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Gazzola M.,Laval University | Lortie K.,Laval University | Henry C.,Laval University | Mailhot-Larouche S.,Laval University | And 9 more authors.
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2017

Force adaptation, a process whereby sustained spasmogenic activation (viz., tone) of airway smooth muscle (ASM) increases its contractile capacity, has been reported in isolated ASM tissues in vitro, as well as in mice in vivo. The objective of the present study was to assess the effect of tone on airway responsiveness in humans. Ten healthy volunteers underwent methacholine challenge on two occasions. One challenge consisted of six serial doses of saline followed by a single high dose of methacholine. The other consisted of six low doses of methacholine 5 min apart followed by a higher dose. The cumulative dose was identical for both challenges. After both methacholine challenges, subjects took a deep inspiration (DI) to total lung capacity as another way to probe ASM mechanics. Responses to methacholine and the DI were measured using a multifrequency forced oscillation technique. Compared with a single high dose, the challenge preceded by tone led to an elevated response measured by respiratory system resistance (Rrs) and reactance at 5 Hz. However, there was no difference in the increase in Rrs at 19 Hz, suggesting a predominant effect on smaller airways. Increased tone also reduced the efficacy of DI, measured by an attenuated maximal dilation during the DI and an increased renarrowing post-DI. We conclude that ASM tone increases small airway responsiveness to inhaled methacholine and reduces the effectiveness of DI in healthy humans. This suggests that force adaptation may contribute to airway hyperresponsiveness and the reduced bronchodilatory effect of DI in asthma. © 2017 the American Physiological Society.


Almqvist C.,Karolinska Institutet | Almqvist C.,Woolcock Institute of Medical Research | Garden F.,Woolcock Institute of Medical Research | Kemp A.S.,Childrens Hospital | And 9 more authors.
Paediatric and Perinatal Epidemiology | Year: 2010

Variation in the observed association between pet ownership and allergic disease may be attributable to selection bias and confounding. The aim of this study was to suggest a method to assess disease-related modification of exposure and second to examine how cat acquisition or dog ownership in early life affects atopy and asthma at 5 years. Information on sociodemographic factors and cat and dog ownership was collected longitudinally in an initially cat-free Australian birth cohort based on children with a family history of asthma. At age 5 years, 516 children were assessed for wheezing, and 488 for sensitisation. Data showed that by age 5 years, 82 children had acquired a cat. Early manifestations of allergic disease did not foreshadow a reduced rate of subsequent acquisition of a cat. Independent risk factors for acquiring a cat were exposure to tobacco smoke at home odds ratio (OR) 1.92 95% confidence interval (CI) 1.13, 3.26, maternal education ≤12 years OR 1.95 1.08, 3.51 and dog ownership OR 2.23 1.23, 4.05 Cat or dog exposure in the first 5 years was associated with a decreased risk of any allergen sensitisation, OR 0.50 0.28, 0.88 but no association with wheeze OR 0.96 0.57, 1.61 This risk was not affected by age at which the cat was acquired or whether the pet was kept in- or outdoors. In conclusion, cat or dog ownership reduced the risk of subsequent atopy in this high-risk birth cohort. This cannot be explained by disease-related modification of exposure. Public health recommendations on the effect of cat and dog ownership should be based on birth cohort studies where possible selection bias has been taken into account. © 2010 Blackwell Publishing Ltd.


Bosse Y.,Providence Health Care St Pauls Hospital | Chapman D.G.,Woolcock Institute of Medical Research | Chapman D.G.,University of Sydney | Chapman D.G.,Cooperative Research Center for Asthma | And 9 more authors.
Respiratory Physiology and Neurobiology | Year: 2011

