Measurements Of Airway Responsiveness Research Articles

The Influence of Sensitization on Mechanisms of Organophosphorus Pesticide–Induced Airway Hyperreactivity

We previously demonstrated that antigen sensitization increases vulnerability to airway hyperreactivity induced by the organophosphorus pesticide (OP) parathion. Sensitization also changes the mechanism of parathion-induced airway hyperreactivity to one that is dependent on IL-5. To determine whether this effect can be generalized to other OPs, and to other classes of pesticides, we measured airway responsiveness to vagal stimulation or intravenous acetylcholine in nonsensitized and ovalbumin-sensitized guinea pigs 24 hours after a single subcutaneous injection of the OPs diazinon or chlorpyrifos, or the pyrethroid permethrin. Sensitization exacerbated the effects of chlorpyrifos on bronchoconstriction in response to vagal stimulation or intravenous acetylcholine. Pretreatment with function-blocking IL-5 antibody prevented chlorpyrifos-induced airway hyperreactivity in sensitized, but not in nonsensitized, guinea pigs. In sensitized guinea pigs, blocking IL-5 decreased eosinophil activation, as measured by decreased eosinophil major basic protein in the trachea. In contrast, sensitization did not alter diazinon-induced airway hyperreactivity, and permethrin did not cause airway hyperreactivity in either nonsensitized or sensitized guinea pigs. None of the pesticides affected inflammatory cells in the bronchoalveolar lavage fluid or blood. We have previously shown that three different OPs cause airway hyperreactivity via loss of neuronal M2 muscarinic receptor function. Similar to parathion, but unlike diazinon, the mechanism of chlorpyrifos-induced airway hyperreactivity is changed by sensitization. Thus, OP-induced airway hyperreactivity is dependent on sensitization status and on the OP used, which may influence therapeutic approaches.

Sevoflurane inhibits nuclear factor-κB activation in lipopolysaccharide-induced acute inflammatory lung injury via toll-like receptor 4 signaling.

BackgroundInfection is a common cause of acute lung injury (ALI). This study was aimed to explore whether Toll-like receptors 4 (TLR4) of airway smooth muscle cells (ASMCs) play a role in lipopolysaccharide (LPS)-induced airway hyperresponsiveness and potential mechanisms.Methods In vivo: A sensitizing dose of LPS (50 µg) was administered i.p. to female mice before anesthesia with either 3% sevoflurane or phenobarbital i.p. After stabilization, the mice were challenged with 5 µg of intratracheal LPS to mimic inflammatory attack. The effects of sevoflurane were assessed by measurement of airway responsiveness to methacholine, histological examination, and IL-1, IL-6, TNF-α levels in bronchoalveolar lavage fluid (BALF). Protein and gene expression of TLR4 and NF-κB were also assessed. In vitro: After pre-sensitization of ASMCs and ASM segments for 24h, levels of TLR4 and NF-κB proteins in cultured ASMCs were measured after continuous LPS exposure for 1, 3, 5, 12 and 24h in presence or absence of sevoflurane. Constrictor and relaxant responsiveness of ASM was measured 24 h afterwards.ResultsThe mRNA and protein levels of NF-κB and TLR4 in ASM were increased and maintained at high level after LPS challenge throughout 24h observation period, both in vivo and in vitro. Sevoflurane reduced LPS-induced airway hyperresponsiveness, lung inflammatory cell infiltration and proinflammatory cytokines release in BALF as well as maximal isometric contractile force of ASM segments to acetylcholine, but it increased maximal relaxation response to isoproterenol. Treatment with specific NF-κB inhibitor produced similar protections as sevoflurane, including decreased expressions of TLR4 and NF-κB in cultured ASMCs and improved pharmacodynamic responsiveness of ASM to ACh and isoproterenol.ConclusionsThis study demonstrates the crucial role of TLR4 activation in ASMCs during ALI in response to LPS. Sevoflurane exerts direct relaxant and anti-inflammatory effects in vivo and in vitro via inhibition of TLR4/NF-κB pathway.

