Association between Recent Acetaminophen Use and Asthma: Modification by Polymorphism at TLR4

The risk of asthma has been increasing in parallel with use of acetaminophen, which is a potential source of oxidative stress. Toll-like receptor 4 (TLR4) plays a critical role not only in innate immunity, but also in mediating reactive oxygen species induced inflammation. Therefore, we investigated associations between acetaminophen usage and TLR4 polymorphism on asthma and bronchial hyperresponsiveness (BHR). The number of 2,428 elementary school children in Seoul and Jeongeup cities was recruited. Subjects who used acetaminophen with a family history of asthma had an increased risk of both asthma diagnosis ever and current asthma. Individuals with CT+TT genotypes at the TLR4 polymorphism, in combination with acetaminophen usage, also demonstrated an increased risk of asthma diagnosis ever (aOR, 2.08; 95% confidence interval [CI], 1.10-3.92). Family history of asthma and acetaminophen usage were risk factors for BHR. Although TLR4 was not an independent risk factor for BHR, individuals with CT+TT genotypes at the TLR4 polymorphism had an increased risk of BHR when combined with acetaminophen usage (aOR, 1.74; 95% CI, 1.03-2.94). In conclusion, acetaminophen usage may be associated with asthma and BHR in genetically susceptible subjects. This effect may be modified by polymorphism at TLR4.

The effects of pycnogenol on antioxidant enzymes in a mouse model of ozone exposure

BACKGROUND/AIMS: Ozone is an environmentally reactive oxidant, and pycnogenol is a mixture of flavonoid compounds extracted from pine tree bark that have antioxidant activity. We investigated the effects of pycnogenol on reactive nitrogen species, antioxidant responses, and airway responsiveness in BALB/c mice exposed to ozone. METHODS: Antioxidant levels were determined using high performance liquid chromatography with electrochemical detection. Nitric oxide (NO) metabolites in bronchoalveolar lavage (BAL) fluid from BALB/c mice in filtered air and 2 ppm ozone with pycnogenol pretreatment before ozone exposure (n = 6) were quantified colorimetrically using the Griess reaction. RESULTS: Uric acid and ascorbic acid concentrations were significantly higher in BAL fluid following pretreatment with pycnogenol, whereas gamma-tocopherol concentrations were higher in the ozone exposed group but were similar in the ozone and pycnogenol pretreatment groups. Retinol and gamma-tocopherol concentrations tended to increase in the ozone exposure group but were similar in the ozone and pycnogenol pretreatment groups following ozone exposure. Malonylaldehyde concentrations increased in the ozone exposure group but were similar in the ozone and pycnogenol plus ozone groups. The nitrite and total NO metabolite concentrations in BAL fluid, which parallel the in vivo generation of NO in the airways, were significantly greater in the ozone exposed group than the group exposed to filtered air, but decreased with pycnogenol pretreatment. CONCLUSIONS: Pycnogenol may increase levels of antioxidant enzymes and decrease levels of nitrogen species, suggesting that antioxidants minimize the effects of acute ozone exposure via a protective mechanism.

Protector mechanisms of the association between gastroesophageal reflux disease and asthma: experimental study in rats / Mecanismos protetores: doença do refluxo gastroesofágico e asma: estudo experimental em ratos

BACKGROUND: It is well known the association between gastroesophageal reflux disease and asthma. The hyperreactivity of the airways is a characteristic of an asthmatic. Many studies associate the increase of the airways reactivity with gastroesophageal reflux disease. AIM: In this study we have evaluated the effect of the intraluminal exposition to gastric juice of trachea on the reactivity to methacholine from rats submitted to a pulmonary allergic inflammation. METHODS: Group of rats were sensitized and challenged with ovalbumin. After 24 hours the animals were sacrificed, and their tracheae were removed to be cultured with gastric juice. The gastric juice was obtained from a donor rat. Subsequently the segments were placed into plastic plates with RPMI-1640 for incubation, under suitable atmosphere and time. After the period of incubation the segments were put into chambers for the analysis of the contractile response to methacholine. RESULTS: We observed reduction in the contractile response of trachea cultured with gastric juice from allergic rats. This result was confirmed by the pharmacological treatments with compound 48/80 and dissodium cromoglicate (mast cells blockade), L-NAME (nitric oxide inhibitor, NO), capsaicin (neuropeptides depletion) and indomethacin (ciclooxigenase inhibitor). CONCLUSIONS: Our results highlight to the existence of a complex interaction between pulmonary allergy and gastric juice in the airways. The involvement of the non-adrenergic non-cholinergic system, NO, prostanoids and mast cells are directly related to this interaction. We suggest that the reduced contractile response observed in vitro may represent a protector mechanism of the airways. Despite its presence in the human body it can not be observed due to the predominant effects of excitatory the non-adrenergic non-cholinergic system.

