Effects of exercise training on airway closure in asthmatics

We previously reported that responsiveness to methacholine (Mch) in the absence of deep inspiration (DI) decreased in healthy subjects after a short course of exercise training. We assessed whether a similar beneficial effect of exercise on airway responsiveness could occur in asthmatics. Nine patients (male/female: 3/6; mean age ± SD: 24 ± 2 yr) with mild untreated asthma [forced expiratory volume in 1 s (FEV(1)): 100 ± 7.4% pred; FEV(1)/vital capacity (VC): 90 ± 6.5%] underwent a series of single-dose Mch bronchoprovocations in the absence of DI in the course of a 10-wk training rowing program (6 h/wk of submaximal and maximal exercise), at baseline (week 0), and at week 5 and 10. The single-dose Mch was established as the dose able to induce ≥15% reduction in inspiratory vital capacity (IVC) and was administered to each subject at every challenge occasion. Five asthmatics (male/female: 1/4; mean age ± SD: 26 ± 3 yr) with similar baseline lung function (FEV(1): 102 ± 7.0% predicted; FEV(1)/VC: 83 ± 6.0%; P = 0.57 and P = 0.06, respectively) not participating in the exercise training program served as controls. In the trained group, the Mch-induced reduction in IVC from baseline was 22 ± 10% at week 0, 13 ± 11% at week 5 (P = 0.03), and 11 ± 8% at week 10 (P = 0.028). The Mch-induced reduction in FEV(1) did not change with exercise (P = 0.69). The reduction in responsiveness induced by exercise was of the same magnitude of that previously obtained in healthy subjects (50% with respect to pretraining). Conversely, Mch-induced reduction in IVC in controls remained unchanged after 10 wk (%reduction IVC at baseline: 21 ± 20%; after 10 wk: 29 ± 14%; P = 0.28). This study indicates that a short course of physical training is capable of reducing airway responsiveness in mild asthmatics.     

Global Metabolomic Profiling Reveals an Association of Metal Fume Exposure and Plasma Unsaturated Fatty Acids

Background

Welding-associated air pollutants negatively affect the health of exposed workers; however, their molecular mechanisms in causing disease remain largely unclear. Few studies have systematically investigated the systemic toxic effects of welding fumes on humans.

Objectives

To explore the effects of welding fumes on the plasma metabolome, and to identify biomarkers for risk assessment of welding fume exposure.

Methods

The two-stage, self-controlled exploratory study included 11 boilermakers from a 2011 discovery panel and 8 boilermakers from a 2012 validation panel. Plasma samples were collected pre- and post-welding fume exposure and analyzed by chromatography/mass spectrometry.

Results

Eicosapentaenoic or docosapentaenoic acid metabolic changes post-welding were significantly associated with particulate (PM_2.5) exposure (p<0.05). The combined analysis by linear mixed-effects model showed that exposure was associated with a statistically significant decline in metabolite change of eicosapentaenoic acid [(95% CI) = −0.013(−0.022∼−0.004); p = 0.005], docosapentaenoic acid n₃ [(95% CI) = −0.010(−0.018∼−0.002); p = 0.017], and docosapentaenoic acid n₆ [(95% CI) = −0.007(−0.013∼−0.001); p = 0.021]. Pathway analysis identified an association of the unsaturated fatty acid pathway with exposure (p _Study−₂₀₁₁ = 0.025; p _Study−₂₀₁₂ = 0.021; p _Combined = 0.009). The functional network built by these fatty acids and their interactive genes contained significant enrichment of genes associated with various diseases, including neoplasms, cardiovascular diseases, and lipid metabolism disorders.

Conclusions

High-dose exposure of metal welding fumes decreases unsaturated fatty acids with an exposure-response relationship. This alteration in fatty acids is a potential biological mediator and biomarker for exposure-related health disorders.     

