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Dr David Chapman


Dr David Chapman completed his PhD studies at the Woolcock Institute of Medical Research, University of Sydney, in 2011. During these studies, he mastered several techniques for measuring small airway function in humans while investigating the physiological determinants of airway hyperresponsiveness in asthma. Dr Chapman was subsequently awarded an Early Career Fellowship by the National Health and Medical Research Council of Australia to partake in post-doctoral training under the mentorship of Prof. Charles Irvin at the University of Vermont, USA. During this period, he gained considerable expertise in the use of animal models of respiratory disease, including models of allergic airways disease, Idiopathic Pulmonary Fibrosis and tobacco-related disease.

Dr Chapman has recently returned to Australia to develop the Translational Airways Group with laboratory facilities located at both UTS and the Woolcock Institute of Medical Research. He aims to utilise the entire bench to bedside research spectrum by combining both mouse models and human clinical research to investigate respiratory disease.


Professional Activities

I am a member of the Thoracic Society of Australia and New Zealand (TSANZ), American Thoracic Society (ATS) and European Respiratory Society (ERS).

Chancellor's Postdoctoral Research Fellow, School of Life Sciences
PhD (Medicine)

Research Interests

Human Research
The effect of Obesity on Chronic Obstructive Pulmonary Disease (COPD)
COPD patients experience reduced pulmonary airflow due to tissue damage and small airway scarring. This reduced airflow leads to trapped gas within the lung, resulting in a condition known as hyperinflation. Hyperinflation causes patients to breathe at abnormally elevated tidal lung volumes, consequently reducing exercise tolerance due to the restriction of tidal volume expansion. However, obesity is known to reduce lung volumes and would be expected to partially counteract hyperinflation. However, the interaction between obesity and COPD on airway mechanics and clinical outcomes is currently poorly understood. We are currently investigating how obesity alters lung function in COPD to determine whether aspects of obesity could be mimicked to improve quality of life in non-obese patients.
The effect of Obesity on Asthma 
It is well accepted that obesity increases the severity of pre-existing asthma and increases the risk for future development of the disease. However, much uncertainly surrounds the mechanism by which obesity alters asthma. I have been at the forefront of research suggesting that the mechanical effect of increased adiposity induces small airway dysfunction leading to increased airway closure during spasmogen inhalation (2008, Eur Respir J and 2012, J Appl Physiol).  This ultimately results in increased airway hyperresponsiveness in obese asthmatic patients (2014, Respirology). Furthermore, my research has suggested that obese patients who develop asthma have a distinct physiological phenotype from asthmatic patients who become obese (2014, Am J Respir Crit Care Med).  

Mouse models of Respiratory Disease
The Effect of Electronic Cigarettes  on Asthma
The use of electronic (e-)cigarettes continues to increase worldwide as it is thought to be a safe, or safer, alternative to conventional tobacco cigarettes. However, there remains significant concerns over the potential toxicity of e-cigarettes, due to the presence of nicotine, flavour additives and other constituents. Tobacco smoking is well known to contribute to the development of asthma, while asthmatics who smoke have worse symptoms and reduced response to treatement.  To investigate the potential toxicity of e-cigarettes we are using mouse models of exposure and in doing so hope to provide critical information for the evaluation and implementation of policy decisions regarding the regulation of e-cigarettes.
The Effect of Tobacco Use on Respiratory Disease
Chronic Obstructive Pulmonary Disease (COPD) patients who have frequent exacerbations show particularly exaggerated decline in lung function suggesting that exacerbations directly contribute to long-term decline in lung function. Viruses are identified in almost half of all COPD exacerbations; however, the mechanisms by which viruses interact with COPD pathophysiology to promote the loss of lung function are not well understood. We are currently investigating the molecular mechanisms by which viruses interact with COPD using both in vitro cell culture techniques and mouse models of tobacco exposure.

