Effect of inhaled corticosteroids on bronchial responsiveness in patients with "corticosteroid naive" mild asthma: a meta-analysis.
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BACKGROUND: Inhaled corticosteroids are the most efficacious anti-inflammatory drugs in asthma. International guidelines also advocate the early introduction of inhaled corticosteroids in corticosteroid naive patients. A study was undertaken to assess the effects of inhaled corticosteroids on bronchial hyperresponsiveness in patients with corticosteroid naive asthma by conventional meta-analysis. METHODS: A Medline search of papers published between January 1966 and June 1998 was performed and 11 papers were selected in which the patients had no history of treatment with inhaled or oral corticosteroids. Bronchial responsiveness to bronchoconstricting agents was considered as the main outcome parameter. Doubling doses (DD) of histamine or methacholine were calculated. RESULTS: The total effect size of inhaled corticosteroids (average daily dose 1000 microg) versus placebo in the 11 studies was +1.16 DD (95% confidence interval (CI) +0.76 to +1.57). When only the eight short term studies (2-8 weeks) were analysed the effect size of the bronchoconstricting agent was +0.91 DD (95% CI +0.65 to +1.16). No relationship was found between the dose of inhaled corticosteroid used and the effect on bronchial responsiveness. CONCLUSION: This meta-analysis in patients with corticosteroid naive asthma indicates that, on average, high doses of inhaled corticosteroids decrease bronchial hyperresponsiveness in 2-8 weeks. It remains unclear whether there is a dose-response relationship between inhaled corticosteroids and effect on bronchial hyperresponsiveness. (+info)
Deficiency of nitric oxide in polycation-induced airway hyperreactivity.
(10/493)
Using a perfused guinea-pig tracheal tube preparation, we investigated the role of endogenous nitric oxide (NO) in polycation-induced airway hyperreactivity (AHR) to methacholine. Intraluminal (IL) administration of the NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; 100 microM) caused a 1.8 fold increase in the maximal contractile response (Emax) to IL methacholine compared to control, without an effect on the pEC50 (-log10 EC50). The polycation poly-L-arginine (100 microg ml(-1), IL) similarly enhanced the Emax for methacholine; however, the pEC50 value was also increased, by one log10 unit. L-NAME had no effect on the enhanced methacholine response of poly-L-arginine-treated airways, while the enhanced agonist response was completely normalized by the polyanion heparin (25 u ml(-1), IL). In addition, the effect of L-NAME was fully restored in the poly-L-arginine plus heparin treated airways. The results indicate that, in addition to enhanced epithelial permeability, a deficiency of endogenous NO contributes to polycation-induced AHR. The latter finding may represent a novel mechanism of AHR induced by eosinophil-derived cationic proteins in allergic asthma. (+info)
Effect of the leukotriene receptor antagonist pranlukast on cellular infiltration in the bronchial mucosa of patients with asthma.
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BACKGROUND: It has been reported that pranlukast reduces the antigen induced immediate and late phase asthmatic responses, airway hyperreactivity to acetylcholine, and pulmonary eosinophil accumulation in guinea pigs. A study was undertaken to test the hypothesis that pranlukast may reduce the number of inflammatory cells in the bronchial mucosa of patients with asthma. METHODS: A double blind, placebo controlled study was performed in 17 mild to moderate asthmatic subjects to examine changes in inflammatory cell infiltration in response to pranlukast (225 mg orally twice per day for four weeks). Comparisons of the mean daily beta 2 agonist use, symptom score, FEV1 percentage predicted, and airway methacholine responsiveness were made before and after treatment. Using fibreoptic bronchoscopy, bronchial biopsy specimens were obtained before and after treatment with either pranlukast (n = 10) or placebo (n = 7). Immunohistology was performed using monoclonal antibodies for CD3, CD4, CD8, CD68, NP57, AA1, EG1, EG2, gamma GTP and CD19. RESULTS: When the pranlukast and placebo treated groups were compared there were decreases in beta 2 agonist use, symptom score, and airway methacholine responsiveness after pranlukast but no increase in FEV1 was seen. The clinical response in patients treated with pranlukast was accompanied by a reduction in CD3 (median difference -37, 95% confidence interval (CI) -69 to -1; p < 0.05), CD4 (median difference -28, 95% CI -49 to -8; p < 0.01), AA1 (median difference -15, 95% CI -26 to 0; p < 0.05) and EG2 positive cells (95% CI -35 to 0; p < 0.05), but not in EG1 positive eosinophils, gamma GTP positive cells, and CD19 positive plasma cells. CONCLUSIONS: These results support the view that pranlukast may act by inhibition of bronchial inflammation in patients with asthma. (+info)
An improved murine model of asthma: selective airway inflammation, epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen.
