Prolonged eosinophil accumulation in allergic lung interstitium of ICAM-2 deficient mice results in extended hyperresponsiveness.
ICAM-2-deficient mice exhibit prolonged accumulation of eosinophils in lung interstitium concomitant with a delayed increase in eosinophil numbers in the airway lumen during the development of allergic lung inflammation. The ICAM-2-dependent increased and prolonged accumulation of eosinophils in lung interstitium results in prolonged, heightened airway hyperresponsiveness. These findings reveal an essential role for ICAM-2 in the development of the inflammatory and respiratory components of allergic lung disease. This phenotype is caused by the lack of ICAM-2 expression on non-hematopoietic cells. ICAM-2 deficiency on endothelial cells causes reduced eosinophil transmigration in vitro. ICAM-2 is not essential for lymphocyte homing or the development of leukocytes, with the exception of megakaryocyte progenitors, which are significantly reduced. (+info)
Dose-response slope of forced oscillation and forced expiratory parameters in bronchial challenge testing.
In population studies, the provocative dose (PD) of bronchoconstrictor causing a significant decrement in lung function cannot be calculated for most subjects. Dose-response curves for carbachol were examined to determine whether this relationship can be summarized by means of a continuous index likely to be calculable for all subjects, namely the two-point dose response slope (DRS) of mean resistance (Rm) and resistance at 10 Hz (R10) measured by the forced oscillation technique (FOT). Five doses of carbachol (320 microg each) were inhaled by 71 patients referred for investigation of asthma (n=16), chronic cough (n=15), nasal polyposis (n=8), chronic rhinitis (n=8), dyspnoea (n=8), urticaria (n=5), post-anaphylactic shock (n=4) and miscellaneous conditions (n=7). FOT resistance and forced expiratory volume in one second (FEV1) were measured in close succession. The PD of carbachol leading to a fall in FEV1 > or = 20% (PD20) or a rise in Rm or R10 > or = 47% (PD47,Rm and PD47,R10) were calculated by interpolation. DRS for FEV1 (DRSFEV1), Rm (DRSRm) and R10 (DRSR10) were obtained as the percentage change at last dose divided by the total dose of carbachol. The sensitivity (Se) and specificity (Sp) of DRSRm, DRS10 delta%Rm and delta%R10 in detecting spirometric bronchial hyperresponsiveness (BHR, fall in FEV1 > or = 20%) were assessed by receiver operating characteristic (ROC) curves. There were 23 (32%) "spirometric" reactors. PD20 correlated strongly with DRSFEV1 (r=-0.962; p=0.0001); PD47,Rm correlated significantly with DRSRm (r=-0.648; p=0.0001) and PD47,R10 with DRSR10 (r=-0.552; p=0.0001). DRSFEV1 correlated significantly with both DRSRm (r=0.700; p=0.0001) and DRSR10 (r=0.784; p=0.0001). The Se and Sp of the various FOT indices to correctly detect spirometric BHR were as follows: DRSRm: Se=91.3%, Sp=81.2%; DRSR10: Se=91.3%, Sp=95.8%; delta%Rm: Se=86.9%, Sp=52.1%; and delta%R10: Se=91.3%, Sp=58.3%. Dose-response slopes of indices of forced oscillation technique resistance, especially the dose-response slope of resistance at 10Hz are proposed as simple quantitative indices of bronchial responsiveness which can be calculated for all subjects and that may be useful in occupational epidemiology. (+info)
Exhaled and nasal NO levels in allergic rhinitis: relation to sensitization, pollen season and bronchial hyperresponsiveness.
Exhaled nitric oxide is a potential marker of lower airway inflammation. Allergic rhinitis is associated with asthma and bronchial hyperresponsiveness. To determine whether or not nasal and exhaled NO concentrations are increased in allergic rhinitis and to assess the relation between hyperresponsiveness and exhaled NO, 46 rhinitic and 12 control subjects, all nonasthmatic nonsmokers without upper respiratory tract infection, were randomly selected from a large-scale epidemiological survey in Central Norway. All were investigated with flow-volume spirometry, methacholine provocation test, allergy testing and measurement of nasal and exhaled NO concentration in the nonpollen season. Eighteen rhinitic subjects completed an identical follow-up investigation during the following pollen season. Exhaled NO was significantly elevated in allergic rhinitis in the nonpollen season, especially in perennially sensitized subjects, as compared with controls (p=0.01), and increased further in the pollen season (p=0.04), mainly due to a two-fold increase in those with seasonal sensitization. Nasal NO was not significantly different from controls in the nonpollen season and did not increase significantly in the pollen season. Exhaled NO was increased in hyperresponsive subjects, and decreased significantly after methacholine-induced bronchoconstriction, suggesting that NO production occurs in the peripheral airways. In allergic rhinitis, an increase in exhaled nitric oxide on allergen exposure, particularly in hyperresponsive subjects, may be suggestive of airway inflammation and an increased risk for developing asthma. (+info)
Exhaled nitric oxide; relationship to clinicophysiological markers of asthma severity.