Mechanisms regulating Asthma Pathophysiology
The molecular mechanisms contributing to asthma pathophysiology are yet to be fully elucidated but our research in mouse models of allergic airways disease (asthma) have focussed on the role of airway epithelial cells. Our research demonstrated an important role for c-Jun-NH2-terminal-kinase (JNK) in airway epithelial cells in the development of airway fibrosis (2014, Am J Physiol Lung Cell Mol Physiol). We subsequently determined the efficacy of a novel JNK inhibitor in inhibiting fibrosis formation in a mouse model of allergic airways disease through suppression of collagen- and mucin-related gene expression (2016, Clin and Trans Med). Additionally, we have shown the importance of the endoplasmic reticulum stress-induced unfolded protein response in pathophysiology associated with asthma. Firstly, we showed that ERp57 levels are increased in the airway epithelium of asthmatic patients and in mice with allergic airways disease (2016, J Allergy Clin Immunol). This increase in ERp57 is associated with redox modification of proinflammatory, apoptotic, and fibrotic mediators and contributes to airways hyperresponsiveness, a characteristic of asthma. We subsequently reported that inhibition of ER stress in the lungs through the administration of a chemical chaperone reduces airway inflammation, airway hyperresponsiveness and airway fibrosis (2016, Am J Physiol Lung Cell Mol Physiol). This suggests that inhibition of ER stress may be a potential novel therapy in asthma.

Can supervise: Yes
I can supervisor Honours, Masters and PhD students.
Please contact me for further information.

Journal articles

Gazzola, M., Lortie, K., Henry, C., Mailhot-Larouche, S., Chapman, D.G., Couture, C., Seow, C.Y., Paré, P.D., King, G.G., Boulet, L.-.P. & Bossé, Y. 2017, 'Airway smooth muscle tone increases airway responsiveness in healthy young adults.', Am J Physiol Lung Cell Mol Physiol, vol. 312, no. 3, pp. L348-L357.
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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.
Jetmalani, K., Chapman, D.G., Thamrin, C., Farah, C.S., Berend, N., Salome, C.M. & King, G.G. 2016, 'Bronchodilator responsiveness of peripheral airways in smokers with normal spirometry.', Respirology, vol. 21, no. 7, pp. 1270-1276.
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BACKGROUND AND OBJECTIVE: Cigarette smoke exposure increases airway smooth muscle (ASM) contractility. Abnormalities in peripheral airway function in smokers with normal spirometry could be due to the effects of ASM tone. We aimed to determine the contribution of ASM tone to peripheral airway function in smokers with normal spirometry from the response to bronchodilator (BD). METHODS: Ventilation heterogeneity in peripheral conductive (Scond) and acinar (Sacin) airways were measured in 50 asymptomatic smokers and 20 never-smokers using multiple breath nitrogen washout, before and 20min after inhalation of 200µg salbutamol and 80µg ipratropium bromide. Z-scores were calculated to define abnormality in Sacin and Scond. RESULTS: Nineteen smokers had abnormal Sacin, and 12 had abnormal Scond; 7 had abnormalities in both. After BD, Sacin improved in smokers with normal Sacin (6.5±15.9%, P=0.02), smokers with abnormal Sacin (9.2±16.9%, P=0.03) and in control subjects (11.7±18.2%, P=0.01), with no differences in improvements between groups. Sacin remained abnormal in 15/19 smokers and their post-BD values correlated with smoking exposure (r=0.53, P=0.02). After BD, Scond improved in smokers with abnormal Scond (28.3±15.9%, P=0.002) and normalized in 9/12 subjects, but not in those with normal Scond (0.25±32.7%, P=0.44) or control subjects (-1.7±21.2%, P=0.64). CONCLUSION: In smokers with normal spirometry, abnormal conductive airway function could be attributed to increased bronchomotor tone. In contrast, bronchomotor tone in acinar airways is unaffected by smoking and functional abnormality. There may be different causal mechanisms underlying acinar and conductive airway abnormalities in smokers with normal spirometry.
Siddesha, J.M., Nakada, E.M., Mihavics, B.R., Hoffman, S.M., Rattu, G.K., Chamberlain, N., Cahoon, J.M., Lahue, K.G., Daphtary, N., Aliyeva, M., Chapman, D.G., Desai, D.H., Poynter, M.E. & Anathy, V. 2016, 'Effect of a chemical chaperone, tauroursodeoxycholic acid, on HDM-induced allergic airway disease.', Am J Physiol Lung Cell Mol Physiol, vol. 310, no. 11, pp. L1243-L1259.