Effect of stainless steel manual metal arc welding fume on free radical production, DNA damage, and apoptosis induction

Questions exist concerning the potential carcinogenic effects after welding fume exposure. Welding processes that use stainless steel (SS) materials can produce fumes that may contain metals (e.g., Cr, Ni) known to be carcinogenic to humans. The objective was to determine the effect of in vitro and in vivo welding fume treatment on free radical generation, DNA damage, cytotoxicity and apoptosis induction, all factors possibly involved with the pathogenesis of lung cancer. SS welding fume was collected during manual metal arc welding (MMA). Elemental analysis indicated that the MMA-SS sample was highly soluble in water, and a majority (87%) of the soluble metal was Cr. Using electron spin resonance (ESR), the SS welding fume had the ability to produce the biologically reactive hydroxyl radical (^•OH), likely as a result of the reduction of Cr(VI) to Cr(V). In vitro treatment with the MMA-SS sample caused a concentration-dependent increase in DNA damage and lung macrophage death. In addition, a time-dependent increase in the number of apoptotic cells in lung tissue was observed after in vivo treatment with the welding fume. In summary, a soluble MMA-SS welding fume was found to generate reactive oxygen species and cause DNA damage, lung macrophage cytotoxicity and in vivo lung cell apoptosis. These responses have been shown to be involved in various toxicological and carcinogenic processes. The effects observed appear to be related to the soluble component of the MMA-SS sample that is predominately Cr. A more comprehensive in vivo animal study is ongoing in the laboratory that is continuing these experiments to try to elucidate the potential mechanisms that may be involved with welding fume-induced lung disease.     

Comprehensive proteome analysis of nasal lavage samples after controlled exposure to welding nanoparticles shows an induced acute phase and a nuclear receptor,LXR/RXR,activation that influence the status of the extracellular matrix

Background

Epidemiological studies have shown that many welders experience respiratory symptoms. During the welding process a large number of airborne nanosized particles are generated, which might be inhaled and deposited in the respiratory tract. Knowledge of the underlying mechanisms behind observed symptoms is still partly lacking, although inflammation is suggested to play a central role. The aim of this study was to investigate the effects of welding fume particle exposure on the proteome expression level in welders suffering from respiratory symptoms, and changes in protein mediators in nasal lavage samples were analyzed. Such mediators will be helpful to clarify the pathomechanisms behind welding fume particle-induced effects.

Methods

In an exposure chamber, 11 welders with work-related symptoms in the lower airways during the last month were exposed to mild-steel welding fume particles (1 mg/m³) and to filtered air, respectively, in a double-blind manner. Nasal lavage samples were collected before, immediately after, and the day after exposure. The proteins in the nasal lavage were analyzed with two different mass spectrometry approaches, label-free discovery shotgun LC–MS/MS and a targeted selected reaction monitoring LC–MS/MS analyzing 130 proteins and four in vivo peptide degradation products.

Results

The analysis revealed 30 significantly changed proteins that were associated with two main pathways; activation of acute phase response signaling and activation of LXR/RXR, which is a nuclear receptor family involved in lipid signaling. Connective tissue proteins and proteins controlling the degradation of such tissues, including two different matrix metalloprotease proteins, MMP8 and MMP9, were among the significantly changed enzymes and were identified as important key players in the pathways.

Conclusion

Exposure to mild-steel welding fume particles causes measurable changes on the proteome level in nasal lavage matrix in exposed welders, although no clinical symptoms were manifested. The results suggested that the exposure causes an immediate effect on the proteome level involving acute phase proteins and mediators regulating lipid signaling. Proteases involved in maintaining the balance between the formation and degradation of extracellular matrix proteins are important key proteins in the induced effects.

     

Abnormalities in pulmonary function after brief exposure to toxic metal fumes.

A 26-year-old welder became ill after exposure to zinc and cadmium fumes at work. His initial clinical course was consistent with that of metal fume fever, but persistence of symptoms and signs beyond the usual duration in this condition led to suspicion of a toxic pulmonary reaction to cadmium. The finding of high percentages of both metals in the urine confirmed this diagnosis. Pulmonary function tests showed restriction of lung volumes, with increased elastic recoil and reduced diffusion, but no evidence of airways obstruction. Chest roentgenograms indicated central pulmonary edema, which cleared in 6 days. Follow-up assessment 2 years later showed incomplete improvement of the restrictive ventilatory defect.     

