Prevalence of asthma in adults in Busselton,Western Australia.

OBJECTIVE--To estimate whether the prevalence of asthma in adults increased over a nine year interval. DESIGN--Serial cross sectional studies of the population with a protocol that included both subjective and objective measurements. SETTING--Busselton, Western Australia. SUBJECTS--A random sample of 553 subjects aged 18-55 years in 1981, and of 1028 subjects aged 18-55 years in 1990. MAIN OUTCOME MEASURES--Respiratory symptoms measured by self administered questionnaire, bronchial responsiveness measured by bronchial challenge with histamine, and allergy measured by skin prick tests. RESULTS--Symptoms with increased prevalence were those with significant association with allergy in this population. Recent wheeze increased from 17.5% to 28.8% (p < 0.001) and diagnosed asthma increased from 9.0% to 16.3% (p < 0.001). The increase was greatest in subjects less than 30 years old. The prevalence of shortness of breath coming on at rest and of hay fever also increased significantly, but the prevalence of shortness of breath on exertion, chronic cough, bronchial hyperresponsiveness, current asthma (defined as recent wheeze plus bronchial hyperresponsiveness), and allergy did not increase. The severity of bronchial responsiveness did not change significantly in any symptom group. CONCLUSIONS--Young adults showed a significant increase in reporting of symptoms related to allergy but not in the prevalence of current asthma. The increase in symptoms may be due to increased awareness of asthma in this community, to changed treatment patterns, or to increased exposures to allergens.     

Lymphocytes and bronchial hyperresponsiveness

Non-specific bronchial hyperresponsiveness can be defined as an increased responsiveness of the respiratory airways to physical, chemical and pharmacological stimuli. It is a characteristic feature of asthma. Knowledge of the mechanisms contributing to bronchial hyperresponsiveness can provide an insight into the pathogenesis of asthma and could lead to an improved therapy. Several abnormalities have been postulated to underlie the hyperresponsiveness, such as a beta-adrenoceptor dysfunction, hyperreactivity of airway smooth muscle, epithelial dysfunction or damage, increased reflex bronchoconstriction, mucus plugging and mucosal oedema. It is possible that more than one of these abnormalities or other, as yet unknown, mechanisms are involved. In contrast to the role of lymphocytes in the regulation of IgE antibody production, the role of these cells in bronchial hyperresponsiveness has received little attention. We review evidence indicating that lymphocytes are involved in the development of non-specific bronchial hyperresponsiveness in some animal models and in patients with asthma.     

Cyclooxygenase-2/prostaglandin D2/CRTH2 pathway mediates double-stranded RNA-induced enhancement of allergic airway inflammation

Respiratory RNA viruses responsible for the common cold often worsen airway inflammation and bronchial responsiveness, two characteristic features of human asthma. We studied the effects of dsRNA, a nucleotide synthesized during viral replication, on airway inflammation and bronchial hyperresponsiveness in murine models of asthma. Intratracheal instillation of poly I:C, a synthetic dsRNA, increased the airway eosinophilia and enhanced bronchial hyperresponsiveness to methacholine in OVA-sensitized, exposed rats. These changes were associated with induction of cyclooxygenase-2 (COX-2) expression and COX-2-dependent PGD2 synthesis in the lungs, particularly in alveolar macrophages. The direct intratracheal instillation of PGD2 enhanced the eosinophilic inflammation in OVA-exposed animals, whereas pretreatment with a dual antagonist against the PGD2 receptor-(CRTH2) and the thromboxane A2 receptor, but not with a thromboxane A2 receptor-specific antagonist, nearly completely eliminated the dsRNA-induced worsening of airway inflammation and bronchial hyperresponsiveness. CRTH2-deficient mice had the same degree of allergen-induced airway eosinophilia as wild-type mice, but they did not exhibit a dsRNA-induced increase in eosinophil accumulation. Our data demonstrate that COX-2-dependent production of PGD2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenetic factors responsible for the dsRNA-induced enhancement of airway inflammation and responsiveness.     