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Endoplasmic reticulum (ER) stress-induced unfolded protein response plays a critical role in inflammatory diseases, including allergic airway disease. However, the benefits of inhibiting ER stress in the treatment of allergic airway disease are not well known. Herein, we tested the therapeutic potential of a chemical chaperone, tauroursodeoxycholic acid (TUDCA), in combating allergic asthma, using a mouse model of house dust mite (HDM)-induced allergic airway disease. TUDCA was administered during the HDM-challenge phase (preventive regimen), after the HDM-challenge phase (therapeutic regimen), or therapeutically during a subsequent HDM rechallenge (rechallenge regimen). In the preventive regimen, TUDCA significantly decreased HDM-induced inflammation, markers of ER stress, airway hyperresponsiveness (AHR), and fibrosis. Similarly, in the therapeutic regimen, TUDCA administration efficiently decreased HDM-induced airway inflammation, mucus metaplasia, ER stress markers, and AHR, but not airway remodeling. Interestingly, TUDCA administered therapeutically in the HDM rechallenge regimen markedly attenuated HDM-induced airway inflammation, mucus metaplasia, ER stress markers, methacholine-induced AHR, and airway fibrotic remodeling. These results indicate that the inhibition of ER stress in the lungs through the administration of chemical chaperones could be a valuable strategy in the treatment of allergic airway diseases.
Hoffman, S.M., Chapman, D.G., Lahue, K.G., Cahoon, J.M., Rattu, G.K., Daphtary, N., Aliyeva, M., Fortner, K.A., Erzurum, S.C., Comhair, S.A.A., Woodruff, P.G., Bhakta, N., Dixon, A.E., Irvin, C.G., Janssen-Heininger, Y.M.W., Poynter, M.E. & Anathy, V. 2016, 'Protein disulfide isomerase-endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness.', J Allergy Clin Immunol, vol. 137, no. 3, pp. 822-32.e7.
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BACKGROUND: Evidence for association between asthma and the unfolded protein response is emerging. Endoplasmic reticulum resident protein 57 (ERp57) is an endoplasmic reticulum-localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is upregulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown. OBJECTIVES: Here we sought to examine the contribution of airway epithelium-specific ERp57 in the pathogenesis of allergic asthma. METHODS: We examined the expression of ERp57 in human asthmatic airway epithelium and used murine models of allergic asthma to evaluate the relevance of epithelium-specific ERp57. RESULTS: Lung biopsy specimens from asthmatic and nonasthmatic patients revealed a predominant increase in ERp57 levels in epithelium of asthmatic patients. Deletion of ERp57 resulted in a significant decrease in inflammatory cell counts and airways resistance in a murine model of allergic asthma. Furthermore, we observed that disulfide bridges in eotaxin, epidermal growth factor, and periostin were also decreased in the lungs of house dust mite-challenged ERp57-deleted mice. Fibrotic markers, such as collagen and smooth muscle actin, were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for house dust mite-induced endoplasmic reticulum stress and airways fibrosis. CONCLUSIONS: Here we show that ERp57 levels are increased in the airway epithelium of asthmatic patients and in mice with allergic airways disease. The ERp57 level increase is associated with redox modification of proinflammatory, apoptotic, and fibrotic mediators and contributes to airways hyperresponsiveness. The strategies to inhibit ERp57 specifically within the airways epithelium might provide an opportunity to alleviate the allergic asthma phenotype.
Hoffman, S.M., Qian, X., Nolin, J.D., Chapman, D.G., Chia, S.B., Lahue, K.G., Schneider, R., Ather, J.L., Randall, M.J., McMillan, D.H., Jones, J.T., Taatjes, D.J., Aliyeva, M., Daphtary, N., Abdalla, S., Lundblad, L.K.A., Ho, Y.S., Anathy, V., Irvin, C.G., Wouters, E.F.M., Reynaert, N.L., Dixon, A.E., Van Der Vliet, A., Poynter, M.E. & Janssen-Heininger, Y.M.W. 2016, 'Ablation of glutaredoxin-1 modulates house dust mite-induced allergic airways disease in mice', American Journal of Respiratory Cell and Molecular Biology, vol. 55, no. 3, pp. 377-386.