Asthma is characterized by airway inflammation, with a consequent increase in spasmogens, and exaggerated airway narrowing in response to stimuli, termed airway hyperresponsiveness (AHR). The nature of any relationship between inflammation and AHR is less clear. Recent ex vivo data has suggested a novel mechanism by which inflammation may lead to AHR, in which increased basal ASM-tone, due to the presence of spasmogens in the airways, may "strengthen" the ASM and ultimately lead to exaggerated airway narrowing. This phenomenon was termed "force adaptation" [Bossé, Y., Chin, L.Y., Paré, P.D., Seow, C.Y., 2009. Adaptation of airway smooth muscle to basal tone: relevance to airway hyperresponsiveness. Am. J. Respir. Cell Mol. Biol. 40, 13-18]. However, it is unknown whether the magnitude of the effect of force adaptation ex vivo could contribute to exaggerated airway narrowing in vivo. Our aim was to utilize a computational model of ASM shortening in order to quantify the potential effect of force adaptation on airway narrowing when all other mechanical factors were kept constant. The shortening in the model is dictated by a balance between physiological loads and ASM force-generating capacity at different lengths. The results suggest that the magnitude of the effect of force adaptation on ASM shortening would lead to substantially more airway narrowing during bronchial challenge at any given airway generation. We speculate that the increased basal ASM-tone in asthma, due to the presence of inflammation-derived spasmogens, produces an increase in the force-generating capacity of ASM, predisposing to AHR during subsequent challenge. © 2011 Elsevier B.V.


Downie S.R.,Woolcock Institute of Medical Research | Downie S.R.,University of Sydney | Downie S.R.,Cooperative Research Center for Asthma | Salome C.M.,Woolcock Institute of Medical Research | And 13 more authors.
Journal of Applied Physiology | Year: 2013

The forced oscillation technique (FOT) and multiple-breath nitrogen washout (MBNW) are noninvasive tests that are potentially sensitive to peripheral airways, with MBNW indexes being especially sensitive to heterogeneous changes in ventilation. The objective was to study methacholine-induced changes in the lung periphery of asthmatic patients and determine how changes in FOT variables of respiratory system reactance (Xrs) and resistance (Rrs) and frequency dependence of resistance (Rrs5-Rrs19) can be linked to changes in ventilation heterogeneity. The contributions of air trapping and airway closure, as extreme forms of heterogeneity, were also investigated. Xrs5, Rrs5, Rrs19, Rrs5-Rrs 19, and inspiratory capacity (IC) were calculated from the FOT. Ventilation heterogeneity in acinar and conducting airways, and trapped gas (percent volume of trapped gas at functional residual capacity/vital capacity), were calculated from the MBNW. Measurements were repeated following methacholine. Methacholine-induced airway closure (percent change in forced vital capacity) and hyperinflation (change in IC) were also recorded. In 40 mild to moderate asthmatic patients, increase in Xrs5 after methacholine was predicted by increases in ventilation heterogeneity in acinar airways and forced vital capacity (r2 = 0.37, P < 0.001), but had no correlation with ventilation heterogeneity in conducting airway increase or IC decrease. Increases in Rrs5 and Rrs5-Rrs19 after methacholine were not correlated with increases in ventilation heterogeneity, trapped gas, hyperinflation, or airway closure. Increased reactance in asthmatic patients after methacholine was indicative of heterogeneous changes in the lung periphery and airway closure. By contrast, increases in resistance and frequency dependence of resistance were not related to ventilation heterogeneity or airway closure and were more indicative of changes in central airway caliber than of heterogeneity. Copyright © 2013 the American Physiological Society.


Chapman D.G.,Woolcock Institute of Medical Research | Chapman D.G.,University of Sydney | Chapman D.G.,Cooperative Research Center for Asthma | Chapman D.G.,University of Vermont | And 12 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2014

