Mehrdad Arjomandi

Arginine restores nitric oxide activity and inhibits monocyte accumulation after vascular injury in hypercholesterolemic rabbits

OBJECTIVES This study sought to determine whether the alterations in vascular function and structure after balloon injury in hypercholesterolemic rabbits could be inhibited by dietary arginine. BACKGROUND Administration of arginine (the nitric oxide [NO] precursor) restores vascular NO activity in hypercholesterolemic animals. We and other investigators have shown that enhancement of vascular NO activity can inhibit myointimal hyperplasia after vascular injury in normocholesterolemic animals. METHODS Twenty-eight New Zealand White rabbits received either normal rabbit chow, 0.5% cholesterol diet or 0.5% cholesterol diet plus L-arginine hydrochloride (2.25% wt/vol) in the drinking water. After 6 weeks of dietary intervention, the left iliac artery of each animal was subjected to a balloon injury. Four weeks later, the iliac arteries were harvested for vascular reactivity studies and immunohistochemical analysis. RESULTS Vascular injury induced intimal thickening that was largely composed of vascular smooth muscle cells and extracellular matrix. In the setting of hypercholesterolemia, vascular injury induced an exuberant myointimal lesion that was augmented by the accumulation of lipid-laden macrophages. Dietary arginine reduced intimal thickening in the injured vessels of hypercholes-terolemic animals and substantially inhibited the accumulation of macrophages in the lesion (from 28% to 5% of the lesion area, p < 0.001). CONCLUSIONS We report that lesions induced by vascular injury in hypercholesterolemic animals are markedly reduced by oral administration of arginine. Moreover, we find that the nature of the lesion is altered, with a striking reduction in the percentage of macrophages comprising the lesion.

Effects of Chronic and Acute Ozone Exposure on Lipid Peroxidation and Antioxidant Capacity in Healthy Young Adults

Background There is growing evidence for the role of oxidative damage in chronic diseases. Although ozone (O3) is an oxidant pollutant to which many people are exposed, few studies have examined whether O3 induces oxidative stress in humans. Objectives This study was designed to assess the effect of short-and long-term O3 exposures on biomarkers of oxidative stress in healthy individuals. Methods Biomarkers of lipid peroxidation, 8-isoprostane (8-iso-PGF), and antioxidant capacity ferric reducing ability of plasma (FRAP) were analyzed in two groups of healthy college students with broad ranges of ambient O3 exposure during their lifetimes and previous summer recess either in Los Angeles (LA, n = 59) or the San Francisco Bay Area (SF, n = 61). Results Estimated 2-week, 1-month, and lifetime O3 exposures were significantly correlated with elevated 8-iso-PGF. Elevated summertime exposures resulted in the LA group having higher levels of 8-iso-PGF than the SF group (p = 0.02). Within each location, males and females had similar 8-iso-PGF. No regional difference in FRAP was observed, with significantly higher FRAP in males in both groups (SF: p = 0.002; LA: p = 0.004). An exposure chamber substudy (n = 15) also showed a significant increase in 8-iso-PGF as well as an inhibition of FRAP immediately after a 4-hr exposure to 200 ppb O3, with near normalization by 18 hr in both biomarkers. Conclusions Long-term exposure to O3 is associated with elevated 8-iso-PGF, which suggests that 8-iso-PGF is a good biomarker of oxidative damage related to air pollution.

Effects of antioxidant enzyme polymorphisms on ozone-induced lung function changes

Chronic exposure to ozone (O3) can cause changes in lung function that may reflect remodelling of small airways. It is likely that antioxidant enzyme function affects susceptibility to O3. The aim of the present study was to determine whether polymorphisms in antioxidant enzyme (GSTM1, GSTP1 and NQO1) genes affect the risk of lung function changes related to chronic exposure to O3. In total, 210 young adults who participated in a previous study, which showed a relationship between lifetime exposure to O3 and decreased lung function, were genotyped. Multivariable linear regression was used to model sex-specific associations between genotypes and O3-related lung function changes, adjusting for height, weight, lifetime exposure to nitrogen dioxide and particles with a 50% cut-off aerodynamic diameter of 10 μm, and self-identified race/ethnicity. The GSTM1-null/NQO1 Pro187Pro-combination genotype was significantly associated with increased risk of an O3-related decrease in mean forced expiratory flow between 25–75% of forced vital capacity in females (parameter estimate±se -75±35 mL·s−1), while the GSTP1 Val105 variant genotypes were significantly associated with greater risk of an O3-related decrease in mean forced expiratory flow at 75% of forced vital capacity in males (-81±31 mL·s−1). GSTM1-null status was not significantly associated with any O3-related changes in lung function in either sex. The current authors conclude that the effects of antioxidant enzyme gene polymorphisms on the risk of decreased lung function related to chronic exposure to ozone may be modified by sex-specific factors.