Effect of a cysteinyl leukotriene antagonist, pranlukast hydrate, on acetaldehyde-induced bronchoconstriction in asthmatic patients

Acetaldehyde is a main factor of alcohol-induced asthma. We previously reported that the cysteinyl leukotriene (cys-LT) receptor antagonist, pranlukast hydrate, inhibits acetaldehyde-induced airway hyperresponsiveness in guinea pigs. The purpose of this study was to evaluate the involvement of cys-LT on bronchial responsiveness to acetaldehyde in asthmatic patients. We investigated the bronchial response to inhalation of acetaldehyde in 10 asthmatic patients, who were treated with placebo or pranlukast hydrate (225.5 mg), a cys-LT receptor antagonist, twice a day for 1 wk using a double-blind, randomized, placebo-controlled, cross-over design. Although a remarkable improvement of acetaldehyde bronchoconstriction was observed in 3 out of 10 subjects, PC(20)-AcCHO values were identical between placebo [12.0 (GSEM, 1.192) mg/ml] and pranlukast [14.7 (GSEM, 1.245) mg/ml] groups. The changes in bronchial responsiveness to acetaldehyde were similar in the six patients who had never experienced alcohol-induced asthma and the four who had. In conclusion, cys-LTs are not involved in acetaldehyde-induced bronchoconstriction.     

Attenuation of antigen-induced airway hyperresponsiveness in CGRP-deficient mice

Bronchial hyperresponsiveness and eosinophilia are major characteristics of asthma. Calcitonin gene-related peptide (CGRP) is a neuropeptide that has various biological actions. In the present study, we questioned whether CGRP might have pathophysiological roles in airway hyperresponsiveness and eosinophilia in asthma. To determine the exact roles of endogenous CGRP in vivo, we chose to study antigen-induced airway responses using CGRP gene-disrupted mice. After ovalbumin sensitization and antigen challenge, we assessed airway responsiveness and measured proinflammatory mediators. In the sensitized CGRP gene-disrupted mice, antigen-induced bronchial hyperresponsiveness was significantly attenuated compared with the sensitized wild-type mice. Antigen challenge induced eosinophil infiltration in bronchoalveolar lavage fluid, whereas no differences were observed between the wild-type and CGRP-mutant mice. Antigen-induced increases in cysteinyl leukotriene production in the lung were significantly reduced in the CGRP-disrupted mice. These findings suggest that CGRP could be involved in the antigen-induced airway hyperresponsiveness, but not eosinophil infiltration, in mice. The CGRP-mutant mice may provide appropriate models to study molecular mechanisms underlying CGRP-related diseases.     

Is platelet activating factor (PAF) an important mediator in bronchial asthma?

The development of selective PAF receptor antagonists may provide a novel approach to the treatment of human bronchial asthma. In preclinical animal models of human asthma, PAF receptor antagonists have been found to be efficacious in blocking antigen-induced changes in lung function. However, the majority of these models involve acute inflammatory events and transient changes in lung function and, therefore, their relevance to human asthma is questionable. In a recent study with a primate model of chronic airway inflammation and hyperresponsiveness, we have shown that treatment with a PAF receptor antagonist had no effect on reducing chronic inflammation and hyperresponsiveness. Similarly, recent studies in human asthmatics with PAF receptor antagonists have failed to show efficacy in blocking allergen-induced airway responses or to have any steroid sparing effects in patients with ongoing asthma. Thus, it seems that PAF may not be a key mediator which can be blocked and thereby provide therapy for bronchial asthma.     

Relation of indoor heating with asthma,allergic sensitisation,and bronchial responsiveness: survey of children in south Bavaria.

OBJECTIVE--To investigate the relation between different types of heating and the prevalence of atopic diseases, skin test reactivity, and bronchial hyperresponsiveness. DESIGN--Cross sectional survey among school-children aged 9-11 years. Skin prick tests, pulmonary function tests, and bronchial challenge in the children and self completion of a written questionnaire by the children''s parents. SUBJECTS--1958 children in a rural area in southern Bavaria, Germany. MAIN OUTCOME MEASURES--Prevalence of asthma, hay fever, and atopic dermatitis as determined by parents'' answers to a questionnaire; the atopic status of the child assessed by skin prick tests; and bronchial responsiveness to cold air challenge in the children. RESULTS--After possible confounders were controlled for, the risk of developing hay fever (odds ratio = 0.57; 95% confidence interval 0.34 to 0.98), atopy defined as at least one positive reaction to a panel of common aeroallergens (0.67; 0.49 to 0.93), sensitisation to pollen (0.60; 0.41 to 0.87), and of bronchial hyperresponsiveness (0.55; 0.34-0.90) was significantly lower in children living in homes where coal or wood was used for heating than in children living in homes with other heating systems. CONCLUSIONS--Factors directly or indirectly related to the heating system used in rural Bavarian homes decrease the susceptibility of children to becoming atopic and to developing bronchial hyperresponsiveness.     

