation to saline, standard urban PM (Ottawa dust EHC-93, 10 mg/kg body weight) or endotoxin (lipopolysaccharides LPS, 350 EU/animal) to induce a similar pulmonary inflammation. At 4 h postexposure, hearts were isolated and retrograde perfused in a Langendorff model. The experimental protocol included 35 min of coronary occlusion followed by 120 min of reperfusion, during which left ventricular developing pressure (LDVP), coronary flow (CF), and heart rate (HR) were measured. Baseline LVDP in particle-instilled SH rats was significantly decreased compared to saline-instilled animals. In addition, after ischemia the recovery of LDVP was much slower in rats pretreated with PM or LPS compared to saline instilled rats. The direct effects of the soluble PM fraction and the role of Zn²⁺ were also tested cardiomyocytes (H9C2 cells). Both particle-free filtrate and Zn²⁺ inhibited ATP or ionophore-stimulated calcium influx in cardiomyocytes. This inhibitory effect was related to an effect on calcium channels, as shown with Nifedipine. This study provides evidence that exposure to instillation of PM has reversible acute effects on the recovery of cardiac physiological parameters after ischemia. The effect may be caused by a direct action of soluble metals on calcium homeostasis in heart, but pulmonary inflammation may also play a significant role.     

The Effect of Coarse Ambient Particulate Matter on First,Second, and Overall Hospital Admissions for Respiratory Disease Among the Elderly

Abstract

The objective of this article is to examine differences in the effect of ambient particulate matter on first, second, and overall hospital admissions for respiratory disease among the elderly. We studied 8989 adults 65 yr of age or older living in the greater Vancouver area who were admitted to hospital for any acute respiratory disease (ICD-9 codes 460–519) between June 1, 1995, and March 31, 1999. Time-series analysis was used to evaluate the association between respiratory admissions and daily measures of particulate matter (PM₁₀, PM_2.5, and PM_{10 ? 2.5}) in urban air, after adjustment for gaseous copollutants (CO, O₃, NO₂, and SO₂) and meteorological variables. Repeated admissions for respiratory disease were common among the elderly. Approximately 30% of the subjects were readmitted to hospital after the first admission; 9% had more than 2 admissions for respiratory disease during the 4-yr study period. PM_{10 ? 2.5} was significantly associated with the second and overall admissions for respiratory disease, but not with the first admission. The adjusted relative risks for an increment of 4.2 μ g/m³ in -day average PM_{10 ? 2.5} concentrations were 1.03 (95% confidence interval: 0.98–1.09) for the first admission, 1.22 (1.10–1.36) for the second admission, and 1.06 (1.02, 1.11) for overall admissions. There was no significant association between PM_2.5 and hospital admissions for respiratory disease among the elderly. Our data suggest that (1) people with a history of respiratory admissions are at a higher risk of respiratory disease in relation to particulate air pollution in urban areas, (2) analyses based on overall rather than repeated hospital admissions lead to lower estimates of the risk of respiratory disease associated with particulate air pollution, and (3) PM_{10 ? 2.5} has a larger effect on respiratory admissions than PM_2.5.     

Nasal Responses in Asthmatic and Nonasthmatic Subjects Following Exposure to Diesel Exhaust Particles

Asthma rates have been increasing worldwide, and exposure to diesel exhaust particles (DEP) may be implicated in this increase. DEP may also play a role in the increased morbidity and mortality associated with ambient airborne particulate matter (PM) exposure. Two types of nasal responses have been reported for human subjects nasally instilled with one type of DEP: alterations in cytokines responses, and an increase in immunoglobulin E (IgE) production. Since DEP composition can vary depending on several factors, including fuel composition and engine load, the ability of another DEP particle and ozone-treated DEP to alter nasal IgE and cytokine production was examined. Nonasthmatic and asthmatic subjects were intranasally instilled with 300 μ g NIST 1650 DEP per nostril, NIST 1650 DEP previously exposed to ozone (ozDEP; 300 μ g/nostril), or vehicle. Subjects underwent nasal lavage before DEP exposure, and 4 and 96 h after exposure. Nasal cell populations and soluble mediators in the nasal lavage fluid were characterized. Total cell number, cell types, cell viability, concentrations of soluble mediators (including interleukin [IL]-8, IL-6, IgE, and granulocyte–macrophage colony-stimulating factor [GM-CSF]) were not altered by either DEP or ozDEP exposure. NO levels were not altered by either particle exposure. These findings suggest that DEP can be relatively noninflammatory and nontoxic, and that the physicochemical characteristics of DEP need to be considered when assessing the health effects of exposure to diesel exhaust.     

