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The effect of electronic cigarette (E-cig) vaping on cardiac and vascular function during the healing phase of myocardial infarction (MI), and post-MI remodeling was investigated. Sprague Dawley rats were subjected to left coronary artery ligation to induce MI. One week later, rats were randomized to receive either 12 weeks of exposure to purified air (n = 37) or E-cig vapor (15 mg/ml of nicotine) (n = 32). At 12 weeks, cardiac and vascular function, and post-MI remodeling were assessed. Baseline blood flow in the femoral artery did not differ between groups, but peak reperfusion blood flow was blunted in the E-cig group (1.59 ± 0.15 ml/min) vs. the air group (2.11 ± 0.18 ml/min; p = 0.034). Femoral artery diameter after reperfusion was narrower in the E-cig group (0.54 ± 0.02 mm) compared to the air group (0.60 ± 0.02 mm; p = 0.023). Postmortem left ventricular (LV) volumes were similar in the E-cig (0.69 ± 0.04 ml) and air groups (0.73 ± 0.04 ml; p = NS); and myocardial infarct expansion index did not differ between groups (1.4 ± 0.1 in E-cig group versus 1.3 ± 0.1 in air group; p = NS). LV fractional shortening by echo did not differ between groups at 12 weeks (E-cig at 29 ± 2% and air at 27 ± 1%; p = NS). Exposure to E-cig during the healing phase of MI was associated with altered vascular function with reduced femoral artery blood flow and diameter at reperfusion, but not with worsened LV dilation or worsened cardiac function.

Insulin resistance (IR) and metabolic disorders are non-pulmonary adverse effects induced by fine particulate matter (PM2.5) exposure. The worldwide pandemic of high fructose sweeteners and fat rich modern diets, also contribute to IR development. We investigated some of the underlying effects of IR, altered biochemical insulin action and Insulin/AKT pathway biomarkers. Male Sprague Dawley rats were subchronically exposed to filtered air, PM2.5, a fructose rich diet (FRD), or PM2.5 + FRD. Exposure to PM2.5 or FRD alone did not induce metabolic changes. However, PM2.5 + FRD induced leptin release, systemic hyperinsulinemia, and Insulin/AKT dysregulation in insulin-sensitive tissues preceded by altered AT1R levels. Histological damage and increased HOMA-IR were also observed from PM2.5 + FRD co-exposure. Our results indicate that the concomitant exposure to a ubiquitous environmental pollutant, such as PM2.5, and a metabolic disease risk factor, a FRD, can contribute to the metabolic disorder pandemic occurring in highly polluted locations.

Exposure to traffic-related air pollution consisting of particulate matter (PM) is associated with cognitive decline leading to Alzheimer's disease (AD). In this study, we sought to examine the neurotoxic effects of exposure to ultrafine PM and how it exacerbates neuronal loss and AD-like neuropathology in wildtype (WT) mice and a knock-in mouse model of AD (AppNL-G-F/+-KI) when the exposure occurs at a prepathologic stage or at a later age with the presence of neuropathology. AppNL-G-F/+-KI and WT mice were exposed to concentrated ultrafine PM from local ambient air in Irvine, California, for 12 weeks, starting at 3 or 9 months of age. Particulate matter-exposed animals received concentrated ultrafine PM up to 8 times above the ambient levels, whereas control animals were exposed to purified air. Particulate matter exposure resulted in a marked impairment of memory tasks in prepathologic AppNL-G-F/+-KI mice without measurable changes in amyloid-β pathology, synaptic degeneration, and neuroinflammation. At aged, both WT and AppNL-G-F/+-KI mice exposed to PM showed a significant memory impairment along with neuronal loss. In AppNL-G-F/+-KI mice, we also detected an increased amyloid-β buildup and potentially harmful glial activation including ferritin-positive microglia and C3-positive astrocytes. Such glial activation could promote the cascade of degenerative consequences in the brain. Our results suggest that exposure to PM impairs cognitive function at both ages while exacerbation of AD-related pathology and neuronal loss may depend on the stage of pathology, aging, and/or state of glial activation. Further studies will be required to unveil the neurotoxic role of glial activation activated by PM exposure.