Omalizumab therapy for asthma patients with poor adherence to inhaled corticosteroid therapy

BackgroundOmalizumab, an anti-IgE monoclonal antibody, is administered by injection once or twice monthly in offices and clinics. It offers a potential alternative intervention for patients with allergic asthma that is not well controlled because of recalcitrant poor adherence to inhaled corticosteroid therapy. ObjectiveTo assess the effect of omalizumab therapy by measuring airway responsiveness to adenosine, a marker of allergic airway inflammation, and resource use. MethodsPatients (N = 17) aged 6 to 26 years (mean age, 16.4 years) with poorly controlled persistent allergic asthma, less than 50% adherence to inhaled corticosteroid therapy, a forced expiratory volume in 1 second (FEV1) of 60% predicted or higher, and adenosine provocation concentration that caused a decrease in FEV1 of 20% (PC20) of 60 mg/mL or less were randomized to receive 4 months of omalizumab or placebo in a double-blind, crossover trial with a 3- to 4-month washout between treatments. Patients were instructed to continue taking inhaled corticosteroids throughout the study. The PC20 was measured before and after each period. ResultsFifteen patients completed the study. The mean baseline PC20 was 14.1 mg/mL (95% CI, 10.8–18.4 mg/mL). The fold change PC20 was 0.9 (95% CI, 0.5–1.7) during placebo and 3.1 (95% CI, 1.6–6.2) during omalizumab treatment; the estimated ratio was 3.4 (95% CI, 1.2–9.3; P = .02). Six patients required one or more short courses of oral corticosteroids for asthma exacerbations during placebo, but none required this intervention during omalizumab. During the study, the median prescription refills for inhaled corticosteroids was 0.15 (95% CI, 0.00–0.33) canisters per month. ConclusionOmalizumab therapy is an alternative for patients with more severe poorly controlled asthma in whom adherence does not improve with conventional interventions. Trial Registrationclinicaltrials.gov Identifier: NCT00133042.

P132 Cleaner's Asthma : Now You See It, Now You Don't

A number of epidemiological investigations have identified asthma prevalence in cleaners around 1.5–2.0 times those of reference populations. There are around 700,000 cleaners in the UK, asthma prevalence is around 8%, and that suggests a high burden of work-related disease. However, a clinical diagnosis of occupational asthma in cleaners is established relatively rarely. We have investigated the hypothesis that this discrepancy occurs because cleaner’s asthma is a form of low dose irritant asthma that is visible to epidemiologists but does not have the typical clinical features of occupational asthma. A questionnaire was sent to 1400 cleaners working in local hospitals and universities. 14% had a previous diagnosis of asthma, and in 32% of these the asthma started after they began work as a cleaner. Investigations for possible occupational asthma comprised paired measurements of airway responsiveness at and away from work (n = 13), serial PEF analysed using OASYS-2 (n = 13) and a structured clinical history (n = 10). 5 subjects had a greater than 3 fold improvement in PD20 away from work, and 2 subjects had OASYS score >2.5 indicating a probable occupational effect. 1 subject had both. The clinical histories were sent to 9 physicians with an interest in occupational asthma who were asked to score them for the likelihood of occupational asthma on a scale 0 to100% with and without the OASYS scores and the airway responsiveness measurements. Before seeing the investigation results, 7 of the 90 individual scores (9 physicians x 10 subjects) were above 50% indicating that the diagnosis of occupational asthma was thought likely. After seeing the investigation results, 29 of the 90 scores were above 50%. The mean probability score based on the history alone did not exceed 50% for any cleaner but was above 50% for 2 cleaners when the investigations were taken into account. These findings support the view that cleaner’s asthma has features that make it difficult to identify from the clinical history.

Integrating COPD care in Italy.

Doctors are not short of advice about how to manage their patients. In the case of COPD (Chronic Obstructive Pulmonary Disease) there are a wealth of guidelines, strategies and position papers synthesising an increasing body of data from observational studies and clinical trials into schemes that should help the doctor care for their COPD patients more effectively. In recent years particular attention has been paid to the views of the joint ERS/ATS COPD guidelines [1] and the regularly updated recommendations of the Global initiative for chronic Obstructive Lung Disease (GOLD) [2]. Now a new Italian document has been developed representing the combined efforts of three key Italian respiratory societies AIMAR, AIPO, SIMeR and the society of General Practice, SIMG, whose combined expertise covers almost all those who offer care to the COPD patient. So what does this new guidance tell us and does it add to what we have heard already? Appropriately this new document takes a very wide view of the problems of COPD. It emphasises the need for early accurate diagnosis supported when needed but supplementary physiological investigations such as the measurement of lung volumes and airway responsiveness. It points out the limitations of relying on a fixed FEV1/FVC ratio of 70% or less to support the diagnosis of COPD and suggest instead that the lower limit of normal (LLN) for this ratio is a more reliable guide. There might have been a little more advice for the busy clinician on the best way of accessing appropriate LLN data and perhaps a little more caution on the usefulness of bronchodilator testing in patient evaluation [3]. However there are some excellent figures to guide diagnosis and management as well as useful tabular summaries of what tests should be undertaken by which clinicians and how to approach smoking cessation. The authors have avoided some of the controversy and uncertainty surrounding the new GOLD severity assessment scheme [4], instead focussing on patient sub-groups that correspond to those seen in clinical practice and in clinical trials. Their treatment recommendations are not formally evidence based but closely follow those in guidelines where more extensive evidence evaluations have been conducted [5]. The authors offer clear practical guidance with support from selected but relevant literature citations which help the clinician understand why particular treatment choices have been made. There is an appropriate and pragmatic section emphasising the value of pulmonary rehabilitation together with a particularly helpful review of the role of telemedicine in COPD care, a topic scarcely touched on in other guidelines. This new approach to COPD care is needed in Italy now. As the authors point out, COPD remains a major health problem despite much good work to increase smoking cessation rates and improve air quality. International guidelines offer an overview of COPD care in all settings but there is still a need to develop management strategies which work locally and reflect the needs and perceptions of local physicians and patients. This new initiative has achieved both of these goals admirably.