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

Airway obstruction is a hallmark of allergic asthma and is caused primarily by airway smooth muscle (ASM) hypercontractility. Airway inflammation leads to the release of cytokines that enhance ASM contraction by increasing ras homolog gene family, member A (RhoA) activity. The protective mechanisms that prevent or attenuate the increase in RhoA activity have not been well studied. Here, we report that mice lacking the gene that encodes the protein Milk Fat Globule-EGF factor 8 (Mfge8−/−) develop exaggerated airway hyperresponsiveness in experimental models of asthma. Mfge8−/− ASM had enhanced contraction after treatment with IL-13, IL-17A, or TNF-α. Recombinant Mfge8 reduced contraction in murine and human ASM treated with IL-13. Mfge8 inhibited IL-13–induced NF-κB activation and induction of RhoA. Mfge8 also inhibited rapid activation of RhoA, an effect that was eliminated by an inactivating point mutation in the RGD integrin-binding site in recombinant Mfge8. Human subjects with asthma had decreased Mfge8 expression in airway biopsies compared with healthy controls. These data indicate that Mfge8 binding to integrin receptors on ASM opposes the effect of allergic inflammation on RhoA activity and identify a pathway for specific inhibition of ASM hypercontractility in asthma.

Exposure to medium and high ambient levels of ozone causes adverse systemic inflammatory and cardiac autonomic effects

Epidemiological evidence suggests that exposure to ozone increases cardiovascular morbidity. However, the specific biological mechanisms mediating ozone-associated cardiovascular effects are unknown. To determine whether short-term exposure to ambient levels of ozone causes changes in biomarkers of cardiovascular disease including heart rate variability (HRV), systemic inflammation, and coagulability, 26 subjects were exposed to 0, 100, and 200 ppb ozone in random order for 4 h with intermittent exercise. HRV was measured and blood samples were obtained immediately before (0 h), immediately after (4 h), and 20 h after (24 h) each exposure. Bronchoscopy with bronchoalveolar lavage (BAL) was performed 20 h after exposure. Regression modeling was used to examine dose-response trends between the endpoints and ozone exposure. Inhalation of ozone induced dose-dependent adverse changes in the frequency domains of HRV across exposures consistent with increased sympathetic tone [increase of (parameter estimate ± SE) 0.4 ± 0.2 and 0.3 ± 0.1 in low- to high-frequency domain HRV ratio per 100 ppb increase in ozone at 4 h and 24 h, respectively (P = 0.02 and P = 0.01)] and a dose-dependent increase in serum C-reactive protein (CRP) across exposures at 24 h [increase of 0.61 ± 0.24 mg/l in CRP per 100 ppb increase in ozone (P = 0.01)]. Changes in HRV and CRP did not correlate with ozone-induced local lung inflammatory responses (BAL granulocytes, IL-6, or IL-8), but changes in HRV and CRP were associated with each other after adjustment for age and ozone level. Inhalation of ozone causes adverse systemic inflammatory and cardiac autonomic effects that may contribute to the cardiovascular mortality associated with short-term exposure.

PAI-1 is an essential component of the pulmonary host response during Pseudomonas aeruginosa pneumonia in mice

Rationale Elevated plasma and bronchoalveolar lavage fluid plasminogen activator inhibitor 1 (PAI-1) levels are associated with adverse clinical outcome in patients with pneumonia caused by Pseudomonas aeruginosa. However, whether PAI-1 plays a pathogenic role in the breakdown of the alveolar–capillary barrier caused by P aeruginosa is unknown. Objectives The role of PAI-1 in pulmonary host defence and survival during P aeruginosa pneumonia in mice was tested. The in vitro mechanisms by which P aeruginosa causes PAI-1 gene and protein expression in lung endothelial and epithelial cells were also examined. Methods and results PAI-1 null and wild-type mice that were pretreated with the PAI-1 inhibitor Tiplaxtinin had a significantly lower increase in lung vascular permeability than wild-type littermates after the airspace instillation of 1×107 colony-forming units (CFU) of P aeruginosa bacteria. Furthermore, P aeruginosa in vitro induced the expression of the PAI-1 gene and protein in a TLR4/p38/RhoA/NF-κB (Toll-like receptor 4/p38/RhoA/nuclear factor-κB) manner in lung endothelial and alveolar epithelial cells. However, in vivo disruption of PAI-1 signalling was associated with higher mortality at 24 h (p<0.03) and higher bacterial burden in the lungs secondary to decreased neutrophil migration into the distal airspace in response to P aeruginosa. Conclusions The results indicate that PAI-1 is a critical mediator that controls the development of the early lung inflammation that is required for the activation of the later innate immune response necessary for the eradication of P aeruginosa from the distal airspaces of the lung.