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© 2016 by the American Thoracic Society.Protein S-glutathionylation (PSSG) is an oxidant-induced posttranslational modification of protein cysteines that impacts structure and function. The oxidoreductase glutaredoxin-1 (Glrx1) under physiological conditions catalyzes deglutathionylation and restores the protein thiol group. The involvement of Glrx1/PSSG in allergic inflammation induced by asthma-relevant allergens remains unknown. In the present study, we examined the impact of genetic ablation of Glrx1 in the pathogenesis of house dust mite (HDM)-induced allergic airways disease in mice. Wild-type (WT) or Glrx1-/-mice were instilled intranasally withHDMon 5 consecutive days for 3 weeks. As expected, overall PSSG was increased in Glrx1-/- HDM mice as compared with WT animals. Total cells in bronchoalveolar lavage fluid were similarly increased in HDMtreated WT and Glrx1-/- mice. However, in response to HDM, mice lacking Glrx1 demonstrated significantly more neutrophils and macrophages but fewer eosinophils as compared with HDM-exposed WT mice. mRNA expression of the Th2-associated cytokines IL-13 and IL-6, as well as mucin-5AC (Muc5ac), was significantly attenuated in Glrx1-/- HDM-treated mice. Conversely, mRNA expression of IFN- and IL-17A was increased in Glrx1-/-HDM mice compared with WT littermates. Restimulation of singlecell suspensions isolated from lungs or spleens withHDMresulted in enhanced IL-17A and decreased IL-5 production in cells derived from inflamed Glrx1-/- mice compared with WT animals. Finally, HDM-induced tissue damping and elastance were significantly attenuated in Glrx1-/- mice compared with WT littermates. These results demonstrate that the Glrx1-PSSG axis plays a pivotal role in HDM-induced allergic airways disease in association with enhanced type 2 inflammation and restriction of IFN- and IL-17A.
Hoffman, S.M., Nolin, J.D., Jones, J.T., Lahue, K.G., Chapman, D.G., Aliyeva, M., Daphtary, N., Lundblad, L.K.A., Abdalla, S., Ather, J.L., Ho, Y.-.S., Irvin, C.G., Anathy, V., Wouters, E.F.M., Poynter, M.E. & Janssen-Heininger, Y.M.W. 2016, 'Ablation of the Thiol Transferase Glutaredoxin-1 Augments Protein S-Glutathionylation and Modulates Type 2 Inflammatory Responses and IL-17 in a House Dust Mite Model of Allergic Airway Disease in Mice.', Ann Am Thorac Soc, vol. 13 Suppl 1, p. S97.
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S-glutathionylation has emerged as an oxidant-induced post-translational modification of protein cysteines that affects structure and function. The oxidoreductase glutaredoxin-1 (Glrx1), under physiological conditions, catalyzes deglutathionylation and restores the protein thiol group. The involvement of Grx1/S-glutathionylation in allergic inflammation induced by asthma-relevant allergens remains unknown. In the present study we examined the impact of genetic ablation of Glrx1 for the pathogenesis of house dust mite (HDM)-induced allergic airway disease in mice. Wild-type (WT) or Glrx1(-/-) mice in the BALB/c background were instilled intranasally with 50 g of HDM 5 consecutive days for 3 weeks and killed 72 hours post final exposure. As expected, overall protein S-glutathionylation was increased in Glrx1(-/-) mice exposed to HDM as compared with WT animals. Total cells in the bronchoalveolar lavage fluid were similarly increased in WT and Glrx1(-/-) HDM-treated mice compared with phosphate-buffered saline-treated control mice. However, in response to HDM, mice lacking Glrx1 demonstrated significantly more neutrophils but fewer eosinophils than HDM-exposed WT mice. mRNA expression of the Th2-associated cytokine IL-13, as well as MUC5ac, was significantly attenuated in Glrx1(-/-) HDM-treated mice compared with WT mice. Conversely, expression of IL-17A was increased in Glrx1(-/-) HDM mice compared with WT mice. Last, HDM-induced tissue damping and elastance were significantly attenuated in Glrx1(-/-) mice compared with WT littermates. These results demonstrate that the Grx1/S-glutathionylation redox status plays a pivotal role in HDM-induced allergic inflammation and airway hyperresponsiveness and suggest a potential role of Glrx1/S-glutathionylation in controlling the nature of the HDM-induced adaptive immune responses by promoting Type-2-driven inflammation and restricting IL-17A.
van der Velden, J.L.J., Ye, Y., Nolin, J.D., Hoffman, S.M., Chapman, D.G., Lahue, K.G., Abdalla, S., Chen, P., Liu, Y., Bennett, B., Khalil, N., Sutherland, D., Smith, W., Horan, G., Assaf, M., Horowitz, Z., Chopra, R., Stevens, R.M., Palmisano, M., Janssen-Heininger, Y.M.W. & Schafer, P.H. 2016, 'JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers.', Clin Transl Med, vol. 5, no. 36, pp. 1-18.