Rationale: Airway narrowing is maintained for a prolonged period after acute bronchoconstriction in humans in the absence of deep inspirations (DIs). Objectives: To determine whether maintenance of airway smooth muscle (ASM) shortening is responsible for the persistence of airway narrowing in healthy subjects following transient methacholine (MCh)-induced bronchoconstriction. Methods: On two separate visits, five healthy subjects underwent MCh challenges until respiratory system resistance (Rrs) had increased by approximately 1.5 cm H2O/L/s. Subjects took a DI either immediately after or 30 minutes after the last dose. The extent of renarrowing following the bronchodilator effect of DI was used to assess the continued action of MCh (calculated as percent change in Rrs from the pre-DI Rrs). We then used human bronchial rings to determine whether ASM can maintain shortening during a progressive decrease of carbachol concentration. Measurements and Main Results: The increased Rrs induced by MCh was maintained for 30 minutes despite waning of MCh concentration over that period, measured as attenuated renarrowing when the DI was taken 30 minutes after compared with immediately after the last dose (7 min post-DI, -36.2 ± 11.8 vs. 14.4 ± 13.2%; 12 min post-DI, -39.5 ± 9.8 vs. 15.2 ± 17.8%). Ex vivo, ASMshortening was largely maintained during a progressive decrease of carbachol concentration, even down to concentrations that would not be expected to induce shortening. Conclusions: The maintenance of airway narrowing despite MCh clearance in humans is attributed to an intrinsic ability of ASM to maintain shortening during a progressive decrease of contractile stimulation. Copyright © 2014 by the American Thoracic Society.


Drysdale M.,Queen's University | Drysdale M.,Golder Associates | Bjorklund K.L.,University of Western Australia | Bjorklund K.L.,Cooperative Research Center for Asthma | And 6 more authors.
Environmental Geochemistry and Health | Year: 2012

Simulated lung fluids are solutions designed to mimic the composition of human interstitial lung fluid as closely as possible. Analysis of mineral dusts using such solutions has been used to evaluate the respiratory bioaccessibility of various elements for which solubility in the lungs is a primary determinant of reactivity. The objective of this study was to employ simulated lung fluid analysis to investigate the respiratory bioaccessibility of nickel in soils. Current occupational guidelines in Australia regulate nickel compounds in terms of water solubility, though this may not be an accurate estimation of the total nickel that will dissociate in the lungs. Surface soils were collected from the city of Kalgoorlie in Western Australia, the site of an operational nickel smelter and metal mining activities. The fraction of the samples less than 10 μm was extracted from the soil, and it was this sub-10-μm fraction that was found to hold most of the total nickel present in the soil. The fine fraction was analyzed using a simulated lung fluid (modified Gamble's solution) to isolate the nickel phases soluble in the lungs. In addition, a sequential extraction was employed to compare the bioaccessible fraction to those dissolved from different binding forms in the soil. In all samples, the simulated lung fluid extracted more nickel than the two weakest leaches of the sequential extraction combined, providing a more representative nickel bioaccessibility value than the current water leach method. © 2011 Springer Science+Business Media B.V.


Ljung K.,University of Western Australia | Ljung K.,Cooperative Research Center for Asthma | Maley F.,University of Western Australia | Maley F.,Cooperative Research Center for Asthma | And 2 more authors.
Landscape and Urban Planning | Year: 2010

The adverse environmental outcomes of disturbing acid sulfate soils have long been known, and there is a general consensus that avoiding disturbance is the most cost-efficient solution. However, canal estates are increasing in popularity on the west coast of Australia, in spite of a large proportion of the country's acid sulfate soils being located along its coast. This study examined the mobility and concentration of metals in surface soil, dust and water sampled from one of the earliest canal developments in Western Australia. Soil metal concentrations were significantly elevated compared to an undisturbed reference site. While the dust fraction generally held higher metal concentrations in the original soil of the area, the total metal load was higher in the dredged and deposited material. None of the samples were above guideline values. The surface water of the canals had concentrations of iron and arsenic above the Australian drinking water guideline value while nickel concentrations were above the ecological guideline value. The pH of the water was not affected. The human health consequences of these findings may not be severe as the water is not used for drinking. However, the results highlight the need for transparency in the land development process, where developers are responsible for informing home buyers of the consequences related to developing acid sulfate soil areas and the steps that are being taken towards remediation or avoidance. Moreover, the results show the importance of monitoring metal concentrations in addition to pH in waters potentially affected by acid sulfate soils. © 2010.