Diesel Exhaust Is a Pulmonary Carcinogen in Rats Exposed Chronically by Inhalation

Diesel Exhaust Is a Pulmonary Carcinogen in Rats Exposed Chronicallyby Inhalation. MAUDERLY, J. L., JONES, R. K., GRIFFITH, W. C.,HENDERSON, R. F., AND MCCLELLAN, R. O. (1987). Fundam. Appl.Toxicol 9, 208–221. Male and female F344 rats were exposed7 hr/day, 5 day/week for up to 30 months to automotive dieselengine exhaust at soot concentrations of 0.35, 3.5, or 7.0 mg/m³or were sham-exposed to clean air. Rats were terminated at 6-monthintervals to measure lung burdens of diesel soot and for histopathology.Other rats either died or were terminated after 30 months ofexposure. Lungs were fixed, sectioned into 3-mm slices, andexamined by a dissecting microscope to detect tumors. Lesionswere stained and examined by light microscopy. Survival andbody weight were unaffected by exposure. Focal fibrotic andproliferative lung disease accompanied a progressive accumulationof soot in the lung. The prevalence of lung tumors was significantlyincreased at the high (13%) and medium (4%) dose levels abovethe control prevalence (1%). Four tumor types, all of epithelialorigin, were observed: adenoma. adenocarcinoma, squamous cyst,and squamous cell carcinoma. Logistic regression modeling demonstrateda significant relationship between tumor prevalence and bothexposure concentration and soot lung burden. These results demonstratethat diesel exhaust, inhaled chronically at a high concentration,is a pulmonary carcinogen in the rat.     

Diesel Exhaust Enhanced Susceptibility to Influenza Infection is Associated with Decreased Surfactant Protein Expression

We have previously shown that exposure of respiratory epithelial cells to diesel exhaust (DE) enhances susceptibility to influenza infection and increases the production of interleukin (IL)-6 and interferon (IFN)-β. The purpose of this study was to confirm and expand upon these in vitro results by assessing the effects of DE exposure on the progression of influenza infection and on development of associated pulmonary immune and inflammatory responses in vivo. BALB/c mice were exposed to air or to DE containing particulate matter at concentrations of 0.5 or 2 mg/m³ for 4 h/day for 5 days and subsequently instilled with influenza A/Bangkok/1/79 virus. Exposure to 0.5 mg/m³ (but not the higher 2-mg/m³ dose) of DE increased susceptibility to influenza infection as demonstrated by a significant increase in hemagglutinin (HA) mRNA levels, a marker of influenza copies, and greater immunohistochemical staining for influenza virus protein in the lung. The enhanced susceptibility to infection observed in mice exposed to 0.5 mg/m³ of DE was associated with a significant increase in the expression of IL-6, while antiviral lung IFN levels were unaffected. Analysis of the expression and production of surfactant proteins A and D, which are components of the interferon-independent antiviral defenses, showed that these factors were decreased following exposure to 0.5 mg/m³ of DE but not to the higher 2-mg/m³ concentration. Taken together, the results demonstrate that exposure to DE enhances the susceptibility to respiratory viral infections by reducing the expression and production of antimicrobial surfactant proteins.     

Adjuvant Activity of Ambient Particulate Matter in Macrophage Activity-Suppressed,N-Acetylcysteine-Treated,iNOS- and IL-4-Deficient Mice