Effects of paving asphalt fume exposure on genotoxic and mutagenic activities in the rat lung

Asphalt fumes are complex mixtures of aerosols and vapors containing various organic compounds, including polycyclic aromatic hydrocarbons (PAHs). Previously, we have demonstrated that inhalation exposure of rats to asphalt fumes resulted in dose-dependent induction of CYP1A1 with concomitant down-regulation of CYP2B1 and increased phase II enzyme quinone reductase activity in the rat lung. In the present study, the potential genotoxic effects of asphalt fume exposure due to altered lung microsomal enzymes were studied. Rats were exposed to air or asphalt fume generated under road paving conditions at various concentrations and sacrificed the next day. Alveolar macrophages (AM) were obtained by bronchoalveolar lavage and examined for DNA damage using the comet assay. To evaluate the systemic genotoxic effect of asphalt fume, micronuclei formation in bone marrow polychromatic erythrocytes (PCEs) was monitored. Lung S9 from various exposure groups was isolated from tissue homogenates and characterized for metabolic activity in activating 2-aminoanthracene (2-AA) and benzo[a]pyrene (BaP) mutagenicity using the Ames test with Salmonella typhimurium YG1024 and YG1029. This study showed that the paving asphalt fumes significantly induced DNA damage in AM, as revealed by DNA migration in the comet assay, in a dose-dependent manner, whereas the micronuclei formation in bone marrow PCEs was not detected even at a very high exposure level (1733 mg h/m3). The conversion of 2-AA to mutagens in the Ames test required lung S9-mediated metabolic activation in a dose-dependent manner. In comparison to the controls, lung S9 from rats exposed to asphalt fume at a total exposure level of 479+/-33 mg h/m3 did not significantly enhance 2-AA mutagenicity with either S. typhimurium YG1024 or YG1029. At a higher total asphalt fume exposure level (1150+/-63 mg h/m3), S9 significantly increased the mutagenicity of 2-AA as compared to the control. However, S9 from asphalt fume-exposed rats did not significantly activate the mutagenicity of BaP in the Ames test. These results show that asphalt fume exposure, which significantly altered both phases I and II metabolic enzymes in lung microsomes, is genotoxic to AM and enhances the metabolic activation of certain mutagens through altered S9 content.     

Impact of 1.8-GHz radiofrequency radiation (RFR) on DNA damage and repair induced by doxorubicin in human B-cell lymphoblastoid cells

In the present in vitro study, a comet assay was used to determine whether 1.8-GHz radiofrequency radiation (RFR, SAR of 2 W/kg) can influence DNA repair in human B-cell lymphoblastoid cells exposed to doxorubicin (DOX) at the doses of 0 μg/ml, 0.05 μg/ml, 0.075 μg/ml, 0.10 μg/ml, 0.15 μg/ml and 0.20 μg/ml. The combinative exposures to RFR with DOX were divided into five categories. DNA damage was detected at 0 h, 6 h, 12 h, 18 h and 24 h after exposure to DOX via the comet assay, and the percent of DNA in the tail (% tail DNA) served as the indicator of DNA damage. The results demonstrated that (1) RFR could not directly induce DNA damage of human B-cell lymphoblastoid cells; (2) DOX could significantly induce DNA damage of human B-cell lymphoblastoid cells with the dose–effect relationship, and there were special repair characteristics of DNA damage induced by DOX; (3) E–E–E type (exposure to RFR for 2 h, then simultaneous exposure to RFR and DOX, and exposure to RFR for 6 h, 12 h, 18 h and 24 h after exposure to DOX) combinative exposure could obviously influence DNA repair at 6 h and 12 h after exposure to DOX for four DOX doses (0.075 μg/ml, 0.10 μg/ml, 0.15 μg/ml and 0.20 μg/ml) in human B-cell lymphoblastoid cells.     