Pulmonary function abnormalities in never-smoking flight attendants exposed to secondhand tobacco smoke in the aircraft cabin.

Objective: To determine whether the flight attendants who were exposed to secondhand tobacco smoke in the aircraft cabin have abnormal pulmonary function. Methods: We administered questionnaires and performed pulmonary function testing in 61 never-smoking female flight attendants who worked in active air crews before the smoking ban on commercial aircraft (preban). Results: Although the preban flight attendants had normal FVC, FEV1, and FEV1/FVC ratio, they had significantly decreased flow at mid- and low-lung volumes, curvilinear flow-volume curves, and evidence of air trapping. Furthermore, the flight attendants had significantly decreased diffusing capacity (77.5% ± 11.2% predicted normal) with 51% having a diffusing capacity below their 95% normal prediction limit. Conclusions: This cohort of healthy never-smoking flight attendants who were exposed to secondhand tobacco smoke in the aircraft cabin showed pulmonary function abnormalities suggestive of airway obstruction and impaired diffusion.

Effects of nitrogen dioxide on allergic airway responses in subjects with asthma.

Objective: We sought to determine whether nitrogen dioxide (NO2) can enhance airway inflammation after allergen challenge in asthmatic subjects. Methods: Fifteen house-dust–mite (HDM)-sensitive asthmatic subjects were exposed for 3 hours to filtered air or 0.4 ppm NO2, followed by inhalational challenge with HDM allergen. Markers of inflammation were measured in sputum at 6 hours and 26 hours after allergen challenge. Results: After exposure to NO2, eosinophil concentration decreased significantly in the 6-hour postallergen sputum. No significant NO2-related difference was observed for other variables. Conclusions: Our results suggest that, in most asthmatic individuals, multihour exposure to a high ambient concentration of NO2 does not enhance the inflammatory response to subsequent inhaled allergen as assessed by cell distribution in induced sputum. Because the decrease in airway eosinophils has been reported in previous animal studies, future research should be directed toward the mechanism of this effect.

Low Prevalence of Chronic Beryllium Disease among Workers at a Nuclear Weapons Research and Development Facility

Objective: To study the prevalence of beryllium sensitization (BeS) and chronic beryllium disease (CBD) in a cohort of workers from a nuclear weapons research and development facility. Methods: We evaluated 50 workers with BeS with medical and occupational histories, physical examination, chest imaging with high-resolution computed tomography (N = 49), and pulmonary function testing. Forty of these workers also underwent bronchoscopy for bronchoalveolar lavage and transbronchial biopsies. Results: The mean duration of employment at the facility was 18 years and the mean latency (from first possible exposure) to time of evaluation was 32 years. Five of the workers had CBD at the time of evaluation (based on histology or high-resolution computed tomography); three others had evidence of probable CBD. Conclusions: These workers with BeS, characterized by a long duration of potential Be exposure and a long latency, had a low prevalence of CBD.

Effects of Exercise on Systemic Inflammatory, Coagulatory, and Cardiac Autonomic Parameters in an Inhalational Exposure Study

Background: Intermittent moderate-intensity exercise is used in human inhalational exposure studies to increase the effective dose of air pollutants. Objective: To investigate the inflammatory, coagulatory, and autonomic effects of intermittent moderate-intensity exercise. Methods: We measured hemodynamic, electrocardiographic, inflammatory, and coagulatory parameters in peripheral blood of 25 healthy subjects across an exercise protocol that included running on a treadmill or pedaling a cycle ergometer for 30 minutes every hour over 4 hours in a climate-controlled chamber with a target ventilation of 20 L/min/m2 body surface area. Results: Intermittent moderate-intensity exercise induced a systemic proinflammatory response characterized by increases in leukocyte counts, C-reactive protein, monocyte chemoattractant protein–1, and interleukin-6, but did not change coagulation tendency or heart rate variability. Conclusion: Interpretation of pollutant-induced inflammatory responses in inhalational exposure studies should account for signals and noises caused by exercise, especially when the effect size is small.