O3-induced mucosa-linked airway muscle hyperresponsiveness in the guinea pig.

We investigated the effects of ozone exposure (3.0 ppm, 2 h) on the responsiveness of guinea pig airway muscle in vitro from animals developing bronchial hyperreactivity. Muscarinic reactivity in vivo was determined by measuring specific airway resistance (sRaw) in response to increasing concentrations of aerosolized acetylcholine (ACh) administered before and 30 min after exposure. Immediately after reactivity testing, multiple tracheal rings from ozone- and air-exposed animals were prepared and the contractile responses to increasing concentrations of substance P, ACh, or KCl were assessed in the presence of 10 microM indomethacin with or without 1 microM phosphoramidon, an inhibitor of neutral endopeptidase. Isometric force generation in vitro was measured on stimulation by cumulative concentrations of the agonists, and force generation (in g/cm2) was calculated after determination of muscle cross-sectional area. The smooth muscle of mucosa-intact airways from guinea pigs with ozone-induced bronchial hyper-reactivity proved to be hyperresponsive in vitro to substance P and ACh but not to KCl. Pretreatment with phosphoramidon abolished the increase in substance P responsiveness but had no effect on muscarinic hyperresponsiveness after ozone exposure. Furthermore, substance P responsiveness was not augmented in ozone-exposed airways in which the mucosa had been removed before testing in vitro. Likewise, muscarinic hyperresponsiveness was not present in ozone-exposed airways without mucosa. Our data indicate that airway smooth muscle responsiveness is increased in guinea pigs with ozone-induced bronchial hyperreactivity and suggest that this hyperresponsiveness may be linked to non-cyclooxygenase mucosa-derived factors.     

Selenium serum and urine is associated to mild asthma and atopy. The SUS study.

To examine the associations between selenium (Se) status, asthma, bronchial hyperresponsiveness (BHR), and atopy in 154 male subjects (72 with mild asthma, 41 with BHR and 41 with no respiratory symptoms) aged 18 (range 17-22) years. Each subject underwent a medical interview and FEV1 and FVC were recorded. Histamine bronchial reactivity (Yan method) was measured, skin prick test (inhalant allergens) was performed and Se in urine and serum was analysed (AOAC modified fluometric method). Se in serum 74.04 (10.58) micrograms/L (mean (SD)) was lower in subjects with asthma and the logarithm of the ratio of Se in serum (microgram/L) and urine standardised to creatinine excretion (ng/mg creatinine) 0.748 (0.096) (mean (SD)) was lower in subjects with asthma and atopy compared to subjects with no allergic symptoms 77.79 (10.16) micrograms/L and 0.808 (0.111) respectively (p < 0.05). In subjects with asthma atopy was significantly associated to urine Se 0.24 (0.73) (beta (SE)) (p < 0.05). Subjects with BHR had the same Se status as subjects with no respiratory symptoms and heavy smokers had a lower concentration of Se in serum 73.80 (9.56) micrograms/L than non-smokers 78.16 (10.74) micrograms/L (p < 0.05), Se status was associated to asthma and smoking. Measuring Se in urine might add further information to possible relations between Se status, atopy and asthma.     

Absence of leukotriene B4 receptor 1 confers resistance to airway hyperresponsiveness and Th2-type immune responses

Bronchial asthma is an increasingly common disorder that remains poorly understood and difficult to manage. The disease is characterized by airway hyperresponsiveness, chronic inflammation, and mucus overproduction. Based on the finding that leukotriene B4 receptor 1 (BLT1) is expressed highly in Th2 lymphocytes, we analyzed the roles of BLT1 using an OVA-induced bronchial asthma model. BLT1-null mice did not develop airway hyperresponsiveness, eosinophilic inflammation, and hyperplasia of goblet cells. Attenuated symptoms were accompanied by reduced IgE production, and accumulation of IL-5 and IL-13 in bronchoalveolar lavage fluid, suggesting attenuated Th2-type immune response in BLT1-null mice. Peribronchial lymph node cells of sensitized BLT1-null mice showed much attenuated proliferation and production of Th2 cytokines upon re-stimulation with Ag in vitro. Thus, LTB4-BLT1 axis is required for the development of Th2-type immune response, and blockade of LTB4 functions through BLT1 would be novel and useful in the effort to ameliorate bronchial asthma and related Th2-biased immune disorders.     

