Effect of inhaled glutathione on airway response to 'Fog' challenge in asthmatic patients.
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OBJECTIVE: We report on the effect of glutathione, an antioxidant compound on the airway response to the ultrasonically nebulised distilled water (UNDW, 'fog') challenge. METHODS: 12 subjects with mild-to-moderate bronchial asthma underwent double-blind, cross-over pretreatment, administered 30 min earlier, in a randomised order with inhaled glutathione (G) (600 mg), sodium cromoglycate (SCG) (20 mg) and placebo (P), followed by the challenge. RESULTS: After P pretreatment UNDW challenge caused a mean 20.41% decrease in FEV-1 (p < 0.05), after G, a mean 6.04% fall in FEV-1 (p = n.s.), and after SCG a mean 5.99% fall in FEV-1 (p = n.s.). CONCLUSIONS: G significantly attenuated 'fog'-induced falls in FEV-1 (p < 0.001 compared with P) and showed a protective effect on UNDW-induced bronchoconstriction. (+info)
PACAP reverses airway hyperresponsiveness induced by ozone exposure in guinea pigs.
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BACKGROUND: We previously demonstrated that pituitary adenylate cyclase activating peptide (PACAP) inhibits airway smooth muscle contraction and plasma extravasation. OBJECTIVE: We thus hypothesized that PACAP may regulate airway responsiveness through these effects and examined the effects of exogenously applied PACAP on the airway hyperresponsiveness induced by ozone exposure. METHODS: Ozone exposure was carried out in awake, spontaneously breathing guinea pigs using 3 ppm for 2 h. Airway responsiveness to histamine was determined before and 30 and 90 min after the termination of ozone exposure for 2 h in anesthetized animals. Extravasation of Evans blue was measured before and 90 min after the termination of ozone exposure. Either PACAP (10(-6) mol/kg) or vehicle was administered intravenously 60 min after exposure. The airway responsiveness was expressed as the concentration of histamine required to produce a 200% increase in total pulmonary resistance (PC(200)). RESULTS: Ozone exposure caused a significant decrease in PC(200) (n = 5, p < 0.05) 30 min after ozone exposure which persisted 90 min thereafter, thus suggesting that ozone caused airway hyperresponsiveness. PACAP significantly suppressed the increase in airway hyperresponsiveness induced by ozone 90 min after exposure (n = 5, p < 0.05). In contrast, this peptide did not have any effect on plasma extravasation. CONCLUSION: We thus conclude that PACAP decreases ozone-induced airway responsiveness, and, therefore, intravenously administered PACAP may be useful in reversing airway hyperresponsiveness. (+info)
The NF-kappa B/Rel family of transcription factors induces many genes involved in immune and inflammatory responses. Mice with germline deletions of individual NF-kappa B/Rel subunits have different phenotypes, suggesting that the NF-kappa B/Rel transcription factors have different functions. We tested whether c-Rel promotes allergic asthma using a murine model of allergen-induced pulmonary inflammation and airway hyperresponsiveness. Our investigation focused on c-Rel, which is expressed in lymphoid cells and is important for lymphocyte activation. In response to allergen sensitization and challenge, c-Rel-deficient mice did not develop increases in pulmonary inflammation, bronchoalveolar lavage fluid eosinophilia, or total serum IgE. c-Rel deficiency also prevented the induction of airway hyperresponsiveness. Allergen-treated wild-type mice had increased DNA binding to an NF-kappa B consensus site. Chemokine expression was altered in allergen-treated c-Rel-deficient mice. Monocyte chemoattractant protein-1, which is regulated by NF-kappa B, was decreased in allergen-treated c-Rel-deficient mice relative to wild-type controls. The increase in NF-kappa B/Rel transcription factors after allergen challenge in wild-type mice and the decrease in allergen reactivity found in c-Rel-deficient mice indicate that c-Rel promotes allergic inflammation. Alteration of pulmonary chemokine expression in c-Rel-deficient mice may inhibit allergen-induced pulmonary inflammation and airway hyperresponsiveness. (+info)
Reduction in bronchodilation following a deep inhalation is poorly related to airway inflammation in asthma.
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In patients with bronchial asthma, forced expiratory flows are differently sensitive to a previous volume history. A reduced ability of a deep inhalation (DI) to dilate obstructed airways has been hypothesized to be a physiological marker for the degree of airway responsiveness and to relate to the presence and magnitude of inflammation in the lung, even in mild stable asthma. However, there are at present doubts as to whether functional changes could be used as a substitute for airway inflammation studies. In order to investigate the interrelations among airway inflammation, bronchial hyperresponsiveness and effects of volume history, 58 consecutive asthmatics with mild to moderate asthma were studied. The effects of DI were assessed as the isovolumic ratio of flows from forced expiratory manoeuvres started from maximal (M) or partial (P) lung inflation. Airway inflammation was assessed by using induced sputum. Sputum was analysed for total and differential cell counts, and levels of eosinophil cationic protein (ECP) which reflects eosinophil activation. Airway responsiveness was assessed as the provocative concentration of histamine which caused a 20% fall in forced expiratory volume in one second (FEV1) from control (PC20). The M/P ratio was significantly related to ECP (r=-0.31, p<0.03) and eosinophils (r=-0.29, p<0.03), FEV1/vital capacity (VC) (r=0.32; p<0.01), clinical score (r=-0.33; p<0.03) and age (r=-0.41; p<0.0001). In a stepwise multiple regression analysis including age, score, baseline lung function, ECP, number of eosinophils and the response to beta2-agonist, age (p<0.037) predicted a small amount of the variance in M/P ratio (r2=0.12). It is concluded that volume history response is substantially independent of both sputum outcomes (inflammatory cell number and eosinophil cationic protein) and bronchial hyperresponsiveness; rather it seems to be associated with anthropometric characteristics. Functional aspects do not provide information on eosinophilic, probably central, airway inflammation. (+info)
Effects of respiratory syncytial virus persistence on airway responsiveness and inflammation in guinea-pigs.