In previous studies, we have shown strong adjuvant activity for Ottawa dust (EHC-93) after coexposure of the BALB/c mouse to EHC-93 and ovalbumin. Mice were intranasally sensitized at days 0 and 14 with 200 μg ovalbumin and 150 μg EHC-93, and challenged with ovalbumin at days 35, 38, and 41 with 200 μg ovalbumin. Mice were autopsied at day 42. This adjuvant activity was shown for the antibody response to ovalbumin (immunoglobulins E, G₁, and G_2a), histopathological lesions in the lung, cytokines, and the numbers of eosinophils in lung lavages. To study the mechanisms of this adjuvant activity, mice (BALB/c C.D2-Vil6) with natural-resistance-associated macrophage protein (Nramp1^s), BALB/c mice pretreated with the antioxidant N-acetylcysteine (NAC), mice (B6.129P2-Nos2tmLau) deficient in inducible nitric oxide synthase (iNOS), and mice with interleukin-4 (IL-4) deficiency (BALB/cIl4< tm2Nnt) were coexposed to ovalbumin and EHC-93. Our studies have shown that the adjuvant activity induced after such coexposure does not change if the macrophage activation of the mice is disturbed or if the mice have been pretreated with N-acetylcysteine. In addition, the adjuvant activity does not develop through the pathway in which inducible nitric oxide synthase is involved. Because the histopathological lesions are statistically significant less in the IL-4 knockout strain in comparison with the wild type, we conclude that interleukin-4 might play an important role in the adjuvant activity caused by EHC-93.     

Effects of Subchronic Exposures to Concentrated Ambient Particles (CAPs) in Mice: IV. Characterization of Acute and Chronic Effects of Ambient Air Fine Particulate Matter Exposures on Heart-Rate Variability

Abstract

Long-term exposure to fine particulate air pollution (PM_2.5) has been associated with increased risk of death from cardiopulmonary diseases. Cardiac function parameters have also been affected by ambient particulate matter (PM) exposure, including heart-rate variability (HRV), a measure of autonomic function that has been recognized as a well-defined, quantitative indicator of autonomic dysfunction. However, the role of HRV in ambient PM-induced cardiovascular effects is not fully understood. In an accompanying article, we report significant decreasing patterns of heart rate (HR), body temperature, and physical activity for mice lacking apoliproprotein (ApoE^?/?) over 5 mo of exposure to concentrated ambient PM (CAPs), with smaller and nonsignificant changes for C57 mice. In this article, we report the effects of subchronic CAPs exposure on HRV parameters that are sensitive to cardiac sympathetic and parasympathetic nerve activity. The standard deviation of normal to normal beat intervals (SDNN) and the square root of the mean squared differences of successive RR intervals (RMSSD) in the late afternoon and overnight for the ApoE^?/? mice showed a gradual increase for the first 6 wk, a decline for about 12 more wk, and a slight turn upward at the end of the study period. For C57 mice, there were no chronic effect changes of SDNN or RMSSD in the late afternoon, and a slight increase after 6 wk for the overnight period. The response patterns of ApoE^?/? mice indicated a perturbation of the homeostatic function in the cardiovascular system (initial enhancement and later depression of the HRV parameters). Our results complement the findings in human panel and controlled CAPs exposure studies in demonstrating that increased levels of particle pollution are able to perturb cardiac autonomic function, which may lead to adverse cardiovascular outcomes.     

Alterations in Particle Accumulation and Clearance in Lungs of Rats Chronically Exposed to Diesel Exhaust

Alterations in Particle Accumulation and Clearance in Lungsof Rats Chronically Exposed to Diesel Exhaust. WOLFF, R. K.,HENDERSON, R. F., SNIPES, M. B., GRIFFITH, W. C., MAUDERLY,J. L., CUDDIHY, R. G., AND MCCLELLAN, R. 0. Fundam Appl. Toxicol9, 154–166. F344 rats were chronically exposed to dieselexhaust at target soot concentrations of 0 (control, C), 0.35(low, L), 3.5 (medium, M), and 7.0 (high, H) mg/m³ Accumulatedlung burdens of diesel soot were measured after 6, 12, 18, and24 months of exposure. Parallel measurements of particle depositionand clearance were made to provide insight into the mechanismsof particle accumulation in lungs. The fractional depositionof inhaled ⁶⁷Ga₂O₃ particles after 6, 12, 18, and 24 monthsof exposure and of inhaled ¹³⁴Cs-fused aluminosilicate particlesafter 24 months were similar for all groups. Progressive increasesin lung burdens of soot particles were observed in M and H exposedrats, reaching levels of 11.5 ± 0.5 and 20.5 ±0.8 mg/lung (SE), respectively, after 24 months. Rats in theL group had smaller relative increases in lung burden, reachinglevels of 0.60 ± 0.02 mg/lung after 24 months. Trachealmucociliary clearance measurements, using ^99mTc-macroaggitatedalbumin deposited in the trachea, showed no changes at anytime.There were statistically significant increases inclearance half-timesof inhaled radiolabeled particles of ⁶⁷Ga₂O₃ as early as 6 monthsat the H level and 18 months at the M level; no significantchanges were seen at the L level. Rats inhaled fused aluminosilicateparticles labeled with ¹³⁴Cs after 24 months of diesel exhaustexposure to measure long-term components of pulmonary clearance.The long-term clearance half-times were 79 ± 5, 81 ±5, 264 ± 50, and 240 ± 50 days (± SE) forthe C, L, M, and H groups, respectively. Differences were significantbetween the C and both the M and H exposure groups (p <0.01).Lung burdens of diesel soot were more than expected at the Hand M levels and were also associated with impaired particleclearance while smaller responses were observed in both burdensand clearance at the L level.     