Occupational exposure and respiratory health of workers at small scale industries

Certain occupations like welding, painting, and vehicle repairing are associated with regular exposure to dust, exhausts, fuels, fumes, PM, and vapors of welding, solvents, and paint. Many studies have proved a reduction in lung functions due to exposure to these agents. The present study aims to assess and compare respiratory symptoms and pulmonary functions among exposed and non-exposed persons as well as suggests controls respectively. A cross-sectional case study was carried out among small scale industry workers having matched demographic and anthropometric parameters. Medical Research Council (MRC) questionnaire and Micro Direct computerized automated spirometer were used for recording respiratory ailments and pulmonary function tests (PFT) respectively. The percentages of mechanics, welders and painters were 40.9, 31.8, and 27.3 respectively. The highest reported respiratory symptom was chest tightness and whistling among exposed (22.7%) and unexposed (10%). Among study exposed cases, the occupational exposure was found as often (22.7%), sometimes (68.2%) and never (9.1%) while the reported use of airway protection (masks) was very low. Overall respiratory health of the exposed versus controls was reported as excellent (54.5% vs 73.4%), good (27.3% vs 23.3%) and average (18.2% vs 3.3%) respectively. The exposed group on contrary to control one has decreased mean values for FEV1 (3.12 vs 3.50), FVC (4.12 vs 4.43), FEV1/ FVC % (79.60 vs 80.79) and PEF (414.77 vs 523.16). The present study reveals that exposed workers are at increased risk of developing respiratory symptoms and decreased pulmonary functions as compared to unexposed. Such exposure research studies are instrumental in health status evaluation of workers. However, this area has been neglected by the researchers in Saudi Arabia. It is, thus, strongly recommended to carry out prospective studies to substantiate the study results including large sample size, background pollutants concentrations and biological monitoring. Control strategies should be adopted to reduce the vapor concentration in the ambient air, protect and promote respiratory health of workers.     

Biopersistent Granular Dust and Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis

Objective

Applying a systematic review to identify studies eligible for meta-analysis of the association between occupational exposure to inorganic dust and the development of chronic obstructive pulmonary disease (COPD), and conducting a meta-analysis.

Data Sources

Searches of PubMed and Embase for the time period 1970–2010 yielded 257 cross-sectional and longitudinal studies on people exposed to inorganic dust at the workplace with data on lung function. These studies were independently abstracted and evaluated by two authors; any disagreement was resolved by a third reviewer. Of 55 publications accepted for meta-analysis, 27 investigated the effects of occupational exposure to biopersistent granular dust (bg-dust).

Methods

A random effects meta-analysis allowed us to provide an estimate of the average exposure effect on spirometric parameters presented in forest plots. Between-study heterogeneity was assessed by using I² statistics, with I²>25% indicating significant heterogeneity. Publication bias was investigated by visual inspection of funnel plots. The influence of individual studies was assessed by dropping the respective study before pooling study-specific estimates.

Results

The mean FEV1 of workers exposed to bg-dust was 160 ml lower or 5.7% less than predicted compared to workers with no/low exposure. The risk of an obstructive airway disease—defined as FEV1/FVC < 70%—increased by 7% per 1 mg· m^-3 respirable bg-dust.

Conclusion

Occupational inhalative exposure to bg-dust was associated with a statistically significant decreased FEV1 and FEV1/FVC revealing airway obstruction consistent with COPD.     

The Effect of Exposure to Decreasing Relative Humidity on the Viability of Phytophthora ramorum sporangia

Sporangia of three isolates of Phytophthora ramorum representing three different clonal lineages were subjected to relative humidity (RH) levels between 80 and 100% for exposure periods ranging from 1 to 24 h at 20°C in darkness. Plastic containers (21.5 × 14.5 × 5 cm) were used as humidity chambers with 130 ml of glycerine solution added to each container. Glycerine concentrations corresponded to 100, 95, 90, 85 and 80% RH based on refractive index measurements. Sporangia suspensions were pipeted onto nitrile mesh squares (1.5 × 1.5 cm, 15 micron pore size) which were placed in the humidity chambers and incubated at 20°C in darkness. Following exposure periods of 1, 2, 4, 8, 12 and 24 h, mesh squares were inverted onto Petri dishes of selective medium and sporangia germination assessed after 24 and 48 h. At 100% RH, we observed a mean value of 88% germination after 1 h exposure declining to 18% germination following 24 h incubation. At 95% RH, a steeper decline in germination was noted, with means ranging from 79% at 1 h to less than 1% at 24 h exposure. At 90% RH, no germination was noted after 8 or more h exposure, and values were 57%, 22% and 3% germination for the 1, 2 and 4 h exposures, respectively. Germination was only observed at 1 h exposure for both the 85% RH treatment (52% germination) and the 80% RH treatment (38% germination). The three isolates responded similarly over the range of RH values tested. The germination response of P. ramorum sporangia to RH values between 80% and 100% was comparable to that reported for other Phytophthora species. Knowledge of conditions that affect P. ramorum sporangia germination can shed light on pathogenesis and epidemic potential and lead to improved control recommendations.     