The potential to predict the course of childhood asthma

Many children experience pre-school or early childhood wheezing. In a significant proportion symptoms disappear as the child grows, but others have persistent and troublesome asthma which can be life-long. Tools to predict course of disease in young children are a priority for families and clinicians. This review summarizes evidence from several longitudinal population-based birth-cohort studies that have identified risk factors for persistence and remission of childhood asthma. These factors include clinical characteristics, environmental and other exposures, familial factors, biomarkers of allergic inflammation, measurements of lung function and airway responsiveness, and genetic variants. This review also introduces the concept of polygenic risk and genetic risk scores, and describes results from a recent study that suggests promise for the use of genetic information in predicting the course of childhood asthma. We conclude with a discussion of implications and future directions.

Respiratory Medicine at McMaster University, Hamilton, Ontario: 1968 To 2013

The medical school at McMaster University (Hamilton, Ontario) was conceived in 1965 and admitted the first class in 1969. John Evans became the founding Dean and he invited Moran Campbell to be the first Chairman of the Department of Medicine. Moran Campbell, already a world figure in respiratory medicine and physiology, arrived at McMaster in September 1968, and he invited Norman Jones to be Coordinator of the Respiratory Programme.At that time, Hamilton had a population of 300,000, with two full-time respirologists, Robert Cornett at the Hamilton General Hospital and Michael Newhouse at St Joseph’s Hospital. From the clinical perspective, the aim of the Respiratory Programme was to develop a network approach to clinical problems among the five hospitals in the Hamilton region, with St Joseph’s Hospital serving as a regional referral centre, and each hospital developing its own focus: intensive care and burns units at the Hamilton General Hospital; cancer at the Henderson (later Juravinski) Hospital; tuberculosis and rehabilitation at the Chedoke Hospital; pediatrics and neonatal intensive care at the McMaster University Medical Centre; and community care at the Joseph Brant Hospital in Burlington (Ontario). The network provided an ideal base for a specialty residency program. There was also the need to establish viable research.These objectives were achieved through collaboration, support of hospital administration, and recruitment of clinicians and faculty, mainly from our own trainees and research fellows. By the mid-1970s the respiratory group numbered more than 25; outpatient clinic visits and research had grown beyond our initial expectations. The international impact of the group became reflected in the clinical and basic research endeavours.ASTHMA: Freddy Hargreave and Jerry Dolovich established methods to measure airway responsiveness to histamine and methacholine. Allergen inhalation was shown to increase airway responsiveness for several weeks, and the late response was shown to be an immunoglobulin E-mediated phenomenon. Paul O’Byrne and Gail Gauvreau showed that the prolonged allergen-induced responses were due to eosinophilic and basophilic airway inflammation and, with Judah Denburg, revealed upregulation of eosinophil/basophil progenitor production in bone marrow and airways. The Firestone Institute became the centre of studies identifying the inflammatory pheno-type of patients with difficult-to-control asthma. Freddy Hargreave and others developed methods for sputum induction to identify persisting eosinophilic airway inflammation and documented its presence in the absence of asthma and in patients with persistent cough. Parameswaran Nair has applied these techniques to the management of asthma in routine clinical practice. The Asthma Quality of Life Questionnaire and the Asthma Control Tests were developed by Drs Liz Juniper and Gordon Guyatt. The first Canadian evidence-based clinical guidelines for asthma management in 1989 were coordinated by Freddy Hargreave, Jerry Dolovich and Michael Newhouse.DISTRIBUTION OF INHALED PARTICLES: Michael Newhouse and Myrna Dolovich used inhaled radiolabelled aerosols to study the distribution of inhaled particles and their clearance in normal subjects, smokers and patients with chronic obstructive pulmonary disease. They developed the aerochamber, and were the first to radiolabel therapeutic aerosols to distinguish the effects of peripheral versus central deposition. Particle deposition and clearance were shown to be impaired in ciliary dyskinesia and cystic fibrosis.DYSPNEA: Moran Campbell and Kieran Killian measured psychophysical estimates of the sense of effort in breathing in studies of loaded breathing and exercise to show that dyspnea increased as a power function of both duration and intensity of respiratory muscle contraction, and in relation to reductions in respiratory muscle strength. These principles also applied to dyspnea in cardiorespiratory disorders.EXERCISE CAPACITY: Norman Jones and Moran Campbell developed a system for noninvasive cardiopulmonary exercise testing using an incremental exercise test, and more complex studies with measurement of mixed venousPCO2by rebreathing. The 6 min walk test was validated by Gordon Guyatt. Kieran Killian and Norman Jones introduced routine muscle strength measurements in clinical testing and symptom assessment in exercise testing. Muscle strength training improved exercise capacity in older subjects and patients with chronic obstructive pulmonary disease.METABOLISM AND ACID-BASE CONTROL IN EXERCISE: After showing that imposed acidosis reduced, and alkalosis improved performance, Norman Jones, John Sutton and George Heigenhauser investigated the interactions between acid-base status and metabolism in exercise.HIGH-ALTITUDE MEDICINE: John Sutton and Peter Powles participated in high-altitude research on Mount Logan (Yukon), demonstrating sleep hypoxemia in acute mountain sickness and its reversal by acetazol-amide, and participated in Operation Everest II.EPIDEMIOLOGY: David Pengelly and Tony Kerrigan followed children living in areas with differing air quality to show that lung development was adversely affected by pollution and maternal smoking. Malcolm Sears and Neil Johnstone showed that the ‘return to school’ asthma exacerbation epidemic was due mainly to rhinoviruses. David Muir investigated the effects of silica exposure in hard-rock miners, and mortality in the nickel industry.SUMMARY: The Respirology Division has grown to more than 50 physicians and PhD scientists, and currently provides the busiest outpatient clinic in Hamilton, and has successful training and research programs.