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BACKGROUND: Lung remodeling and pulmonary fibrosis are serious, life-threatening conditions resulting from diseases such as chronic severe asthma and idiopathic pulmonary fibrosis (IPF). Preclinical evidence suggests that JNK enzyme function is required for key steps in the pulmonary fibrotic process. However, a selective JNK inhibitor has not been investigated in translational models of lung fibrosis with clinically relevant biomarkers, or in IPF patients. METHODS: The JNK inhibitor CC-930 was evaluated in the house dust mite-induced fibrotic airway mouse model, in a phase I healthy volunteer pharmacodynamic study, and subsequently in a phase II multicenter study of mild/moderate IPF (n = 28), with a 4-week, placebo-controlled, double-blind, sequential ascending-dose period (50 mg QD, 100 mg QD, 100 mg BID) and a 52-week open-label treatment-extension period. RESULTS: In the preclinical model, CC-930 attenuated collagen 1A1 gene expression, peribronchiolar collagen deposition, airway mucin MUC5B expression in club cells, and MMP-7 expression in lung, bronchoalveolar lavage fluid, and serum. In the phase I study, CC-930 reduced c-Jun phosphorylation induced by UV radiation in skin. In the phase II IPF study, there was a CC-930 dose-dependent trend in reduction of MMP-7 and SP-D plasma protein levels. The most commonly reported adverse events were increased ALT, increased AST, and upper respiratory tract infection (six subjects each, 21.4 %). A total of 13 subjects (46.4 %) experienced adverse events that led to discontinuation of study drug. Nine out of 28 subjects experienced progressive disease in this study. The mean FVC (% predicted) declined after 26-32 weeks at doses of 100 mg QD and 100 mg BID. Changes in MMP-7, SP-D, and tenascin-C significantly correlated with change in FVC (% predicted). CONCLUSIONS: These results illustrate JNK enzymatic activity involvement during pulmonary fibrosis, and support systemic biomarker use for tracking disease progression ...
Jones, C.A., Chapman, D.G., Weimersheimer, P., Fernandez, L., Alejandro Mesa, O., Peters, C., Vanaudenaerde, B.M., Norotsky, M.C. & Vos, R. 2016, 'The Burden of Cost in Bronchiolitis Obliterans Syndrome: Predictions for the Next Decade', Journal of Health Economics and Outcomes Research, vol. 4, no. 2, pp. 119-126.
Chapman, D.G. & Irvin, C.G. 2015, 'Mechanisms of airway hyper-responsiveness in asthma: the past, present and yet to come.', Clin Exp Allergy, vol. 45, no. 4, pp. 706-719.
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Airway hyper-responsiveness (AHR) has long been considered a cardinal feature of asthma. The development of the measurement of AHR 40 years ago initiated many important contributions to our understanding of asthma and other airway diseases. However, our understanding of AHR in asthma remains complicated by the multitude of potential underlying mechanisms which in reality are likely to have different contributions amongst individual patients. Therefore, the present review will discuss the current state of understanding of the major mechanisms proposed to contribute to AHR and highlight the way in which AHR testing is beginning to highlight distinct abnormalities associated with clinically relevant patient populations. In doing so we aim to provide a foundation by which future research can begin to ascribe certain mechanisms to specific patterns of bronchoconstriction and subsequently match phenotypes of bronchoconstriction with clinical phenotypes. We believe that this approach is not only within our grasp but will lead to improved mechanistic understanding of asthma phenotypes and we hoped to better inform the development of phenotype-targeted therapy.
Chapman, D.G., Pascoe, C.D., Lee-Gosselin, A., Couture, C., Seow, C.Y., Paré, P.D., Salome, C.M., King, G.G. & Bossé, Y. 2014, 'Smooth muscle in the maintenance of increased airway resistance elicited by methacholine in humans.', Am J Respir Crit Care Med, vol. 190, no. 8, pp. 879-885.
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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, ASM shortening 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.
Chapman, D.G., Tully, J.E., Nolin, J.D., Janssen-Heininger, Y.M. & Irvin, C.G. 2014, 'Animal models of allergic airways disease: where are we and where to next?', J Cell Biochem, vol. 115, no. 12, pp. 2055-2064.