Increased heat shock protein 70 levels in induced sputum and plasma correlate with severity of asthma patients

Damage-associated molecular pattern molecules such as high-mobility group box 1 protein (HMGB1) and heat shock protein 70 (HSP70) have been implicated in the pathogenesis of asthma. The aim of our study was to examine the induced sputum and plasma concentrations of HSP70 in asthmatic patients to determine their relationship with airway obstruction. Thirty-four healthy controls and 56 patients with persistent bronchial asthma matched for gender and age were enrolled in this study. Spirometry measurements were performed before sputum induction. HSP70 levels in induced sputum and plasma were measured using the ELISA Kit. Sputum and plasma concentrations of HSP70 in asthmatics patients were significantly higher than that in control subjects (sputum, (0.88 ng/ml (0.27–1.88 ng/ml) versus 0.42 ng/ml (0.18–0.85 ng/ml), p < 0.001); plasma, (0.46 ng/ml (0.20–0.98 ng/ml) versus 0.14 ng/ml (0.11–0.37 ng/ml), p < 0.001) and were significantly negatively correlated with forced expiratory volume in 1 s (FEV1), FEV1 (percent predicted), and FEV1/FVC in all 90 participants and 56 patients with asthma. There were no significant differences in HSP70 levels between patients with eosinophilic and non-eosinophilic asthma. HSP70 levels in plasma were positively correlated with neutrophil count, and HSP70 levels in induced sputum were positively correlated with lymphocyte count. In multivariate analysis, independent predictors of sputum HSP70 were diseases and disease severity but not smoking, age, or gender, and independent predictors of plasma HSP70 were also diseases and disease severity. In conclusion, this study indicates that induced sputum and plasma HSP70 could serve as a useful marker for assessing the degree of airway obstruction in patients with asthma. However, further investigation is needed to establish the role of circulating and sputum HSP70 in the pathogenesis of asthma.     

Asthma-COPD overlap is not a homogeneous disorder: further supporting data

Revefenacin is a once-daily long-acting muscarinic antagonist (LAMA) in clinical development for the treatment of patients with chronic obstructive pulmonary disease (COPD). In a dose-ranging study, nebulized once-daily revefenacin had a long duration of action in patients after 7 days’ administration of doses up to 700 μg. In this multiple-dose study, the bronchodilation efficacy and adverse events profile were characterized in patients administered nebulized revefenacin once daily for 28 days. A total of 355 COPD patients (mean age 62 years, mean forced expiratory volume in 1 s [FEV1] 44% of predicted) were randomized in a double-blind, placebo-controlled parallel group study. Inhaled corticosteroids as well as short-acting bronchodilators were permitted. Once-daily treatments (44, 88, 175 or 350 μg revefenacin or matching placebo) were administered by a standard jet nebulizer, for 28 days. The primary endpoint was change from baseline in D28 trough FEV1, and secondary endpoints included weighted mean FEV1 over 0 to 24 h and rescue medication (albuterol) use. Safety evaluations included adverse events, laboratory assessments, electrocardiograms and 24-h Holter profiles. Revefenacin (88, 175 and 350 μg) significantly improved D28 trough FEV1 over placebo (187.4, 166.6 and 170.6 mL, respectively, all p < 0.001); 44 μg produced a sub-therapeutic response. At doses ≥88 μg, more than 80% of patients achieved at least a 100-mL increase from baseline FEV1 in the first 4 h post dose compared with 33% of placebo patients. For doses ≥88 μg, D28 24 h weighted mean differences from placebo for FEV1 were numerically similar to respective trough FEV1 values, indicating bronchodilation was sustained for 24 h post dose. Doses ≥88 μg reduced the average number of albuterol puffs/day by more than one puff/day. The 350 μg dose did not demonstrate additional efficacy over that observed with 175 μg revefenacin. Revefenacin was generally well tolerated, with minimal reports of systemic anti-cholinergic effects. These data suggest that 88 and 175 μg revefenacin are appropriate doses for use in longer-term safety and efficacy trials. Revefenacin offers the potential for the first once-daily LAMA for nebulization in patients with COPD who require or prefer a nebulized drug delivery option. ClinicalTrials.gov NCT02040792 . Registered January 16, 2014.     