Chronic Nose-only Inhalation Study in Rats,comparing Room-aged Sidestream Cigarette Smoke and Diesel Engine Exhaust

Nose-only exposure of male and female Wistar rats to a surrogate for environmental tobacco smoke, termed room-aged sidestream smoke (RASS), to diesel engine exhaust (DEE), or to filtered, fresh air (sham) was performed 6 hours/day, 7 days/week for 2 years, followed by a 6-month post-exposure period. The particulate concentrations were 3 and 10 mg/m³. Markers of inflammation in bronchoalveolar lavage showed that DEE (but not RASS) produced a dose-related and persistent inflammatory response. Lung weights were increased markedly in the DEE (but not RASS) groups and did not decrease during the 6-month post-exposure period. Bulky lung DNA adducts increased in the RASS groups, but not in the DEE groups. Cell proliferation in the lungs was unaffected by either experimental treatment. Histopathological responses in the RASS groups were minimal and almost completely reversible; lung tumors were similar in number to those seen in the sham-exposed groups. Rats exposed to DEE showed a panoply of dose-related histopathological responses: largely irreversible and in some cases progressive. Malignant and multiple tumors were seen only in the DEE groups; after 30 months, the tumor incidence (predominantly bronchiolo-alveolar adenomas) was 2% in the sham-exposed groups, 5%in the high RASS groups, and 46% in the high DEE groups (sexes combined). Our results suggest that in rats exposed to DEE, but not to RASS, the following series of events occurs: particle deposition in lungs → lung “overload” → pulmonary inflammation → tumorigenesis, without a significant modifying role of cell proliferation or DNA adduct formation.     

老年呼吸道感染患者的药物敏感性与血药浓度监测

目的:了解老年呼吸道感染患者的病原菌分布情况、药物敏感性及有效血药浓度范围.方法:以NCCLS常规方法检测痰中病原菌,以K-B纸片法测药物敏感性,以微生物法测定血药浓度.结果:288例患者痰液中共分离出病原菌400株,其中革兰氏阴性(G-)杆菌147株(36.75%),以肺炎克雷伯菌及铜绿假单胞菌为主;革兰氏阳性(G )球菌133株(33.25%),以肺炎链球菌和金黄色葡萄球菌为主;真菌120株(30%),以白色念珠菌为主.给药20 h后血药浓度仍在2.7～116 μg/mL范围内.结论:对于老年呼吸道感染患者,在进行病原菌、药物敏感性检测时应同时测定血药浓度,以保证敏感药物在足够剂量时发挥最佳抗菌效果.     

Pulmonary Inflammation and DNA Adducts in Rats Inhaling Diesel Exhaust or Carbon Black

Abstract

Inhaled diesel exhaust has been shown to be carcinogenic to rats. Two mechanisms have been suggested: a genotoxic effect of organic compounds associated with the diesel soot, and an epigenetic effect resulting from large accumulations of particles that produce chronic inflammation and epithelial proliferation in the lung. To gain insights into the possible roles of these two mechanisms, we compared inflammatory responses and DNA adducts in lungs of rats exposed to diesel exhaust (33% extractable organic compounds by mass) and carbon black (0.04% extractable), which are similar carbonaceous particles with virtually no organic compounds. Male rats were exposed 7 h/day, 5 days/wk for 12 wk to diesel exhaust or carbon black, both at a concentration of 70.0 mg/m³, or to filtered air: Both diesel exhaust and carbon black exposures caused mild inflammation in the lung, as evidenced by increases in numbers of neutrophils and in the protein content of bronchoalveolar lavage fluids. The levels of DNA adducts, as measured by ³²P postlabeling, were increased more by exposure to diesel exhaust than to carbon black. Although it remains unclear whether the carcinogenicity of diesel exhaust is related primarily to DNA injury or primarily to the loading of the lung with particles, our findings are consistent with an initiation-promotion mechanism that involves both DNA damage and lung inflammation.     