Pereira G.,University of Western Australia | Pereira G.,Cooperative Research Center for Asthma | Nassar N.,University of Western Australia | Nassar N.,University of Sydney | And 3 more authors.
Australian and New Zealand Journal of Public Health | Year: 2011

Background: This study, in a region with relatively low industrial activity, used a highly specific marker for traffic emissions, accounted for the inherent fetal growth potential, and used complete record linkage of births, midwife notifications, deaths, hospital morbidity and birth defect records. Methods: Clinical records were obtained for pregnancies between 2000 and 2006 in three areas of Perth, Western Australia (n=3,501). We used carbon monoxide as a marker for locally derived traffic emissions, and assessed exposure using the AusRoads dispersion model. Fetal growth was characterised by proportion of optimal birth weight and investigated using multivariate mixed-effects regression. Results: Exposure in the third trimester was associated with a -0.49% (sd=0.23%) change in proportion of optimal birth weight per 10 μg/m3 increase in locally derived traffic emissions. However, this result was confined to one of the three study areas due to elevated exposure misclassification among women in the other two areas. Among this group, a neonate who would have otherwise attained an optimal birth weight of 3.5 kg would be expected to be born 58 g lighter for an interquartile increase in third trimester exposure, which was approximately half of the effect observed for maternal smoking during pregnancy. Conclusion: We observed an association between maternal exposure to traffic emissions and reduced fetal growth. This effect was supported by sensitivity analyses but only observed in one of the three study areas. Further studies are required to corroborate our results.


Pereira G.,University of Western Australia | Pereira G.,Cooperative Research Center for Asthma | Cook A.,University of Western Australia | Cook A.,Cooperative Research Center for Asthma | And 4 more authors.
American Journal of Obstetrics and Gynecology | Year: 2012

We sought to investigate seasonal variation in fetal growth, accounting for important sociodemographic, biological, and environmental exposures. Records of births 1998 through 2006 in Perth, Western Australia were obtained (N = 147,357). We investigated small for gestational age and sex and the proportion of optimal birthweight (POBW) in relation to seasonal exposures (season, temperature, sunlight) by trimester of pregnancy. Adjustment was made for a wide range of risk factors. The POBW for neonates with third trimesters predominantly in summer was 0.18% (0.00-0.36%) lower than for those in winter. POBW decreased by 0.14% (0.01-0.27%) per interquartile range increase in third-trimester temperature (9.15°C). An interquartile range increase in temperature over pregnancy (0.73°C) was associated with an odds ratio of 1.02 (95% confidence interval, 1.001.05) for small for gestational age and sex. Reduced fetal growth was associated with elevated ambient temperatures throughout and late in pregnancy, independently of air pollution and other risk factors.


Chapman D.G.,Woolcock Institute of Medical Research | Chapman D.G.,Cooperative Research Center for Asthma | Chapman D.G.,University of Sydney | King G.G.,Woolcock Institute of Medical Research | And 12 more authors.
Respiratory Physiology and Neurobiology | Year: 2010

Airway hyperresponsiveness is characterised by a leftward shift of the dose-response curve (DRC) and an increase in the maximal response. Deep inspiration (DI) avoidance increases responsiveness in non-asthmatic, but not asthmatic, subjects. The aim was to determine the effect of DI avoidance on the sensitivity and maximal response of the FEV1 DRC to methacholine. Thirteen non-asthmatic and ten asthmatic subjects underwent a standard cumulative high-dose methacholine challenge (0.1-200μmol). Subsequently, on separate days, increasing single doses of methacholine were administered after 10min of DI avoidance. A sigmoidal equation was fitted to the data to obtain values for α, the position constant, as a measure of sensitivity. The fall in FEV1 at the highest common dose was used as a measure of the maximal response. The change in flow at 40% control vital capacity on the maximal (V̇40m) and partial (V̇40p) curves were calculated from the first manoeuvre after methacholine and the ratio of the values for V̇40m and V̇40p was calculated as a measure of the bronchodilator effect of DI (BDDI). In non-asthmatic subjects, avoiding DI increased the maximum fall in FEV1 at the highest common dose (p=0.0001) but did not alter α (p=0.75). Avoiding DI before challenge did not alter BDDI (p=0.13). DI avoidance had no effect on airway responsiveness in asthmatic subjects. In non-asthmatic subjects, DI avoidance increases airway responsiveness by increasing the maximal response, but does not alter the sensitivity, suggesting that the loss of the effect of DI in asthma contributes to excessive bronchoconstriction. © 2010 Elsevier B.V.

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