Systemic inflammation,depression and obstructive pulmonary function: a population-based study

Background

Levels of Interleukin-6 (IL-6) and C-creative protein (CRP) indicating systemic inflammation are known to be elevated in chronic diseases including chronic obstructive pulmonary disease (COPD) and depression. Comorbid depression is common in patients with COPD, but no studies have investigated whether proinflammatory cytokines mediate the association between pulmonary function and depressive symptoms in healthy individuals with no known history of obstructive pulmonary diseases.

Methods

In a population-based sample (n = 2077) of individuals aged 55 and above with no known history of obstructive pulmonary disease in the Singapore Longitudinal Ageing Study (SLAS), we analyzed the relationships between IL-6 and CRP, depressive symptoms (GDS-15 ≥5) and obstructive pulmonary function (FEV1% predicted and FEV1/FVC% predicted).

Results

High serum levels of IL-6 and CRP were associated with greater prevalence of depressive symptoms (p < 0.05). High IL-6, high CRP and depressive symptoms were independently associated with decreased FEV1% predicted and FEV1/FVC% predicted after adjusting for smoking status, BMI and number of chronic inflammatory diseases. Increasing grades of combination of inflammatory markers and/or depressive symptoms was associated with progressive increases in pulmonary obstruction. In hierarchical models, the significant association of depressive symptoms with pulmonary obstruction was reduced by the presence of IL-6 and CRP.

Conclusions

This study found for the first time an association of depressive symptoms and pulmonary function in older adults which appeared to be partly mediated by proinflammatory cytokines. Further studies should be conducted to investigate proinflammatory immune markers and depressive symptoms as potential phenotypic indicators for chronic obstructive airway disorders in older adults.     

Mutagenicity of fume particles from metal arc welding on stainless steel in the Salmonella/microsome test.

Mutagenic activity of fume particles produced by metal arc welding on stainless steel (ss) is demonstrated by using the Salmonella/microsome mutagenicity test described by Ames et al., with strain TA100 (base-pair substitution) and TA98 (frame-shift reversion). Results of a representative but limited selection of processes and materials show that mutagenic activity is a function of process and process parameters. Welding on stainless steel produces particles that are mutagenic, whereas welding on mild steel (ms) produces particles that are not. Manual metal arc (MMA) welding on stainless steel produces particles of higher mutagenic activity than does metal inert gas (MIG) welding, and fume particles produced by MIG welding under short-arc transfer. Further studies of welding fumes (both particles and gases) must be performed to determine process parameters of significance for the mutagenic activity.     

Chronic exposure to ozone causes tolerance to airway hyperresponsiveness in guinea pigs: lack of SOD role