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BACKGROUND: Existing murine models of asthma lack many of the inflammatory and epithelial changes that are typical of the human disease. Moreover, these models are frequently complicated by allergic alveolitis. METHODS: High IgE responder BALB/c mice were systemically sensitised to ovalbumin and chronically challenged with low particle mass concentrations of aerosolised ovalbumin. Titres of antiovalbumin IgE in serum were measured at two weekly intervals by enzyme immunoassay, accumulation of inflammatory cells and histopathological abnormalities of the epithelium were quantified morphometrically in the trachea and the lungs, and airway reactivity was assessed by measuring bronchoconstriction following intravenous administration of methacholine. RESULTS: Mice sensitised by two intraperitoneal injections of ovalbumin developed high titres of IgE antibodies to ovalbumin. Following exposure to low concentrations of aerosolised antigen for up to eight weeks these animals developed a progressive inflammatory response in the airways, characterised by the presence of intraepithelial eosinophils and by infiltration of the lamina propria with lymphoid/mononuclear cells, without associated alveolitis. Goblet cell hyperplasia/metaplasia was induced in the intrapulmonary airways, while epithelial thickening and subepithelial fibrosis were evident following chronic exposure. In parallel, the mice developed increased sensitivity to induction of bronchospasm, as well as increased maximal reactivity. Non-immunised mice exposed to aerosolised ovalbumin had low or absent antiovalbumin IgE and did not exhibit inflammatory or epithelial changes, but developed airway hyperreactivity. CONCLUSIONS: This experimental model replicates many of the features of human asthma and should facilitate studies of pathogenetic mechanisms and of potential therapeutic agents. (+info)
Repeatability of lung function tests during methacholine challenge in wheezy infants.
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BACKGROUND: The repeatability of lung function tests and methacholine inhalation tests was evaluated in recurrently wheezy infants over a one month period using the rapid thoracic compression technique. METHODS: Eighty-one wheezy, symptom free infants had pairs of methacholine challenge tests performed one month apart. Maximal flow at functional residual capacity (VmaxFRC) and transcutaneous oxygen tension (Ptco2) were measured at baseline and after methacholine inhalation. Provocative doses of methacholine causing a 15% fall in Ptco2 (PD15 Ptco2) or a 30% fall in VmaxFRC (PD30 VmaxFRC) were determined. RESULTS: Large changes in VmaxFRC were measured from T1 to T2 with a mean difference between measurements (T2-T1) of 7 (113) ml/s and a 95% range for a single determination for VmaxFRC of 160 ml/s. The mean (SD) difference between pairs of PD30 VmaxFRC measurements was 0.33 (1.89) doubling doses with a 95% range for a single determination of 2.7 doubling doses. Repeatability of PD15Ptco2 was similar. A change of 3.7 doubling doses of methacholine measured on successive occasions represents a significant change. CONCLUSIONS: Baseline VmaxFRC values are highly variable in wheezy, symptom free infants. Using either VmaxFRC or Ptco2 as the outcome measure for methacholine challenges provided similar repeatability. A change of more than 3.7 doubling doses of methacholine is required for clinical significance. (+info)
Eosinophils in the bronchial mucosa in relation to methacholine dose-response curves in atopic asthma.