RACIONAL: É bem estabelecida a relação entre a doença do refluxo gastroesofágico e a asma. A hiperreatividade das vias aéreas é uma das características que o indivíduo asmático desenvolve e diversos estudos associam o aumento da reatividade das vias aéreas com o refluxo gastroesofágico. OBJETIVO: Avaliar a reatividade à metacolina de traquéia exposta intraluminalmente ao suco gástrico de ratos submetidos a inflamação alérgica pulmonar. MÉTODOS: Grupos de ratos foram sensibilizados e broncoprovocados com ovoalbumina. Após 24 horas, os animais foram sacrificados e a traquéia removida para preenchimento de seu lúmen com suco gástrico obtido de um animal doador. A seguir, os segmentos foram colocados em placas plásticas com RPMI-1640 e mantidos em estufa por 3 horas em condições ambientais adequadas. Após o tempo de incubação, os fragmentos foram montados em cubas de vidro para órgão isolado para registro isométrico de contração, através da construção de curvas concentração-efeito à metacolina. RESULTADOS: Observou-se redução da resposta contrátil em traquéia exposta ao suco gástrico proveniente de ratos alérgicos. Os tratamentos farmacológicos com composto 48/80 e cromoglicato de sódio (bloqueio de mastócitos), L-NAME (inibidor de óxido nítrico, NO), capsaicina (depleção de neuropeptídios) e indometacina (inibidor da ciclooxigenase) corroboraram esta observação. CONCLUSÕES: Os resultados apontam para a existência de complexa interação entre a alergia pulmonar e o suco gástrico nas vias aéreas, com o envolvimento do sistema não-adrenérgico não-colinérgico, NO, prostanóides e mastócitos. À luz das evidências in vivo sobre a hiperreatividade das vias aéreas na associação asma e refluxo gastroesofágico, sugere-se que a reduzida resposta contrátil detectada in vitro pode representar um mecanismo protetor das vias aéreas. A despeito de sua presença, esta redução pode não ser observada in vivo devido à proeminência dos efeitos do sistema não-adrenérgico ...

Volatile Organic Compounds Contribute to Airway Hyperresponsiveness

BACKGROUND: Volatile organic compounds (VOCs) in concentrations found in both the work and home environments may influence lung function. We investigated the prevalence of airway responsiveness in workers exposed to VOCs. METHODS: We used allergic skin tests, nonspecific airway hyperresponsiveness testing and questionnaires to study twenty exposed workers and twenty-seven control subjects. Atopy was defined as a reactor who showed >3+ response to one or more allergens on the skin prick tests. Airway hyperresponsiveness (BRindex) was defined as log [% fall of FEV1/ log (last concentration of methacholine) +10]. RESULTS: The VOC exposed workers, in comparison with the control subjects, tended to have a higher BRindex (1.19+/-0.07 vs. 1.15+/-0.08, respectively). Workers exposed to VOCs with atopy or smoker, as compared with the workers exposed to VOCs with non-atopy and who were non-smokers and the control subjects with non-atopy and who were non-smokers, had a significantly higher BRindex (1.20+/-0.05 vs. 1.14+/-0.06 vs. 1.10+/-0.03, respectively p<0.05). The BRindex was not correlated with atopy, the smoking status or the duration of VOC exposure. CONCLUSIONS: These findings suggest that VOCs may act as a contributing factor of airway hyperresponsiveness in workers exposed to VOCs.

Fluticasone propionate and bronchial hyperresponsiveness in childhood asthma.

Bronchial asthma is now agreed as being a chronic inflammatory disease of the airways. Inhaled steroids are widely accepted as a preventive medication in asthmatic patients of all ages and severity. However, the optimal use of inhaled steroids and the important issue of safety and efficacy still remain of concern, particularly in children. Recently, fluticasone propionate (FP) has been developed for use as an inhaled preparation for the treatment of asthma. Because of its high topical potency and increased lipophilicity, it is claimed that FP has an improved risk/benefit compared with other inhaled steroids. In order to evaluate the use of FP in children, we have studied the efficacy of high dose FP (500 microg/day) in asthmatic children. Thirteen children (9 boys and 4 girls), aged 7-17 years (10.8 +/- 2.6), were instructed to use a pressurized metered-dose inhaler connected to a Volumetric spacer. The standard methacholine bronchial challenge test was used as a principal outcome parameter. The PD20, a cumulative dose of methacholine inducing a 20% decrease in FEV1, was measured pre- and post-treatment with inhaled FP. After 4 weeks of FP, PD20 significantly increased from 21.6 +/- 14.3 inhalation unit to 106.6 +/- 78.5 inhalation unit (4.9 fold, p = 0.004) reflecting the improvement of airway reactivity. All subjects improved clinically. These results demonstrate that the anti-inflammatory action of FP 500 microg a day for four weeks can markedly reduce bronchial hyperresponsiveness, the basic physiologic abnormality in bronchial asthma.