Tolerance torespiratory effects of O₃ has beendemonstrated for anatomic and functional changes, but information abouttolerance to O₃-induced airwayhyperresponsiveness (AHR) is scarce. In guinea pigs exposed to air orO₃ (0.3 parts/million, 4 h/day,for 1, 3, 6, 12, 24, or 48 days, studied 16-18 h later), pulmonaryinsufflation pressure changes induced by intravenous substance P (SP,0.032-3.2 µg/kg) were measured, then the animals were subjectedto bronchoalveolar lavage (BAL). Bronchial rings with or withoutphosphoramidon were also evaluated 3 h after air or a singleO₃ exposure.O₃ caused in vivo AHR (increasedsensitivity) to SP after 1, 3, 6, 12, and 24 days of exposure comparedwith control. However, after 48 days of exposure,O₃ no longer caused AHR. Totalcell, macrophage, neutrophil, and eosinophil counts in BAL wereincreased in most O₃-exposedgroups. When data from all animals were pooled, we found a highlysignificant correlation between degree of airway responsiveness andtotal cells (r = 0.55), macrophages(r = 0.54), neutrophils(r = 0.47), and eosinophils(r = 0.53), suggesting that airwayinflammation is involved in development of AHR to SP. Superoxidedismutase (SOD) levels in BAL fluids were increased (P < 0.05) after 1, 3, 6, and 12 days of O₃ exposure and returned to basal levels after 24 and 48 days of exposure.O₃ failed to inducehyperresponsiveness to SP in bronchial rings, and phosphoramidon increased responses to SP in air- andO₃-exposed groups, suggesting thatneutral endopeptidase inactivation was not involved inO₃-induced AHR to SP in vivo. Weconclude that chronic exposure to 0.3 ppm O₃, a concentration found inhighly polluted cities, resulted in tolerance to AHR to SP in guineapigs by an SOD-independent mechanism.

     

Novel effects of PGF2 alpha on airway function in asthmatic subjects

The effects of inhaled prostaglandin F2 alpha (PGF2 alpha) have been examined in eight subjects with asthma. Incremental PGF2 alpha aerosol concentrations, ranging from 1 to 5,000 micrograms/ml, were administered at 15-min intervals. Plethysmographic specific airway conductance (sGaw), forced expiratory volume at 1 s (FEV1), and maximum expiratory flow at 50% vital capacity breathing air (Vmax50% air) and 80% He-20% O2 (Vmax50% He-O2) were measured after each dose and compared with saline control values. We observed unexpected triphasic dose-response characteristics, i.e., an initial decline in physiological variables at low concentrations (1-100 micrograms/ml), followed by improvement at intermediate concentrations (100-1,000 micrograms/ml) and a subsequent steep decline at high concentrations (1,000-5,000 micrograms/ml). Improvement in FEV1 and Vmax50% air between 100 and 1,000 micrograms/ml was associated with sGaw increases above control levels in six subjects and a significant fall in density-dependent index (Vmax50% He-O2/Vmax50% air) when compared with values before challenge and at low concentrations. Inhaled atropine (5 mg) improved prechallenge lung function but had no effect on PGF2 alpha dose-response characteristics. Intermediate PGF2 alpha concentrations given as a single dose consistently induced greater FEV1 reductions than the same concentration during graded dose challenges. Our findings are consistent with the demonstration of in vivo airway tachyphylaxis and indicate that airway effects of PGF2 alpha are far more complex than previously reported. Moreover, these novel effects suggest that, in addition to its well-known bronchoconstrictor effects, PGF2 alpha directly or indirectly causes airway relaxation, predominantly in large airways.     

Regulation of vascular angiotensin II receptors by EGF

After vascular endothelial injury, angiotensin II (ANG II) playsa role in the resulting hypertrophic response, and expression ofepidermal growth factor (EGF) is enhanced. Therefore, we tested thepossibility that EGF regulates vascular ANG II action and receptorexpression. Incubation of cultured aortic vascular smooth muscle cells(VSMC) with EGF (or basic fibroblast growth factor but notplatelet-derived growth factor isoforms) resulted inconcentration-dependent (1-50 ng/ml EGF), time-dependent (>8 h),and reversible decreases in ANG II surface receptor density. Forexample, a 50% reduction was observed after exposure to 50 ng/ml EGFfor 24 h. Incubation of cultured VSMC with 50 ng/ml EGF for 24 hresulted in a 77% reduction in ANG II-stimulated inositol phosphateformation. EGF not only prevented but also reversed ANG II receptorupregulation by 100 nM corticosterone. The specifictyrosine kinase inhibitor tyrphostin A48 (50 µM) reducedEGF-stimulated thymidine incorporation and EGF-stimulatedphosphorylation of mitogen-activated protein kinase but did not preventEGF from reducing ANG II receptor density. Neither pertussis toxin (100 ng/ml) nor downregulation of protein kinase C by phorbol myristateacetate (100 nM for 24 h) prevented EGF from reducing ANG II receptordensity. In summary, EGF is a potent negative regulator of vascular ANGII surface receptor density and ANG II action by mechanisms that do notappear to include tyrosine phorphorylation, pertussis toxin-sensitive G proteins, or phorbol ester-sensitive protein kinase C. The possibility that EGF shifts the cell culture phenotype to one that exhibits reducedsurface ANG II density cannot be eliminated by the present studies.