In vivo PAF-induced airway eosinophil accumulation reduces bronchial responsiveness to inhaled histamine

Chronic eosinophilic bronchitis and bronchial hyperresponsiveness have been considered to be the fundamental features of bronchial asthma. However, the role of airway eosinophils in bronchial responsiveness in vivo has not been fully discussed. The aim of this study was to investigate the direct effect of airway eosinophil accumulation on bronchial responsiveness in vivo. Guinea pigs were transnasally treated with platelet activating factor (PAF) or vehicle twice a week for a total of 3 weeks. Anesthetized guinea pigs were surgically cannulated and artificially ventilated 48 h after the last administration of PAF or vehicle. Ten minutes after the installation of artificial ventilation, ascending doses of histamine were inhaled. In a subsequent study, selective inhibitors of diamine oxidase and histamine N-methyltransferase were intravenously administered before the histamine inhalation in the PAF-treated animals. Next study was conducted 20 min after treatment with indomethacin in this study line. Finally, ascending doses of methacholine were inhaled in our animal model. Proportion of eosinophils and the number of nuclear segmentation in bronchoalveolar lavage fluid significantly increased in guinea pigs treated with PAF compared with vehicle and this finding was confirmed histologically. Nevertheless, bronchial responsiveness to inhaled histamine, but not methacholine, was significantly decreased by the PAF treatment. This bronchoprotective effect induced by PAF remained following aminoguanidine and histamine N-methyltransferase administration, but abolished by treatment of indomethacin. These results suggest that in vivo airway eosinophils may reduce nonspecific bronchial responsiveness through production of inhibitory or bronchoprotective prostanoids, but not through histaminase production.     

Factors Associated with the Perception of Speed among Recreational Skiers

Background

Skiers have to differ between slow to moderate and fast skiing speed to determine their skiing style according to the ISO 11088 standard for setting binding release values. Despite existing evidence that males ski significantly faster than females, no sex-specific factor was inserted into the ISO 11088 standard.

Objective

To evaluate factors potentially associated with the perception of individual skiing speed among recreational skiers.

Methods

Skiing speeds of 416 adult skiers (62% males,) were measured with a radar speed gun. Skiers were interviewed about their age, sex, skill level, risk taking behaviour and helmet use. Finally, skiers had to rate their perceived speed on one out of three speed categories (fast, moderate, slow).

Results

The measured mean speed of this cohort was 48.2±14.3 km/h (30.0±8.9 mph). A total of 32%, 52%, and 16% of skiers perceived their actual speed as fast, moderate and slow, respectively. Mean speed differed significantly between the 3 speed categories with a mean of about 53.5±13.7 km/h (33.2±8.5 mph) for fast, 47.6±14.0 km/h (29.6±8.7 mph) for moderate, and 39.4±12.2 km/h (24.5±7.6 mph) for slow skiing, respectively. Sex (η² = .074), skill level (η² = .035) and risk taking behavior (η² = .033) showed significant differences of skiing speeds with regard to the 3 categories of speed perception (all p < .001) while age groups and ski helmet use did not. Males, more skilled skiers and risky skiers perceived their actual speed as fast, moderate and slow, when skiing up to 10 km/h (6 mph) faster compared to females, less skilled and cautious skiers.

Conclusion

The perception of skiing speed as fast, moderate or slow depends on sex, skill level, and risk taking behaviour. These findings should be considered when discussing the introduction of a sex factor into the ISO 11088 standard for setting binding release values.     

Involvement of p42/44 MAPK and RhoA protein in augmentation of ACh-induced bronchial smooth muscle contraction by TNF-alpha in rats.