Hiperreactividad en 30 niños sin asma con dermatitis atópica / Bronchial hyperreactivity in children with atopic dermatitis

Introducción. La importancia de la dermatitis atópica (DA) no sólo radica en su alta morbilidad, con topografía y morfología dérmica características, sino que además existen manifestaciones extracutáneas, de las cuales la hiperreactividad bronquial (HRB) puede estar presente expresándose posteriomente como asma bronquial, por este motivo el objetivo del trabajo fue determinar la presencia de HRB en 30 niños con DA sin diagnóstico de asma o afección pulmonar previa. Material y métodos. Se realizó un estudio prospectivo, transversal, en 30 niños de 6 a 16 años de edad que acudieron al Hospital Infantil de México Federico Gómez con diagnóstico de DA. Para determinar la presencia de HRB se realizaron pruebas de función pulmonar (espirometría basal y posterior al reto con diferentes concentraciones de metacolina). El análisis estadístico se llevó a cabo por la prueba t de Student pareada con corrección de Kurtosis. Resultados. La edad media fue de 11 años, con una relación femenino/masculino de 1.5: 1. De los 30 pacientes, 21 tuvieron reto positivo, demostrado por el descenso del VEF1 con respecto a la basal de 20 por ciento acompañándose de tos, opresión torácica y sibilancias. Al analizar los valores del VEF1 se encontró significancia estadística (P=0.0125) de los basales comparados con cada reto. De esta manera se observa que 70 por ciento tuvo HRB, concordando con lo reportado por otros autores, en los cuales más de la mitad de los pecientes con DA presentan HRB. Conclusión. Es necesario vigilar estrechamente a los pacientes con DA ya que como se demostró en este estudio, existe la posibilidad de que en algún momento de la vida pudieran presentar asma bronquial y aunque no se pueda evitar en su totalidad sí se podrían tomar las medidas necesarias para disminuir esta posibilidad basados en la pevención

The modulatory effect of antigen- and PAF-induced asthmatic reaction by aerosol administration of OKY-046 in guinea pigs.

The therapeutic effect of a thromboxane A2 (TXA2) synthetase inhibitor on asthma is still controversial. This study was aimed at clarifying its effect on asthmatic reactions in guinea pigs. Both ovalbumin (OVA)- and platelet activating factor (PAF)-induced dual phase airway spasm and hyperreactivity in guinea pigs were used as the asthma model. Our results demonstrated that aerosol administration of OKY-046 could inhibit both OVA- and PAF-induced late phase bronchoconstriction and airway hyperreactivity to methacholine in OVA sensitized guinea pigs. PAF administration could also induced dual phase bronchoconstriction in normal guinea pigs. Similarly, late phase airway spasm and airway hyperreactivity after PAF exposure was also blocked by OKY-046. In conclusion, aerosol administration of OKY-046 is a safe and effective way to modulate OVA- and PAF-induced asthmatic reactions. The protective effect of OKY-046 on OVA- and PAF-induced late phase bronchoconstriction and airway hyperreactivity indicates that TXA2 might play an important role in the late phase asthmatic reaction and airway hyperreactivity. The normalization of PAF-induced airway hyperreactivity by OKY-046 also indicates that PAF induced airway inflammation might be through the generation of TXA2.

Exposición aguda a diversas concentraciones de ozono en el cobayo: correlación entre inflamación e hiperreactividad de las vías aéreas / Acute exposure to several ozone concentrations in the guinea pig: correlation between inflammation and airway hyperresponsiveness