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Recurrent wheezing and asthma often develop after acute respiratory syncytial virus (RSV) bronchiolitis, but the mechanisms of these sequelae are poorly understood. Using a guinea-pig model of human RSV lung infection, the effects of long-term viral persistence on three hallmarks of asthma: nonspecific airway responsiveness, airway inflammation and airway remodelling were examined. Guinea-pigs were studied 100 days after intranasal instillation of either human RSV or uninfected vehicle, using: 1) acetylcholine challenge to test for airway hyperresponsiveness (AHR); 2) lung histology to quantify the numbers of airway eosinophils and metachromatic cells (mast cells/basophils); 3) airway morphometry of the areas of the airway subepithelial connective tissue, smooth muscle and adventitia, to test for airway remodelling; and 4) immunohistochemistry to identify lung cells containing RSV antigens. The RSV-inoculated group had significantly elevated AHR and airway eosinophils compared to uninfected control animals (p<0.05). There were no significant differences between the two groups in terms of numbers of airway metachromatic cells, or the areas of subepithelial connective tissue, smooth muscle or adventitia. Viral proteins were identified by immunohistochemistry within several types of lung cells. In conclusion, long-term persistence of respiratory syncytial virus in the guinea-pig lung is associated with airway hyperresponsiveness and airway eosinophilia, and these changes may be pertinent to the pathogenesis of postbronchiolitis wheezing and asthma in children. (+info)
Role of neutrophil elastase in ozone-induced airway responses in guinea-pigs.
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Ozone-induced airway hyperresponsiveness occurs concurrently with neutrophilic inflammation and epithelial injury in various species including humans. The mechanism of neutrophil-induced airway hyperresponsiveness, however, has not yet been fully clarified. Neutrophil elastase (NE) is a multipotent protease released from activated neutrophils, which may play a role in ozone-induced airway hyperresponsiveness. In order to address this issue, the effects of ONO-5046, a specific NE inhibitor, were investigated in ozone-exposed guinea-pigs. Awake animals were exposed to ozone at 3 parts per million for 2 h, airway responsiveness to acetylcholine (ACh) measured and examination of bronchoalveolar lavage fluid (BALF) performed. Ozone exposure increased airway responsiveness to both inhaled and intravenous ACh, the concentration of NE in BALF and the number of neutrophils and airway epithelial cells in BALF. Although pretreatment with ONO-5046 (200 mg x kg(-1), i.p.) had no effect on these changes immediately after the exposure, it significantly inhibited airway hyperresponsiveness to inhaled ACh, whilst decreasing the number of neutrophils and epithelial cells in BALF 3-5 h after the exposure. In contrast, ONO-5046 showed no significant effect on airway hyperresponsiveness to intravenous ACh at any time. These results suggest that neutrophil elastase contributes to ozone-induced airway hyperresponsiveness developing during the hours after exposure, presumably by means of inducing epithelial injury. (+info)
Lack of a late asthmatic response after hypertonic saline challenge in children.
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Hypertonic saline challenge has become a standardized method for measuring airway responsiveness. However, there is still uncertainty about the occurrence of a late asthmatic response. Therefore, the present study was designed to assess a possible late asthmatic response after hypertonic saline challenge in children. Twenty-one children with mild to moderate bronchial hyperresponsiveness were studied. On days 1 and 2, forced expiratory volume in one second (FEV1) was measured hourly from 10:00 h to 22:00 h to assess diurnal variation of lung function. On the third study day, a hypertonic saline challenge was performed and FEV1 was measured as on control days. The possibility of a late asthmatic response was tested by comparing FEV1 levels up to 12 h after the challenge on the intervention day to FEV1 levels on control days. In no subjects were the FEV1 values following the challenge found to be considerably below the individual mean of the control days. Furthermore, a nonparametric approach was applied for each child and the population looked into as a whole. Again, no late asthmatic response was detectable. The results of this study suggest that in children with mild to moderate bronchial hyperresponsiveness a late asthmatic response does not occur 4-12 h after a 4.5% saline challenge. (+info)
Quantitative trait locus mapping of airway responsiveness to chromosomes 6 and 7 in inbred mice.
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Quantitative trait locus (QTL) mapping was used to identify chromosomal regions contributing to airway hyperresponsiveness in mice. Airway responsiveness to methacholine was measured in A/J and C3H/HeJ parental strains as well as in progeny derived from crosses between these strains. QTL mapping of backcross [(A/J x C3H/HeJ) x C3H/HeJ] progeny (n = 137-227 informative mice for markers tested) revealed two significant linkages to loci on chromosomes 6 and 7. The QTL on chromosome 6 confirms the previous report by others of a linkage in this region in the same genetic backgrounds; the second QTL, on chromosome 7, represents a novel locus. In addition, we obtained suggestive evidence for linkage (logarithm of odds ratio = 1.7) on chromosome 17, which lies in the same region previously identified in a cross between A/J and C57BL/6J mice. Airway responsiveness in a cross between A/J and C3H/HeJ mice is under the control of at least two major genetic loci, with evidence for a third locus that has been previously implicated in an A/J and C57BL/6J cross; this indicates that multiple genetic factors control the expression of this phenotype. (+info)