Bronchial asthma is characterized by chronic inflammation of airway tissues and nonspecific airway hyperresponsiveness (AHR), but the underlying mechanisms of AHR have yet to be elucidated. Recently, tumor necrosis factor-alpha (TNF-alpha) has been identified as a proinflammatory cytokine that might be important in the hyperresponsiveness of airway tissue. We have investigated the effects of SB-203580 (a p38 MAPK inhibitor), U-0126 (an inhibitor of p42/44 MAPK activation), and cycloheximide (an inhibitor of protein synthesis) on TNF-alpha-augmented ACh-induced bronchial smooth muscle contraction. We have also investigated the phosphorylation of p42/44 MAPK and upregulation of RhoA protein by TNF-alpha. Treatment of rat bronchial smooth muscles with TNF-alpha (300 and 1,000 ng/ml for 24 h) resulted in a significant upward shift in the concentration-response curve to ACh, but not to high K(+), compared with control tissues. The effect of TNF-alpha was completely blocked by pretreatment with U-0126 or cycloheximide, but not with SB-203580. Immunoblotting demonstrated that p42/44 MAPK was phosphorylated and RhoA protein was increased in bronchial tissue by TNF-alpha. Furthermore, the TNF-alpha-induced upregulation of RhoA protein was abolished by U-0126 pretreatment. In conclusion, we suggest that TNF-alpha might be one of the important mediators involved in the pathogenesis of augmented bronchial smooth muscle contractility in AHR. For the first time, we have demonstrated that augmentation of ACh-induced contractile response evoked by TNF-alpha was mediated by synthesis of protein, such as RhoA, through activation of p42/44, but not p38 MAPK, in rat bronchial smooth muscle.     

Assessment of plasma opioid peptides, beta-endorphin and met-enkephalin, at the end of an international nordic ski race

Plasma met-enkephalin, beta-endorphin, cortisol and lactic acid concentrations were measured in seventeen volunteer male subjects at rest and after a long-distance nordic ski race. Immediately after the race, mean plasma met-enkephalin did not show any significant change, but significant rises in beta-endorphin, cortisol and lactic acid were noted in all skiers. The change in beta-endorphin with exercise was significantly related to the change in cortisol (r = 0.68; p less than 0.001) and to the change in plasma lactic acid (r = 0.60; p less than 0.001). Furthermore, the experienced skiers training over 150 km X week-1 of nordic ski had significantly faster skiing times in this event and showed greater beta-endorphin, cortisol and lactic acid levels than the recreational skiers who trained for 20 km X week-1. Our results imply that the changes in plasma beta-endorphin depend on the intensity of exercise. However the significance of higher levels of skiing training or previous nordic ski experience in the release of beta-endorphin is expected and cannot be excluded.     

Correlation between airway responsiveness and proteoglycan production by bronchial fibroblasts from normal and asthmatic subjects

Asthma is characterized by an airway remodeling process involving altered extracellular matrix deposition such as collagen, fibronectin and proteoglycans. Proteoglycans determine tissue mechanical properties and are involved in many important biological aspects. Not surprisingly, it has been suggested that proteoglycan deposition may alter airway properties in asthma including airway hyperresponsiveness. In chronically inflamed airway tissues, fibroblasts likely represent an activated fibrotic phenotype that contributes to the excessive deposition of different extracellular matrix components. To investigate whether this was the case for proteoglycans, the production of hyaluronan, perlecan, versican, small heparan sulphate proteoglycans (HSPGs), decorin and biglycan was quantified in the culture medium of primary bronchial fibroblast cultures, established from four normal and six asthmatic subjects. Values were further correlated to the airway responsiveness (PC(20) methacholine) of donor subjects. Fibroblasts from subjects with the most hyperresponsive airways produced up to four times more total proteoglycans than cells from subjects with less hyperresponsive or normoresponsive airways. We observed a significant negative correlation between the PC(20) and perlecan, small HSPGs and biglycan, while such correlation was absent for decorin and close to significant for hyaluronan and versican. Altered proteoglycan metabolism by bronchial fibroblasts may contribute to the increased proteoglycan deposition in the bronchial mucosa and to airway hyperresponsiveness characterizing asthma.     