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Asthma is characterized by both local infiltration of eosinophils in the bronchial mucosa and bronchial hyperreactivity (BHR). A detailed characterization of BHR implies analysis of a histamine or methacholine dose-response curve yielding not only the dose at 20% fall of baseline forced expiratory volume in 1 s (FEV1), but also a plateau (P) representing the maximal narrowing response in terms of percent change in FEV1 and reactivity as the steepest slope at 50% of P (%FEV1/doubling dose). In the baseline condition, the specific airway conductance (sGaw) may be considered closely related to airway lumen diameter. In 20 nonsmoking asthmatic patients, methacholine dose-response curves were obtained, and a sigmoid model fit yielded the BHR indexes. Immunohistochemistry with the monoclonal antibodies (EG1 and EG2) was used to recognize the total number of eosinophils and activated eosinophils, respectively. The number of activated eosinophils was significantly correlated to both P (r = 0.62; P < 0.05) and sGaw (r = -0.52; P < 0.05), whereas weaker and nonsignificant correlations were found for dose at 20% fall of baseline FEV1 and the total number of eosinophils. We conclude that the number of activated eosinophils can be considered a marker of the inflammation-induced decrease of airway lumen diameter as represented by the plateau index and sGaw. (+info)
Exposure of healthy volunteers to swine house dust increases formation of leukotrienes, prostaglandin D2, and bronchial responsiveness to methacholine.
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BACKGROUND: Acute exposure of healthy subjects to swine house dust causes increased bronchial responsiveness to methacholine but no acute bronchoconstriction. The role of cysteinyl leukotrienes and mast cells in increased bronchial responsiveness is unclear. METHODS: Ten non-asthmatic subjects were exposed to swine dust for three hours while weighing pigs in a piggery. Urine was collected prior to and for up to 12 hours after entering the piggery and at the same times five days before and the day after exposure. As indices of whole body leukotriene production and mast cell activation, urinary levels of leukotriene E4 (LTE4) and 9 alpha, 11 beta-PGF2, the earliest appearing urinary metabolite of prostaglandin D2 (PGD2), were measured. Bronchial responsiveness to methacholine was determined five days before and the day after the exposure. RESULTS: Methacholine PD20FEV1 decreased from 1.32 mg (95% CI 0.22 to 10.25) before exposure to 0.38 mg (95% CI 0.11 to 1.3) after exposure (p < 0.01). Associated with the increase in bronchial responsiveness there was a significant mean difference between post- and prechallenge levels of LTE4 (difference 38.5 ng/mmol creatinine (95% CI 17.2 to 59.8); p < 0.01) and 9 alpha, 11 beta-PGF2 (difference 69 ng/mmol creatinine (95% CI 3.7 to 134.3); p < 0.05) on the day of exposure to swine dust. Swine dust exposure induced a 24-fold increase in the total cell number and a 12-fold increase in IL-8 levels in the nasal lavage fluid. The levels of LTB4 and LTE4 in nasal lavage fluid following exposure also increased 5.5-fold and 2-fold, respectively. CONCLUSIONS: The findings of this study indicate that cysteinyl leukotrienes and other mast cell mediators contribute to the development of increased bronchial responsiveness following inhalation of organic swine dust. (+info)
Altered airway and cardiac responses in mice lacking G protein-coupled receptor kinase 3.
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Contraction and relaxation of airway smooth muscles is mediated, in part, by G protein-coupled receptors (GPCRs) and dysfunction of these receptors has been implicated in asthma. Phosphorylation of GPCRs, by G protein-coupled receptor kinase (GRK), is an important mechanism involved in the dampening of GPCR signaling. To determine whether this mechanism might play a role in airway smooth muscle physiology, we examined the airway pressure time index and heart rate (HR) responses to intravenous administration of the cholinergic agonist methacholine (MCh) in genetically altered mice lacking one copy of GRK2 (GRK2 +/-), homozygous GRK3 knockout (GRK3 -/-), and wild-type littermates. (GRK2 -/- mice die in utero.) GRK3 -/- mice demonstrated a significant enhancement in the airway response to 100 and 250 microgram/kg doses of MCh compared with wild-type and GRK2 +/- mice. GRK3 -/- mice also displayed an enhanced sensitivity of the airway smooth muscle response to MCh. In addition, GRK3 -/- mice displayed an altered HR recovery from MCh-induced bradycardia. Although direct stimulation of cardiac muscarinic receptors measured as vagal stimulation-induced bradycardia was similar in GRK3 -/- and wild-type mice, the baroreflex increase in HR associated with sodium nitroprusside-induced hypotension was significantly greater in GRK3 -/- than wild-type mice. Therefore, these data demonstrate that in the mouse, GRK3 may be involved in modulating the cholinergic response of airway smooth muscle and in regulating the chronotropic component of the baroreceptor reflex. (+info)