Bronchial asthma is an airway disorder associated with bronchial hyperresponsiveness, variable airflow obstruction and elevated levels of nitric oxide (NO) in exhaled air. The variables all reflect, in part, the underlying airway inflammation in this disease. To understand their interrelationships we have investigated the relationship between exhaled NO levels and clinicophysiological markers of asthma severity. Twenty-six steroid naive atopic asthmatics participated in the analysis. All were given diary cards and were asked to record their peak expiratory flow (PEF) rates twice daily together with their asthma symptom scores and beta-agonist use. Diary cards were collected 2 weeks later and measurements of exhaled NO levels, FEV1 and histamine bronchial hyperreactivity (PC20 histamine) were undertaken. Exhaled NO levels were significantly higher in our study population than in normal control subjects and correlated negatively with PC20 histamine (r = -0.51; P = 0.008) and positively with PEF diurnal variability (r = 0.58; P = 0.002), but not with symptom scores, beta-agonist use of FEV1 (%). We conclude that a significant relationship exists between exhaled NO levels and the two characteristic features and markers of asthma severity, namely bronchial hyperreactivity and PEF diurnal variability. The lack of correlation between symptom score and beta-agonist use, of FEV1 (%) predicted and exhaled NO suggests that these measures are reflective of differing aspects of asthma. (+info)
IL-5 and eosinophils are essential for the development of airway hyperresponsiveness following acute respiratory syncytial virus infection.
Viral respiratory infections can cause bronchial hyperresponsiveness and exacerbate asthma. In mice, respiratory syncytial virus (RSV) infection, which induces an immune response dominated by IFN-gamma, results in airway hyperresponsiveness (AHR) and eosinophil influx into the airways, both of which are prevented by pretreatment with anti-IL-5 Ab. To delineate the role of IL-5, IL-4, and IFN-gamma in the development of RSV-induced AHR and lung eosinophilia, we tested the ability of mice deficient in each of these cytokines to develop these symptoms of RSV infection. Mice deficient in either IL-5, IL-4, or IFN-gamma were administered infectious RSV intranasally, and 6 days later, airway responsiveness to inhaled methacholine was assessed by barometric body plethysmography, and numbers of lung eosinophils and production of IFN-gamma, IL-4, and IL-5 by mononuclear cells from peribronchial lymph nodes were monitored. RSV infection resulted in airway eosinophilia and AHR in both IL-4- and IFN-gamma-deficient mice, but not in IL-5-deficient mice. Reconstitution of IL-5-deficient mice with IL-5 restored these responses and enhanced the responses in IL-4-deficient mice. Anti-VLA-4 (very late Ag-4) treatment prevented lung eosinophilia and AHR following RSV infection and IL-5 reconstitution. We conclude that in response to RSV, IL-5 is essential for the influx of eosinophils into the lung and that eosinophils in turn are critical for the development of AHR. IFN-gamma and IL-4 are not essential for these responses to RSV infection. (+info)
Effect of inhaled corticosteroids on bronchial responsiveness in patients with "corticosteroid naive" mild asthma: a meta-analysis.
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.
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)
Update on the "Dutch hypothesis" for chronic respiratory disease.
BACKGROUND: Many patients with chronic obstructive lung disease show increased airways responsiveness to histamine. We investigated the hypothesis that increased airways responsiveness predicts the development and remission of chronic respiratory symptoms. METHODS: We used data from 24-year follow-up (1965-90) of 2684 participants in a cohort study in Vlagtwedde and Vlaardingen, Netherlands. Increased airways responsiveness was defined as a PC10 value (concentration of histamine for which challenge led to a 10% fall in forced expiratory volume in 1 s) of less than 8 mg/ml. Information on respiratory symptoms was collected by means of a standard questionnaire every 3 years. Logistic regression was used to control for age, area of residence, cigarette smoking status, and sex. FINDINGS: Participants with increased airways responsiveness (1281 observations) were more likely than those without increased airways responsiveness (5801 observations) to develop the following symptoms during any 3-year follow-up interval: chronic cough (odds ratio 1.9 [95% CI 1.2-2.9]), chronic phlegm (2.0 [1.3-3.0]), dyspnoea (2.3[1.5-3.5]), asthmatic attacks (3.7[2.2-6.1]), and persistent wheeze (2.7[1.7-4.4]). The estimate of the odds ratio for the development of any of the six symptoms was 1.7 (1.2-2.3). Participants with increased airways responsiveness were less likely than those without this characteristic to show remission of these respiratory symptoms. The estimate of the odds ratio for the remission of any of the six symptoms was 0.42 (0.28-0.61). INTERPRETATION: These prospective analyses show that increased airways responsiveness is positively associated with the development of chronic respiratory symptoms and negatively associated with the remission of these symptoms in adults. (+info)