Lovastatin inhibits bronchial hyperresponsiveness by reducing RhoA signaling in rat allergic asthma

Recent studies revealed an importance of a monomeric GTP-binding protein, RhoA, in contraction of bronchial smooth muscle (BSM). RhoA and its downstream have been proposed as a new target for the treatment of airway hyperresponsiveness in asthma. Statins are known to inhibit the functional activation of RhoA via the depletion of geranylgeranylpyrophosphate. To determine the beneficial effects of statins on the airway hyperresponsiveness in allergic bronchial asthma, we investigated the effects of systemic treatment with lovastatin on the augmented BSM contraction and activation of RhoA in rats with allergic bronchial asthma. Rats were sensitized and repeatedly challenged with 2,4-dinitrophenylated Ascaris suum antigen. Animals were also treated with lovastatin (4 mg kg(-1) day(-1) ip) once a day before and during the antigen inhalation period. Repeated antigen inhalation caused a marked BSM hyperresponsiveness to ACh with the increased expression and translocation of RhoA. Lovastatin treatments significantly attenuated both the augmented contraction and RhoA translocation to the plasma membrane. Lovastatin also reduced the increased cell number in bronchoalveolar lavage fluids and histological changes induced by antigen exposure, whereas the levels of immunoglobulin E in sera and interleukins-4, -6, and -13 in bronchoalveolar lavage fluids were not significantly changed. These findings suggest that lovastatin ameliorates antigen-induced BSM hyperresponsiveness, an important factor of airway hyperresponsiveness in allergic asthmatics, probably by reducing the RhoA-mediated signaling.     

Airway responses in offspring of dogs with and without airway hyperreactivity

We examined airway responsiveness to aerosols of Ascaris suum, citric acid, and methacholine chloride in the offspring of two highly allergic breeds of dogs: Basenji-greyhounds (BG) and Basenjis (B). The BG parents had airway hyperresponsiveness to citric acid and methacholine, whereas the B parents did not. Both BG and B offspring were allergic as measured by many positive skin tests. BG offspring, like their parents, were hyperresponsive to citric acid and methacholine, whereas B offspring were not. We conclude that familial rather than environmental factors are important for the development of nonspecific airway hyperresponsiveness as well as allergy in the BG dog model of asthma. Allergic asthma in these animals represents a combination of two discrete processes: allergy and nonspecific airway hyperresponsiveness.     

Cytokines, from atopy to asthma: the Th2 dogma revisited.

Asthma is a spreading condition in Western countries, in most cases in relationship with atopy. Atopy is defined by an individual predisposition to develop allergic diseases in response to environmental allergens. The atopic immune system is characterized by a Th2 deviation determined by genetic and environmental factors. Among these factors, the role of allergen exposure, dietary behavior, air pollution and early exposure to microbes is discussed. In asthma, a Th2 cell activation is evident, but is accompanied by a Tc1 cell activation. These Tc1 cells probably down-regulate Th2 cells, but are also relevant to the bronchial hyperresponsiveness characterizing asthma. We propose that Tc1 activation in asthma could be the link between allergy and bronchial hyperresponsiveness.     

Effect of thromboxane A2 (TXA2) synthase inhibitor and TXA2 receptor antagonist alone and in combination on antigen-induced bronchoconstriction in guinea pigs

Thromboxane A2 (TXA2) causes bronchoconstriction and bronchial hyperresponsiveness. Two types of TXA2 modifiers, one synthase inhibitor and one receptor antagonist, are widely used for the treatment of asthma in Japan. Although the target of TXA2 modifiers is to inhibit bioactivity of TXA2, the pharmacological properties are somewhat different between these drugs. We studied the inhibitory effects of the TXA2 synthase inhibitor CS-518 and the TXA2 receptor antagonist S-1452 alone and in combination on antigen-induced bronchoconstriction in passively sensitized guinea pigs treated with diphenhydramine. Both CS-518 and S-1452 inhibited the antigen-induced bronchoconstriction dose-dependently with the plateau. The combination of these drugs at the maximal inhibitory doses did not have any more effect compared with each single dosing. The combination at the submaximal doses tended to show an additive effect, but the effect was not significant. These findings suggest that other prostanoids such as PGE2, PGI2, PGD2 and PGF2alpha may not take an important role in the antiasthmatic effects of TXA2 modifiers.