Pulmonary Retention of Particulate Matter is Associated with Airway Inflammation in Allergic Rats Exposed to Air Pollution in Urban Detroit

A collaborative research study was conducted in order to improve our understanding of the source-to-receptor pathway for ambient fine particulate matter (aerodynamic diameter ≤ 2.5 μ m; PM_2.5) and subsequently to investigate the identity and sources of toxic components in PM_2.5 responsible for adverse health effects in allergic humans. This research used a Harvard fine particle concentrator to expose Brown Norway rats, with and without ovalbumin-induced allergic airway disease, to concentrated air particles (CAPs) generated from ambient air in an urban Detroit community where the pediatric asthma rate was three times higher than the national average. Rats were exposed to CAPs during the exposure periods in July (mean = 676 μg/m³) and September (313 μg/m³) of 2000. Twenty-four hours after exposures lung lobes were either lavaged with saline to determine cellularity and protein in bronchoalveolar lavage fluid (BALF), or removed for analysis by inductively coupled plasma–mass spectrometry (ICP-MS) to detect ambient PM_2.5-derived trace element retention. PM_2.5 trace elements of anthropogenic origin, lanthanum (La), vanadium (V), manganese (Mn), and sulfur (S), were recovered from the lung tissues of CAPs-exposed rats. Recovery of those pulmonary anthropogenic particles was further increased in rats with allergic airways. In addition, eosinophils and protein in BALF were increased only in allergic animals exposed to CAPs. These results demonstrate preferential retention in allergic airways of air particulates derived from identified local combustion sources after a short-term exposure. Our findings suggest that the enhancement of allergic airway responses by exposure to PM_2.5 is mediated in part by increased pulmonary deposition and localization of potentially toxic elements in urban air.     

Diesel Exhaust Is Not a Pulmonary Carcinogen in CD-1 Mice Exposed under Conditions Carcinogenic to F344 Rats

Differences among laboratory animal species in the pulmonarycarcinogenicity of chronic inhalation exposure to diesel exhausthave raised several important interpretive issues. Under similarheavy exposure conditions, it is clear that diesel exhaust isa pulmonary carcinogen in rats, but not in Syrian hamsters.Previous reports give conflicting views of the response of mice,which is presently considered equivocal. This report describescarcinogenicity results from a bioassay of CD-1 mice conductedin parallel with a previously reported bioassay of F344 rats(Mauderly et al. (1987) Fundam. Appl. Toxicol. 9, 208–221).Exposure to whole diesel exhaust 7 hr/day, 5 days/week for 24months at soot concen trations of 0.35, 3.5, or 7.1 mg/m³ causedaccumulations of soot in mouse lungs similar to those in lungsof rats and, like the results from rats, did not significantlyaffect survival or body weight. In contrast to the dose-relatedneoplastic response of rats, however, the exposures of micedid not increase the incidence of lung neoplasms. This findingis consistent with other data showing that mice, as well asSyrian hamsters, differ from rats in their lung neoplastic andnonneoplastic responses to heavy, chronic inhalation exposureto diesel exhaust soot and several other particles. Althoughrodents serve as useful indicators of potential human carcinogenichazards, it is not yet clear which, if any, rodent species havelung neoplastic responses that are useful for quantitative predictionsof human lung cancer risk from chronic inhalation of poorlysoluble, respirable particles.     