BackgroundFine particulate matter (PM2.5) exposure accelerates atherosclerosis and contains known ovotoxic chemicals. However, effects of exposure to PM2.5 on the finite ovarian follicle pool have hardly been investigated, nor have interactions between ovarian and cardiovascular effects. We hypothesized that subchronic inhalation exposure to human-relevant concentrations of PM2.5 results in destruction of ovarian follicles via apoptosis induction, as well as accelerated recruitment of primordial follicles into the growing pool. Further, we hypothesized that destruction of ovarian follicles enhances the adverse cardiovascular effects of PM2.5 in females.ResultsHyperlipidemic apolipoprotein E (Apoe) null ovary-intact or ovariectomized female mice and testis-intact male mice were exposed to concentrated ambient PM2.5 or filtered air for 12 weeks, 5 days/week for 4 h/day using a versatile aerosol concentration enrichment system. Primordial, primary, and secondary ovarian follicle numbers were decreased by 45%, 40%, and 17%, respectively, in PM2.5-exposed ovary-intact mice compared to controls (P

E-cigarette or vaping product use-associated lung injury was recognized in the United States in the summer of 2019 and is typified by acute respiratory distress, shortness of breath, chest pain, cough, and fever, associated with vaping. It can mimic many of the manifestations of coronavirus disease 2019 (COVID-19). Some investigators have suggested that E-cigarette or vaping product use-associated lung injury was due to tetrahydrocannabinol or vitamin E acetate oil mixed with the electronic cigarette liquid. In experimental rodent studies initially designed to study the effect of electronic cigarette use on the cardiovascular system, we observed an E-cigarette or vaping product use-associated lung injury-like condition that occurred acutely after use of a nichrome heating element at high power, without the use of tetrahydrocannabinol, vitamin E, or nicotine. Lung lesions included thickening of the alveolar wall with foci of inflammation, red blood cell congestion, obliteration of alveolar spaces, and pneumonitis in some cases; bronchi showed accumulation of fibrin, inflammatory cells, and mucus plugs. Electronic cigarette users should be cautioned about the potential danger of operating electronic cigarette units at high settings; the possibility that certain heating elements may be deleterious; and that E-cigarette or vaping product use-associated lung injury may not be dependent upon tetrahydrocannabinol, vitamin E, or nicotine.

Air pollution is linked to brain inflammation, which accelerates tumorigenesis and neurodegeneration. The molecular mechanisms that connect air pollution with brain pathology are largely unknown but seem to depend on the chemical composition of airborne particulate matter (PM). We sourced ambient PM from Riverside, California, and selectively exposed rats to coarse (PM2.5-10: 2.5-10 µm), fine (PM

FTY720 sequesters lymphocytes in secondary lymphoid organs through effects on sphingosine-1-phosphate (S1P) receptors. However, at higher doses than are required for immunosuppression, FTY720 also functions as an anticancer agent in multiple animal models. Our published work indicates that the anticancer effects of FTY720 do not depend on actions at S1P receptors but instead stem from FTY720s ability to restrict access to extracellular nutrients by down-regulating nutrient transporter proteins. This result was significant because S1P receptor activation is responsible for FTY720s dose-limiting toxicity, bradycardia, that prevents its use in cancer patients. Here, we describe diastereomeric and enantiomeric 3- and 4-C-aryl 2-hydroxymethyl pyrrolidines that are more active than the previously known analogues. Of importance is that these compounds fail to activate S1P1 or S1P3 receptors in vivo but retain inhibitory effects on nutrient transporter proteins and anticancer activity in solid tumor xenograft models. Our studies reaffirm that the anticancer activity of FTY720 does not depend upon S1P receptor activation and uphold the promise of using S1P receptor-inactive azacyclic FTY720 analogues in human cancer patients.

A factorial design study was performed to examine the acute effects of inhaled acid particles alone and in mixtures with ozone to test the hypothesis that acid particles and ozone would act synergistically. Sprague-Dawley rats were exposed nose-only for a single 4-h period to all 9 possible combinations of purified air and 2 concentrations each of O(3) (0.3 and 0.6 ppm) and submicrometer (0.3 μm mass median diameter [MMD]) sulfuric acid aerosols H(2)SO(4) (0.5 and 1.0 mg/m(3)). Respiratory-tract injury and impairment of alveolar macrophage functions were evaluated. Two-way analyses of variance were used to test for significance of main effects and statistical interactions, and Tukey multiple comparison tests were used to test the significance of differences between group mean values. Addition of H(2)SO(4) to O(3)-containing atmospheres resulted in significant H(2)SO(4) concentration-dependent reductions in O(3)-induced inflammatory responses, and H(2)SO(4), alone and in combination with O(3), depressed some functions of innate immunity. DNA synthesis in nasal, tracheal, and lung tissue following pollutant exposure, which is an index of injury or killing of epithelial cells, was significantly increased by O(3) but not by H(2)SO(4) when administered alone, compared to purified air. When administered with O(3), H(2)SO(4) did not reduce the effects of O(3) on DNA synthesis in the trachea or the lung, but did reduce the DNA synthesis response to O(3) in the nose. No significant changes in antibody-directed Fc receptor (FcR) binding of sheep red blood cells by alveolar macrophages were observed, but macrophage phagocytic activity was significantly reduced by the pollutant exposures. In summary, the results of this study indicate significant interactions between O(3) and H(2)SO(4) in concurrent exposures; however, the findings do not support the hypothesis that O(3) and H(2)SO(4) act synergistically in rats after single 4-h exposures.