Respiratory medicine at McMaster University, Hamilton, Ontario: 1968 to 2013.

The medical school at McMaster University (Hamilton, Ontario) was conceived in 1965, and admitted the first class in 1969. John Evans became the founding Dean and he invited EJ Moran Campbell to be the first Chairman of the Department of Medicine. Moran Campbell, already a world figure in respiratory medicine and physiology, arrived at McMaster in September 1968, and he invited Norman Jones to be Coordinator of the Respiratory Programme.At that time, Hamilton had a population of 300,000, with two full-time respirologists, Robert Cornett at the Hamilton General Hospital and Michael Newhouse at St Joseph’s Hospital. From the clinical perspective, the aim of the Respiratory Programme was to develop a network approach to clinical problems among the five hospitals in the Hamilton region, with St Joseph’s Hospital serving as a regional referral centre, and each hospital developing its own focus: intensive care and burns units at the Hamilton General Hospital; cancer at the Henderson (later Juravinski) Hospital; tuberculosis and rehabilitation at the Chedoke Hospital; pediatrics and neonatal intensive care at the McMaster University Medical Centre; and community care at the Joseph Brant Hospital in Burlington. The network provided an ideal base for a specialty residency program. There was also the need to establish viable research.These objectives were achieved through collaboration, support of hospital administration, and recruitment of clinicians and faculty, mainly from our own trainees and research fellows. By the mid-1970s, the respiratory group numbered more than 25; outpatient clinic visits and research had grown beyond our initial expectations. The international impact of the group became reflected in the clinical and basic research endeavours.ASTHMA: Freddy Hargreave and Jerry Dolovich established methods to measure airway responsiveness to histamine and methacholine. Allergen inhalation was shown to increase airway responsiveness for several weeks, and the late response was shown to be an immunoglobulin E-mediated phenomenon. Paul O’Byrne and Gail Gauvreau showed that the prolonged allergen-induced responses were due to eosinophilic and basophilic airway inflammation and, with Judah Denburg, revealed upregulation of eosinophil/basophil progenitor production in bone marrow and airways. The Firestone Institute became the centre of studies identifying the inflammatory phenotype of patients with difficult-to-control asthma. Freddy Hargreave and others developed methods for sputum induction to identify persisting eosinophilic airway inflammation and documented its presence in the absence of asthma, and in patients with persistent cough. Parameswaran Nair has applied these techniques to the management of asthma in routine clinical practice. The Asthma Quality of Life Questionnaire and the Asthma Control Tests were developed by Liz Juniper and Gordon Guyatt. The first Canadian evidence-based clinical guidelines for asthma management in 1989 were coordinated by Freddy Hargreave, Jerry Dolovich and Michael Newhouse.DISTRIBUTION OF INHALED PARTICLES: Michael Newhouse and Myrna Dolovich used inhaled radiolabelled aerosols to study the distribution of inhaled particles and their clearance in normal subjects, smokers and patients with chronic obstructive pulmonary disease. They developed the aerochamber, and were the first to radiolabel therapeutic aerosols to distinguish the effects of peripheral versus central deposition. Particle deposition and clearance were shown to be impaired in ciliary dyskinesia and cystic fibrosis.DYSPNEA: Moran Campbell and Kieran Killian measured psychophysical estimates of the sense of effort in breathing in studies of loaded breathing and exercise to show that dyspnea