Effects of Concentrated Ambient Particles on Heart Rate,Blood Pressure,and Cardiac Contractility in Spontaneously Hypertensive Rats

Epidemiological studies have shown that particulate matter (PM) air pollution is associated with cardiovascular mortality and morbidity, especially for particles with aerodynamic diameters under 2.5 μm (PM_2.5). Recent studies have revealed an association between PM pollution and autonomic functions including heart rate (HR), blood pressure (BP), and heart-rate variability. However, the association and linking mechanisms have not been clearly demonstrated in animal studies. Utilizing a novel approach that employs a mixed-effects model to overcome the problems of variations in diseased animals and circadian cycles, we have previously demonstrated an association between concentrated PM_2.5 and changes of HR and BP in pulmonary hypertensive rats. The objective of this study is to test the plausibility of this methodology and to demonstrate the particle effects under different pathophysiology. The feasibility of cardiac contractility (measured as QA interval, QAI) as an indicator for PM toxicology was also explored. Four spontaneously hypertensive (SH) rats were repeatedly exposed to concentrated PM_2.5 during spring and summer. The mass concentration of particles during the 5 h of exposure was 202.0 ± 68.8 (mean ± SE) and 141.0 ± 54.9 μg/m³ for spring and summer experiments, respectively. During spring exposures, the maximum increase of HR and mean BP noted at the end of exposure were 51.6 bpm (p < .001) and 8.7 mm Hg (p = .002), respectively. The maximum decrease of QAI noted at the same time was 1.6 ms (p = .001). Though a similar pattern was demonstrated during summer exposures, the responses were less prominent. We conclude that concentrated PM_2.5 may increase HR and mean BP and decrease QAI in SH rats. Our results also show that QAI may be used as an indicator in PM toxicology.     

Ozone Adaptation in Rats after Chronic Exposure to a Simulated Urban Profile of Ozone

Studies in both humans and rats have indicated that certainpulmonary responses induced by exposure to an acute provocativeconcentration of ozone (O₃) will eventually attenuate if theexposure is repeated on a daily basis. This phenomenon is commonlyreferred to as O₃ adaptation. Whether or not a "state" of adaptationdevelops due to long-term low level O₃ exposure is unknown.Two human studies have reported adaptation in subjects livingin Los Angeles during periods when ambient O₃ concentrationshave been relatively high. At present, however, we are not awareof comparable information from rats. This study assessed O₃adaptation in rats following chronic (12 or 18 months) exposureand after a 4-month recovery period. A chronic exposure pattern,similar to that found in an urban area during the summer (0.06ppm O₃ for 13 hr/day, 7 days/week; Monday–Friday, peakto 0.25 ppm O₃, over 9 hr), was used. To assess whether adaptationhad occurred and/or persisted, awake rats were challenged withhigh provocative concentrations of O₃ for up to 2 hr. Duringa challenge, rats were monitored for typical O₃-induced alterationsin spontaneous breathing parameters (e.g., increase in breathingfrequency and decrease in tidal volume). Adaptation was definedas attenuation of breathing response during the challenge inrats chronically exposed to O₃ as compared to that in "control"rats (chronically exposed to air). Adaptation was found in therats within 8 hr following the chronic O₃ exposure but not afterthe 4-month recovery period. Spontaneous breathing parametersthat were significantly attenuated in the chronically exposedrats were breathing frequency, tidal volume, inspiratory andexpiratory times, and maximum expiratory flow. We conclude thatrats demonstrated adaptation to O₃ after long-term exposureto an urban-type O₃ profile and that the adaptation was notseen 4 months postexpo-sure. These results suggest that exposureto environmental O₃ in Los Angeles air may have been responsiblefor the adaptation found in residential subjects.     

The Cellular and Genomic Response of an Immortalized Microglia Cell Line (BV2) to Concentrated Ambient Particulate Matter