El ozono (O3) es uno de los principales contaminates atmosfericos en las grandes urbes como la Ciudad de México. Entre las alteraciones que ocasiona están la infiltración neutrofílica y la hiperreactividad de las vías aéreas, pero aún existe controversia de si ambos fenómenos son independientes o tienen una relación causa-efecto. Para evaluar esta última posibilidad, se realizaron curvas dosis-repuesta no acumulativas con histamina (0.01 a 1.8 µg/kg, i.v.) en cobayos machos con o sin exposición previa a O3 (0.15, 0.3, 0.6 ó 1.2 ppm por 4h, 16-18 h antes del estudio). En todos los cobayos se realizó lavado broncoalveolar (LBA) al final de la curva a histamina. La respuesta broncoconstrictora a la histamina se evaluó como incremento de la presión de insuflación pulmonar. Se observó que la exposición aguda a O3 aumentó significativamente la sensibilidad de las vías aéreas a la histamina en los cobayos expuestos a 1.2 ppm de O3 (p<0.01), existiendo correlación entre el grado de reactividad de todos los grupos y la concentración de O3 inhalada (p<0.0003). El número de células totales se incrementó en el grupo de 1.2 ppm de O3 (p<0.05) y en forma global tuvo correlación con la concentración de O3 (r=0.37, p<0.05) y con la reactividad a la histamina (r=0.35, p<0.05). Asimismo, la población de neutrófilos se incrementó en los grupos expuestos a 0.3 (p<0.01) y 1.2 ppm de O3 (p<0.05). Sin embargo, no existió correlación entre el número de neutrófilos y la reactividad a la histamina o la concentración de O3. Estos resultados sugieren que el O3 aumenta la sensibilidad de las vías aéreas a la histamina de manera proporcional a la concentración de O3 inhalada, y que dicha hiperreactividad se presenta como consecuencia de un proceso inflamatorio, sin que se haya podido determinar cuál es el principal tipo celular involucrado en este fenómeno

Reduction of Sephadex-induced lung inflammation and bronchial hyperreactivity by rapamycin

Rapamycin is a macrolide antibiotic whose potent immunosuppressor activity was recently described in vivo and in vitro. The aim of the present work was to determine if rapamycin could affect an established inflammatory response. Conscious pathogen-free Dunkin-Hartley guinea pigs (300-400 g) were injected intravenously with Sephadex beads (G50, superfine, 10 to 40 microns, 24 mg/kg) to induce lung inflammation and bronchial hyperreactivity. Bronchoalveolar lavage (BAL) fluid was collected 2, 12 and 24 h after Sephadex administration and the cells were counted. Bronchial tissue was used to construct dose-response (contraction, g) curves to histamine and acetylcholine 24 h after the Sephadex injection, using a cascade system. Results are presented as area under the log dose-response curves. Test animals were injected with rapamycin (5 mg/kg) or its vehicle by the intramuscular route either 2 or 12 h after Sephadex injection and BAL fluid collected 24 h after Sephadex administration. Rapamycin administration 2 h after Sephadex reduced eosinophil and lymphocyte numbers in BAL by 52 and 55 per cent , respectively, but not ex vivo bronchial hyperreactivity induced by Sephadex injection. However, rapamycin administration 12 h after Sephadex reduced BAL eosinophil and lymphocyte numbers (55 and 62 per cent , respectively) and bronchial hyperreactivity. The increase in neutrophil numbers in BAL induced by Sephadex injection was not modified by rapamycin. Since lymphocyte numbers in BAL were significantly increased in Sephadex-treated animals at 12 h but not at 2 h after Sephadex injection, the present results suggest that the inhibition of bronchial hyperreactivity by rapamycin may be dependent on the presence of lymphocytes elicited into the airways by Sephadex injection

Pulmonary flow rates and methacholine bronchial challenge in Egyptian petroleum workers

Pulmonary flow rates and methacholine inhalation challenge were assessed in 150 Egyptian male petroleum workers and 50 male normal control subjects to study the effect of exposure to pollutants in petroleum industry on airways. According to methacholine inhalation challenge [MIC] the workers were distinguished into positive [PW+, n=27] and negative [PW-, n=123] responders. The positive response is 20% or more fall in FEV1. In the [PW+] pulmonary flow and MIC assessment were repeated after three months away from exposure. The pulmonary flow rates of the [PW+] and [PW-] were similar and significantly lower than those of normal subjects. The slope and intercept of the methacholine dose-response curves of [PW+] and [PW-] were significantly different from those of the normal subjects indicating bronchial hyperreactivity and hypersensitivity in petroleum workers whether positive or negative methacholine responders. Three months away from exposure in [PW+] resulted in significant changes of the intercept without changes of the slope of the curve suggesting improvement of bronchial sensitivity without affection of the reactivity. From the obtained data we may suggest that the pollutants in petroleum industry lead to bronchial hyperreactivity and hypersensitivity even in those workers who are not currently complaining. Measurements of pulmonary flow rates is not a sufficient tool, whereas MIC and analysis of the dose- response curve for the slope and the intercept is useful in distinguishing the subjects at high risk from those at low risk