increased as a power function of both duration and intensity of respiratory muscle contraction, and in relation to reductions in respiratory muscle strength. These principles also applied to dyspnea in cardiorespiratory disorders.EXERCISE CAPACITY: Norman Jones and Moran Campbell developed a system for noninvasive cardiopulmonary exercise testing using an incremental exercise test, and more complex studies with measurement of mixed venousPCO2by rebreathing. The 6 min walk test was validated by Gordon Guyatt. Kieran Killian and Norman Jones introduced routine muscle strength measurements in clinical testing and symptom assessment in exercise testing. Muscle strength training improved exercise capacity in older subjects and patients with chronic obstructive pulmonary disease.METABOLISM AND ACID-BASE CONTROL IN EXERCISE: After showing that imposed acidosis reduced, and alkalosis improved performance, Norman Jones, John Sutton and George Heigenhauser investigated the interactions between acid-base status and metabolism in exercise.HIGH-ALTITUDE MEDICINE: John Sutton and Peter Powles participated in high-altitude research on Mount Logan (Yukon), demonstrating sleep hypoxemia in acute mountain sickness and its reversal by acetazolamide, and participated in Operation Everest II.EPIDEMIOLOGY: David Pengelly and Tony Kerrigan followed children living in areas with differing air quality to show that lung development was adversely affected by pollution and maternal smoking. Malcolm Sears and Neil Johnstone showed that the ‘return to school’ asthma exacerbation epidemic was due mainly to rhinoviruses. David Muir investigated the effects of silica exposure in hard-rock miners, and mortality in the nickel industry.SUMMARY: The Respirology Division has grown to more than 50 physicians and PhD scientists, currently provides the busiest outpatient clinic in Hamilton, and has successful training and research programs.

Comparison of phenotypes of childhood wheeze and cough in 2 independent cohorts

Among children with wheeze and recurrent cough there is great variation in clinical presentation and time course of the disease. We previously distinguished 5 phenotypes of wheeze and cough in early childhood by applying latent class analysis to longitudinal data from a population-based cohort (original cohort). To validate previously identified phenotypes of childhood cough and wheeze in an independent cohort. We included 903 children reporting wheeze or recurrent cough from an independent population-based cohort (validation cohort). As in the original cohort, we used latent class analysis to identify phenotypes on the basis of symptoms of wheeze and cough at 2 time points (preschool and school age) and objective measurements of atopy, lung function, and airway responsiveness (school age). Prognostic outcomes (wheeze, bronchodilator use, cough apart from colds) 5 years later were compared across phenotypes. When using a 5-phenotype model, the analysis distinguished 3 phenotypes of wheeze and 2 of cough as in the original cohort. Two phenotypes were closely similar in both cohorts: Atopic persistent wheeze (persistent multiple trigger wheeze and chronic cough, atopy and reduced lung function, poor prognosis) and transient viral wheeze (early-onset transient wheeze with viral triggers, favorable prognosis). The other phenotypes differed more between cohorts. These differences might be explained by differences in age at measurements. Applying the same method to 2 different cohorts, we consistently identified 2 phenotypes of wheeze (atopic persistent wheeze, transient viral wheeze), suggesting that these represent distinct disease processes. Differences found in other phenotypes suggest that the age when features are assessed is critical and should be considered carefully when defining phenotypes.