Ambient particulate matter (PM) damages pulmonary tissue through oxidative stress (OS) pathways. Several reports indicate that the brain is another affected target of PM exposure. Since microglia (brain macrophages) are critical to OS-mediated neurodegeneration, the cellular and genomic response of immortalized mouse microglia (BV2) was examined in response to fine (≤ 2.5 μ m) concentrated ambient particles (CAPs) collected from Tuxedo, NY. Samples of CAPs were labeled as high potency (HP) or low potency (LP) depending on their stimulation of nuclear factor (NF)-κ B activity in human bronchial epithelial cells. Compositional analysis of these samples, performed during their original collection, indicated a strong correlation between HP CAPs and and the presence of nickel and vanadium (). Exposure of the BV2 microglia to LP CAPs reduced intracellular levels of ATP (≥ 250 μ g/ml) and depolarized mitochondrial membranes (≥ 6 μ g/ml) within 15 min of exposure. HP and LP CAPs (≥ 25 μ g/ml) differentially affected the endogenous scavengers, glutathione and nonprotein sulfhydryl in BV2 microglia after 1.5 h of exposure. Both HP and LP CAPs stimulated the release of proinflammatory cytokines tumor necrosis factor (TNF) α and interleukin (IL)-6 after 6 h of exposures. Microarray analysis of BV2 microglia exposed to either HP or LP CAPs (75 μ g/ml, 4 h) identified 3200 (HP CAPs) and 160 (LP CAPs) differentially expressed (up- and downregulated) genes relative to media controls. Of the 3200 genes significantly affected by HP CAPs, the most prominent upregulated gene probes related to inflammatory pathways associated with Toll-like receptor signaling, MAPK signaling, T- and B-cell receptor signaling, apoptosis, and various proinflammatory cytokines and their receptors. LP CAPs significantly affected 160 genes that related to pathways associated with cellular maintenance and division, cell cycling and nuclear events. These data suggest that HP CAPs, which contained higher levels of nickel and vanadium than LP CAPs, appear to be more inflammatory and selectively upregulated the expression of inflammatory and innate immunity pathways in BV2 microglia.     

Effects of Concentrated Ambient Particles on Airway Responsiveness and Pulmonary Inflammation in Pulmonary Hypertensive Rats

Epidemiological studies have associated particulate air pollution with exacerbation of lung function in human populations. However, the relationship between ambient particles and lung function in animal studies has been inconsistent. In order to investigate the effects of concentrated ambient particles (CAPs) on airway responsiveness, we exposed pulmonary hypertensive rats to CAPs using particle concentrator at an EPA of Taiwan supersite, located at a traffic busy urban area nearing Taipei city. The exposure group (n = 5) was exposed to CAPs for 6 h each day for 3 consecutive days (mean mass concentration = 371.7 μ g/m³), while a control group (n = 6) was exposed to HEPA-filtered air. Whole-body barometric plethysmography was used to measure respiratory frequency, tidal volume, and airway responsiveness before and after exposure. Enhanced pause (Penh) was used as an indicator of airway responsiveness. To improve the accuracy of airway responsiveness measurement, we controlled temperature and humidity. Further, airway responsiveness was determined 5 h after particle exposure to overcome the stress effect in nose-only exposure chambers. After CAPs exposure, we found decreased respiratory frequency and increased tidal volume (p <. 05). Using the methacholine challenge test, a significant difference of Penh measured before and after experiment was observed in the CAPs group (p <. 05), but not in the filtered air group. Further analysis showed that the Penh difference before and after exposure in the CAPs group was significantly greater than that in the filtered air group (p <. 05). We conclude that CAPs could induce airway hyperresponsiveness in pulmonary hypertensive rats.     

下呼吸道感染患儿支气管肺泡灌洗液病原菌分布及耐药性分析

目的:了解下呼吸道感染患儿支气管肺泡灌洗液(BALF)中病原菌种类及耐药情况,为临床合理用药提供参考。方法:采集2012-2014年在我院儿科住院给予纤维支气管镜支气管肺泡灌洗治疗的368例患儿的BALF,采用美国MicroScan WalkAway 40型微生物分析仪及中国DL 微生物分析仪对细菌进行鉴定并做药敏试验。结果:368份BALF共培养分离病原菌213株,其中革兰阴性菌197株(92.5%),革兰阳性菌10株(4.7%),白色念珠菌6株(2.8%)。主要细菌依次是肺炎克雷伯菌、铜绿假单胞菌、鲍曼不动杆菌、大肠埃希菌。常规检测主要细菌对12种抗菌药物的耐药情况显示,鲍曼不动杆菌耐药性较低,对各抗菌药物的耐药率均<30%;铜绿假单胞菌对替卡西林/克拉维酸、哌拉西林/他唑巴坦、头孢他啶、亚胺培南、阿米卡星、环丙沙星、左氧氟沙星的耐药率均<20%;肺炎克雷伯菌、大肠埃希菌对亚胺培南的耐药率为0,对其他抗菌药物不同程度耐药。结论:下呼吸道感染患儿BALF中主要细菌为革兰阴性杆菌,不同细菌对不同抗菌药物的耐药性不同,合理用药是控制感染的关键。