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In a complex inflammatory airways disease such as asthma, abnormalities in a plethora of molecular and cellular pathways ultimately culminate in characteristic impairments in respiratory function. The ability to study disease pathophysiology in the setting of a functioning immune and respiratory system therefore makes mouse models an invaluable tool in translational research. Despite the vast understanding of inflammatory airways diseases gained from mouse models to date, concern over the validity of mouse models continues to grow. Therefore the aim of this review is twofold; firstly, to evaluate mouse models of asthma in light of current clinical definitions, and secondly, to provide a framework by which mouse models can be continually refined so that they continue to stand at the forefront of translational science. Indeed, it is in viewing mouse models as a continual work in progress that we will be able to target our research to those patient populations in whom current therapies are insufficient.
Al-Alwan, A., Bates, J.H.T., Chapman, D.G., Kaminsky, D.A., DeSarno, M.J., Irvin, C.G. & Dixon, A.E. 2014, 'The nonallergic asthma of obesity. A matter of distal lung compliance.', Am J Respir Crit Care Med, vol. 189, no. 12, pp. 1494-1502.
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RATIONALE: The pathogenesis of asthma in obesity is poorly understood, but may be related to breathing at low lung volumes. OBJECTIVES: To determine if lung function in obese patients with asthma and control subjects would respond differently to weight loss. METHODS: Lung function was evaluated by conventional clinical tests and by impulse oscillometry in female late-onset, nonallergic patients with asthma and control subjects before, and 12 months after, bariatric surgery. MEASUREMENTS AND MAIN RESULTS: Patients with asthma (n = 10) had significantly lower FEV1 (79.8 ± 10.6 vs. 95.5 ± 7.0%) and FVC (82.4 ± 13.2 vs. 93.7 ± 8.9%) compared with control subjects (n = 13). There were no significant differences in FRC or TLC at baseline. Twelve months after surgery, control subjects had significant increases in FEV1 (95.5 ± 7.0 to 100.7 ± 5.9), FVC (93.6 ± 8.9 to 98.6 ± 8.3%), FRC (45.4 ± 18.5 to 62.1 ± 15.3%), and TLC (84.8 ± 15.0 to 103.1 ± 15.3%), whereas patients with asthma had improvement only in FEV1 (79.8 ± 10.6 to 87.2 ± 11.5). Control subjects and patients with asthma had a significantly different change in respiratory system resistance with weight loss: control subjects exhibited a uniform decrease in respiratory system resistance at all frequencies, whereas patients with asthma exhibited a decrease in frequency dependence of resistance. Fits of a mathematical model of lung mechanics to these impedance spectra suggest that the lung periphery was more collapsed by obesity in patients with asthma compared with control subjects. CONCLUSIONS: Weight loss decompresses the lung in both obese control subjects and patients with asthma, but the more pronounced effects of weight loss on lung elastance suggest that the distal lung is inherently more collapsible in people with asthma.
Kaminsky, D.A., Daud, A. & Chapman, D.G. 2014, 'Relationship between the baseline alveolar volume-to-total lung capacity ratio and airway responsiveness.', Respirology, vol. 19, no. 7, pp. 1046-1051.
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BACKGROUND AND OBJECTIVE: Ventilation heterogeneity (VH) has been linked to airway responsiveness (AR) based on various measures of VH involving inert gas washout, forced oscillation and lung imaging. We explore whether VH at baseline, as measured by the simple ratio of single breath alveolar volume to plethysmographically determined total lung capacity (VA/TLC), would correlate with AR as measured by methacholine challenge testing. METHODS: We analysed data from spirometry, lung volumes, diffusing capacity and methacholine challenge to derive the VA/TLC and the dose-response slope (DRS) of forced expiratory volume in 1s (DRS-FEV1) during methacholine challenge from 136 patients. We separated out airway closure versus narrowing by examining the DRS for forced vital capacity (DRS-FVC) and the DRS for FEV1/FVC (DRS-FEV1/FVC), respectively. Similarly, we calculated the DRS for sGaw (DRS-sGaw) as another measure of airway narrowing. We performed statistical analysis using Spearman rank correlation and multifactor linear regression using a backward stepwise modelling procedure. RESULTS: We found that the DRS-FEV1 correlated with baseline VA/TLC (rho=-0.26, P<0.01), and VA/TLC and FEV1 were independently associated with DRS-FEV1 (R(2) =0.14, P=0.01). In addition, VA/TLC was associated with both airway narrowing and closure in response to methacholine. CONCLUSIONS: These results confirm that baseline VA/TLC is associated with AR, and reflects both airway closure and airway narrowing following methacholine challenge.