Low-dose salbutamol suppresses airway responsiveness to histamine but not methacholine in subjects with asthma

Airway hyperresponsiveness is a cardinal feature of asthma. Although the modulation of cholinergic neuroeffector transmission may play a role in airway responsiveness, in vivo evidence remains scarce. It is well known that histamine causes bronchoconstriction partly via vagal reflex, whereas methacholine does not. To investigate the significance of modulating neuroeffector transmission, we compared the effect of low-dose salbutamol-a β2-adrenoceptor agonist-on airway responsiveness to histamine with that to methacholine. We enrolled 12 subjects with stable asthma. After screening confirmed that inhalation of low-dose salbutamol (1μg) did not change their basic pulmonary function, subjects underwent measurement of airway responsiveness to inhaled histamine and methacholine with or without pretreatment with low-dose salbutamol, in a randomized, crossover fashion. Airway responsiveness was measured by an astograph by which respiratory conductance (Grs) was assessed by the forced oscillation method during continuous inhalation of histamine or methacholine in stepwise incremental concentrations. Airway responsiveness was calculated as the cumulative dose of bronchoconstrictors that induced a decrease of 35% in Grs. Inhalation of 1μg of salbutamol significantly attenuated airway responsiveness to histamine but not methacholine. This selective attenuation was observed irrespective of disease severity or phenotype, namely atopy or non-atopy. Low-dose salbutamol suppresses airway responsiveness to histamine but not methacholine in subjects with asthma. The present study may provide a novel insight into the bronchoprotective mechanism of β2-adorenoceptor agonist in clinical settings.

Correlation of bronchoalveolar eosinophilic percentage with airway responsiveness in cats with chronic bronchial disease

To retrospectively assess the relationship between bronchoalveolar lavage fluid analysis and lung function parameters as assessed by means of barometric whole body plethysmography and airway responsiveness testing in cats with chronic bronchial disease and to evaluate the potential application of barometric whole body plethysmography and airway responsiveness testing to distinguish between eosinophilic and non-eosinophilic bronchitis. Twelve cats presented for chronic bronchial disease with complete bronchoalveolar lavage fluid and barometric whole body plethysmography data were identified. Cats were retrospectively assigned to eosinophilic bronchitis or non-eosinophilic bronchitis groups on the basis of bronchoalveolar lavage fluid eosinophil percentage (threshold 17%). Airway responsiveness was quantified by calculating the concentration of carbachol-inducing bronchoconstriction (C-Penh-300), defined as a 300% increase of basal enhanced pause (Penh). Log Penh was significantly higher and C-Penh-300 significantly lower in eosinophilic bronchitis cats compared to non-eosinophilic bronchitis cats (P=0·031 and P=0·032, respectively). Bronchoalveolar lavage fluid eosinophil percentage was moderately correlated with log Penh (P=0·012, r=0·70) and showed a weak inverse correlation with C-Penh-300 (P=0·047, r=-0·58). This study provides supportive evidence of a correlation between airway eosinophilic inflammation and plethysmographic measures of bronchoconstriction and airway responsiveness. Further investigation of the use of barometric whole body plethysmography to differentiate between forms of chronic bronchial disease in cats is indicated.

Measurement of Airway Responsiveness on Vigil and Unrestrained Mouse

Airway hyperresponsiveness to methacholine is an important characteristic of asthma. This protocol describes how to measure airway response to methacholine in vigil and unrestraint mouse. The enhanced pause (PenH) is an index of the airway response to increasing doses of methacholine recorded by whole-body barometric plethysmography.

Measurement of Airway Responsiveness in the Anesthetized Mouse

[Abstract] Airway hyperresponsiveness to methacholine is an important characteristic of asthma. Many devices can be used to measure airway responsiveness in the mouse but it is well established that the invasiveness of a measurement technique is correlated with its precision and reproducibility. This protocol describes how to measure airway responses to aerosolized methacholine in anesthetized, tracheotomized, and mechanically ventilated mice using the forced oscillation technique with FlexiVent ® (SCIREQ). This is a computer-controlled precision piston pump that can intersperse mechanical ventilation with volume and pressure controlled manoeuvres to obtain accurate, reproducible measurement of respiratory mechanics.