     

Tear cytokine and ocular surface alterations following brief passive cigarette smoke exposure

Purpose: To prospectively investigate the effects of acute passive cigarette smoke exposure on the ocular surface and tear film in healthy non-smokers. Methods: Twelve right eyes of 12 subjects without any ocular diseases were examined before, 5 min, and 24 h after 5 min of passive cigarette smoke exposure in a controlled smoke chamber. Tear samples were obtained before, 5 min and 24 h after smoke exposure to detect tear hexanoyl-lysine (HEL), acrolein and inflammatory cytokine concentrations. Tear evaporation rate, DR-1 tear film lipid layer interferometry, tear film break-up time (TBUT), ocular surface fluorescein staining (FS) and Rose Bengal staining (RB), Schirmer I test were performed before, 5 min, and 24 h after smoke exposure. Conjunctival impression cytology (IC) and brush cytology (BC) were carried out before and 24 h after smoke exposure. Results: Tear evaporation rate, tear lipid spread time, tear film break-up time, and vital staining scores showed significant worsening with passive smoke exposure. Tear HEL and IL-6 concentrations increased significantly 24 h after smoke exposure. Tear acrolein level showed an insignificant increase at 5 min. IC and RT-PCR revealed a significant reduction in goblet cell density, a shift toward higher squamous metaplasia grades and a significant downregulation of MUC5AC mRNA expression at 24 h. Conclusion: Even brief passive exposure to cigarette smoke in healthy non-smoker subjects was associated with adverse effects on the ocular surface health as evidenced by an increase of tear inflammatory cytokines, tear lipid peroxidation products and decrease of mucosal defense resulting in tear instability and damage to the ocular surface epithelia.     

Bronchial hyperreactivity is associated with enhanced grain dust-induced airflow obstruction.

Bronchial hyperreactivity (BHR) is associated with the presence of airway inflammation in asthma and is seen in individuals occupationally exposed to grain dust. To better understand the relationship between BHR and pulmonary inflammation after grain dust exposure, we carried out an inhalation challenge to corn dust extract (CDE) on seven subjects with BHR [a 20% or greater decrease in forced expiratory volume in 1 s (FEV(1)) compared with diluent FEV(1) with a cumulative dose of histamine 相似文献   

Ship noise‐induced temporary hearing threshold shift in the Chinese sucker Myxocyprinus asiaticus (Bleeker, 1864)

The study objective was to explore the effects of noise generated by a 2000 hp containership on the reaction of Chinese sucker Myxocyprinus asiaticus. The noise was played back for various durations (1, 2, 4, 8, 24 h) at 142.8 dB re 1 μPa. Immediately after the noise exposure, hearing abilities of the fish were tested using the auditory evoked potential (AEP) protocol and compared with the response to a control group with no noise exposure. After 1 h noise exposure no significant differences were found compared to control fish; however, significant auditory threshold shifts began to occur at 800 Hz after 2 h of noise exposure. After 24 h of noise exposure, significant auditory threshold shifts were found at all tested frequencies (100–3000 Hz) when compared to control fish. Recoveries were also measured until the auditory thresholds returned to the hearing levels of the control fish. Auditory thresholds of all Chinese suckers fully returned to control levels within 96 h of recovery time. The results indicate that ship noise exposure can lead to threshold shifts in Chinese sucker and that these threshold shifts are temporary, referred to as temporary threshold shift (TTS).