A mobile whole-body exposure system was developed for exposing mice to concentrated ambient particulate matter smaller than 2.5 microm in mass median aerodynamic diameter (MMAD). Each 20-L exposure cage was designed to hold 9 mice within individual compartments. This allowed for transport and subsequent exposure. Airflow mixing and the potential for stagnant areas within the compartments were modeled using computational fluid dynamic modeling (CFD). CFD analysis showed no stagnant areas and good mixing throughout the exposure cage. The actual performance of the exposure system was determined for 0.5 to 2.0 microm diameter aerosols by measuring (1) uniformity of aerosol distribution and (2) particle deposition in the tracheobronchial and pulmonary regions of mice exposed in the system. A 0.6-microm MMAD (GSD=2.0) cigarette smoke aerosol was used to experimentally measure the uniformity of aerosol distribution to the nine individual compartments. The average data from three runs showed no statistically significant difference among individual compartments. Particle deposition efficiency in adult male BALB/c mice was measured after exposure (30 min) in the system using monodisperse fluorescent polystyrene latex particles (0.5, 1, and 2 microm aerodynamic diameter). The measured deposition efficiency in this mobile exposure system for the combined tracheobronchial and pulmonary regions of the adult male BALBc mice was 21% for 0.5 microm, 11% for 1.0 microm, and 6.5% for 2.0 microm particles. These deposition efficiencies are similar to those reported for mice exposed in a nose-only exposure system, which indicates that particle losses to animal fur and exposure system surfaces were acceptable.

Methamphetamine treatment of mice rapidly and severely depleted levels of dopamine and its metabolites, homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) in the caudate nucleus. Exposure of mice to cigarette smoke by means of nose-only breathing apparatus for 20 min twice daily over 3 days prior to drug treatment significantly attenuated the neurotoxicity of methamphetamine as judged by a lesser depletion of dopamine, DOPAC and HVA. The lesser effect of methamphetamine upon content of serotonin level was unaltered by prior inhalation of smoke. Results suggest a specific protective effect of inhaled tobacco smoke upon the effects of methamphetamine upon dopaminergic circuitry.

Respiratory tract injury resulting from inhalation of mixtures of ozone (O3) and nitrogen dioxide (NO2) and of O3 and formaldehyde (HCHO) was studied in Sprague-Dawley rats under exposure conditions of rest and exercise. Focal inflammatory injury induced in lung parenchyma by O3 exposure was measured morphometrically and HCHO injury to the nasal respiratory epithelium was measured by cell turnover using tritium-labeled thymidine. Mixtures of O3 (0.35 or 0.6 ppm) with NO2 (respectively 0.6 or 2.5 ppm) doubled the level of lung injury produced by O3 alone in resting exposures to the higher concentrations and in exercising exposures to the lower concentrations. Formaldehyde (10 ppm) mixed with O3 (0.6 ppm) resulted in reduced lung injury compared to O3 alone in resting exposures, but exercise exposure to the mixture did not show an antagonistic interaction. Nasal epithelial injury from HCHO exposure was enhanced when O3 was present in a mixture. Mixtures of O3 and NO2 at high and low concentrations formed respectively 0.73 and 0.02 ppm nitric acid (HNO3) vapor. Chemical interactions among the oxidants, HNO3, and other reaction products (N2O5 and nitrate radical) and lung tissue may be the basis for the O3-NO2 synergism. Increased dose and dose rate associated with exercise exposure may explain the presence of synergistic interaction at lower concentrations than observed in resting exposure. No oxidation products were detected in O3-HCHO mixtures, and the antagonistic interaction observed in lung tissue during resting exposure may result from irritant breathing pattern interactions.