Airway Hyperresponsiveness and Quality of Life in Western Red Cedar Asthmatics Removed from Exposure

ObjectivesMost western red cedar asthmatics (WRCA) continue to have symptoms even after removal from exposure. Consequently, health-related quality of life (HRQL) is often impaired. The objective of this study was to evaluate the relationship between two measures of AHR and HRQL scores in those with WRCA.MethodsHRQL was determined by the short form 36 (SF-36) in 46 male, non-smoking individuals with WRCA removed from exposure to western red cedar, on average, 15 years earlier. The relationships between the SF-36 total score and its eight domains with 2 indices from methacholine-stimulated airway hyperresponsiveness (the provocative concentration of methacholine causing a 20% fall in FEV1 [PC20] and bronchial reactivity index [BRI]) were analyzed by the Pearson correlation and multiple linear regression.ResultsPC20 was significantly correlated with the SF-36 total score and its two domains of bodily pain and general health (r = 0.34, 0.40, 0.40, p = 0.023, 0.006, 0.006, respectively). BRI was significantly correlated with bodily pain and general health (r = −0.35, −0.42, p = 0.017, 0.004, respectively); correlations remain significant after adjusting for age, ethnicity, years since diagnosis, years since last exposure and use of inhaled corticosteroid. BRI and other measures of airway responsiveness were not associated with inhaled corticosteroids use.ConclusionsIn Western red cedar asthmatics removed from exposure, measures of airway responsiveness are associated with HRQL.

S131 Identifying Occupational Asthma Among a Cohort of Cleaners in the North East England

IntroductionWe have demonstrated a prevalence of asthma of 14% in a survey of 1400 UK hospital and university cleaners, and an estimated incidence of asthma of 3.3/1000 person-years. 26% of...

Leukotriene D4 and methacholine bronchial provocation tests for identifying leukotriene-responsiveness subtypes

Both leukotriene D(4) (LTD(4)) and methacholine bronchial provocation tests are measurements of airway responsiveness; however, their correlation and distinction remain unexplored. We sought to compare the 2 tests and classify leukotriene-responsiveness subtypes in asthmatic patients. In this randomized cross-over study we enrolled healthy subjects and asthmatic patients with different control statuses. All subjects underwent both tests with a 2- to 14-day interval. Distribution and correlation of cumulative doses inducing a 20% decrease in FEV(1), LTD(4)/methacholine potency ratio, diagnostic value, and adverse events were recorded and analyzed. Asthmatic patients with a lower cumulative dose for LTD(4) and a higher leukotriene/methacholine potency ratio than geometric means were regarded as leukotriene responsive. Twenty patients with uncontrolled, 22 with partly controlled, and 20 with controlled asthma and 21 healthy subjects were enrolled. Geometric means of cumulative doses for LTD(4) and methacholine (0.272 nmol vs 0.945 μmol) were lowest in patients with uncontrolled asthma, followed by those with partly controlled (0.387 nmol vs 1.933 μmol) and controlled (1.484 nmol vs 3.946 μmol) asthma. The average potency ratio was highest in those with partly controlled asthma (5000.2), followed by those with uncontrolled (3477.7) and controlled (2702.6) asthma. Eighteen leukotriene-responsive asthmatic patients (29.03%) with a cumulative dose of LTD(4) of 0.533 nmol or less and a potency ratio of 3647 or greater were identified. Adverse events, including tachypnea and chest tightness, were similar and mild. No serious adverse event was reported. Diagnostic value and safety were ideal in both tests. The combination of cumulative dose for LTD(4) and potency ratio might be useful to identify leukotriene-responsive asthmatic patients.

Counterpoint: Alterations in airway smooth muscle phenotype do not cause airway hyperresponsiveness in asthma

We have been assigned the task of showing that “alterations in airway smooth muscle phenotype DO NOT cause the airways hyperresponsiveness of asthma.” In the following paragraphs we will briefly review the overwhelming lack of evidence that any fundamental change in the intrinsic properties of

A pilot study of office-based spirometry in patients with systemic lupus erythematosus

Although pulmonary involvement is common in systemic lupus erythematosus (SLE), its effects on healthy lifestyle physical activity and its association with fatigue have not been well characterized. The goals of this study were to describe pulmonary function measured by office-based spirometry in patients with SLE and to compare spirometry with physical activity and systemic fatigue. During an office visit, 49 patients with SLE completed spirometry assessing: a) forced expiratory volume in 1 s (FEV(1), a measure of airway patency and responsiveness); b) forced vital capacity (FVC, a measure of lung volume); and c) maximum voluntary ventilation (MVV, a measure of volume of air moved during rapid breathing) which has been hypothesized to be decreased in SLE due to muscle fatigue. Patients also performed a 2-min corridor walking test and completed self-reported questionnaires measuring weekly physical activity and systemic fatigue. Mean age was 45 years, 45 (92%) were women, mean SLEDAI and SLICC scores were 2.8 and 1.0, respectively. Some 24 patients had a smoking history, and 15 had a history of SLE-related pleuritis, which was not active at enrollment. FEV(1) and FVC were 96% of predicted, but MVV was only 55% of predicted. The distance walked during the corridor test was similar to that of patients with other chronic diseases; however, self-reported physical activity was less than recommended by national guidelines. There were no associations between spirometry values and history of pleuritis, other pulmonary diagnoses, or smoking (p > .10 for all comparisons), however, better FEV(1) (p = .04) and better FVC (p = .04) were associated with more self-reported activity and better FEV(1) (p = .03) was associated with longer distance walked during the corridor test. Most patients reported marked systemic fatigue; however, there were no associations between spirometry values and fatigue scores (p > .10 for all comparisons). MVV was markedly diminished, which supports the hypothesis that SLE may be associated with respiratory muscle fatigue during rapid breathing. MVV was not associated with mild-to-moderate patient-directed physical activity; however, lower FEV(1) and FVC were associated with less self-reported and performance-based physical activity.

Integrated effect of EGFR and PAR-1 signaling crosstalk on airway hyperresponsiveness

Among previous genetic studies for asthma, inconsistent findings were often reported. We used a new approach to examine an integrated effect of haplotype blocks, newly termed 'haplotype cluster' over two different types of receptors which share common intracellular pathways on airway hyperresponsiveness (AHR). We recruited 165 young atopic adults without respiratory symptoms and measured airway responsiveness to methacholine and classified them into two groups, those with AHR (PC20<8.0mg/ml) and without AHR. In addition, we identified haplotype blocks or cluster tagging single nucleotide polymorphisms (SNPs) through two genes, epidermal growth factor receptor (EGFR) and protease activated receptor (PAR)-1, in all subjects, and compared the frequencies of haplotype block or cluster between subject groups. Significant differences in the frequencies were observed in the haplotype blocks within the EGFR gene (rs4947972, rs12718945 and rs2072454; rs4947972, rs12718945 and rs2227983; and rs4947972, rs12718945 and rs2293347) and the PAR-1 gene (rs37243 and rs253072). An integrated effect was also observed in one haplotype cluster consisting of both regions of the EGFR gene (rs2293347) and the PAR-1 gene (rs253072) (P=0.0426). Our results suggest the possibility that the integrated effect of functionally-related EGFR and PAR-1 genes (haplotype cluster) is associated with susceptibility to AHR.

A protective role for periostin and TGF‐β in IgE‐mediated allergy and airway hyperresponsiveness

BackgroundThe pathophysiology of asthma involves allergic inflammation and remodelling in the airway and airway hyperresponsiveness (AHR) to cholinergic stimuli, but many details of the specific underlying cellular and molecular mechanisms remain unknown. Periostin is a matricellular protein with roles in tissue repair following injury in both the skin and heart. It has recently been shown to be up-regulated in the airway epithelium of asthmatics and to increase active TGF-β. Though one might expect periostin to play a deleterious role in asthma pathogenesis, to date its biological role in the airway is unknown.ObjectiveTo determine the effect of periostin deficiency on airway responses to inhaled allergen.MethodsIn vivo measures of airway responsiveness, inflammation, and remodelling were made in periostin deficient mice and wild-type controls following repeated intranasal challenge with Aspergillus fumigatus antigen. In vitro studies of the effects of epithelial cell-derived periostin on murine T cells were also performed.ResultsSurprisingly, compared with wild-type controls, periostin deficient mice developed increased AHR and serum IgE levels following allergen challenge without differences in two outcomes of airway remodelling (mucus metaplasia and peribronchial fibrosis). These changes were associated with decreased expression of TGF-β1 and Foxp3 in the lungs of periostin deficient mice. Airway epithelial cell-derived periostin-induced conversion of CD4+ CD25− cells into CD25+, Foxp3+ T cells in vitro in a TGF-β dependent manner.Conclusions and Clinical RelevanceAllergen-induced increases in serum IgE and bronchial hyperresponsiveness are exaggerated in periostin deficient mice challenged with inhaled aeroallergen. The mechanism of periostin's effect as a brake on allergen-induced responses may involve augmentation of TGF-β-induced T regulatory cell differentiation.