Chapman, D.G., Irvin, C.G., Kaminsky, D.A., Forgione, P.M., Bates, J.H.T. & Dixon, A.E. 2014, 'Influence of distinct asthma phenotypes on lung function following weight loss in the obese', Respirology, vol. 19, no. 8, pp. 1170-1177.
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&copy; 2014 Asian Pacific Society of Respirology.Background and objective: There appears to be two distinct clinical phenotypes of obese patients with asthma - those with early-onset asthma and high serum IgE (TH2-high), and those with late-onset asthma and low serum IgE (TH2-low). The aim of the present study was to determine in the two phenotypes of obese asthma the effect of weight loss on small airway function. Methods: TH2-low (n = 8) and TH2-high (n = 5) obese asthmatics underwent methacholine challenge before and 12 months following bariatric surgery. Dose-response slopes as measures of sensitivity to airway closure and narrowing were measured as maximum % fall forced vital capacity (FVC) and forced expiratory volume in 1 s/FVC, respectively, divided by dose. Resting airway mechanics were measured by forced oscillation technique. Results: Weight loss reduced sensitivity to airway closure in TH2-low but not TH2-high obese asthmatics (pre-post mean change &plusmn; 95% confidence interval: 1.8 &plusmn; 0.8 doubling doses vs -0.3 &plusmn; 1.7 doubling doses, P = 0.04).However, there was no effect ofweight loss on the sensitivity to airway narrowing in either group (P = 0.8, TH2-low: 0.8 &plusmn; 1.0 doubling doses, TH2-high: -1.1 &plusmn; 2.5 doubling doses). In contrast, respiratory resistance (20 Hz) improved in TH2-high but not in TH2-low obese asthmatics (pre-post change median interquartile range: 1.5 (1.3-2.8) cmH2O/L/s vs 0.6 (-1.8-0.8) cmH2O/L/s, P = 0.03). Conclusions: TH2-low obese asthmatics appear to be characterized by increased small airway responsiveness and abnormalities in resting airway function that may persist followingweight loss.However, this was not the case for TH2-high obese asthmatics, highlighting the complex interplay between IgE status and asthma pathophysiology in obesity.
van der Velden, J.L.J., Hoffman, S.M., Alcorn, J.F., Tully, J.E., Chapman, D.G., Lahue, K.G., Guala, A.S., Lundblad, L.K.A., Aliyeva, M., Daphtary, N., Irvin, C.G. & Janssen-Heininger, Y.M.W. 2014, 'Absence of c-Jun NH2-terminal kinase 1 protects against house dust mite-induced pulmonary remodeling but not airway hyperresponsiveness and inflammation.', Am J Physiol Lung Cell Mol Physiol, vol. 306, no. 9, pp. L866-L875.
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Chronic allergic asthma leads to airway remodeling and subepithelial fibrosis via mechanisms not fully understood. Airway remodeling is amplified by profibrotic mediators, such as transforming growth factor-1 (TGF-1), which plays a cardinal role in various models of fibrosis. We recently have identified a critical role for c-Jun-NH2-terminal-kinase (JNK) 1 in augmenting the profibrotic effects of TGF-1, linked to epithelial-to-mesenchymal transition of airway epithelial cells. To examine the role of JNK1 in house dust mite (HDM)-induced airway remodeling, we induced allergic airway inflammation in wild-type (WT) and JNK1-/- mice by intranasal administration of HDM extract. WT and JNK1-/- mice were sensitized with intranasal aspirations of HDM extract for 15 days over 3 wk. HDM caused similar increases in airway hyperresponsiveness, mucus metaplasia, and airway inflammation in WT and JNK1-/- mice. In addition, the profibrotic cytokine TGF-1 and phosphorylation of Smad3 were equally increased in WT and JNK1-/- mice. In contrast, increases in collagen content in lung tissue induced by HDM were significantly attenuated in JNK1-/- mice compared with WT controls. Furthermore HDM-induced increases of -smooth muscle actin (-SMA) protein and mRNA expression as well as the mesenchymal markers high-mobility group AT-hook 2 and collagen1A1 in WT mice were attenuated in JNK1-/- mice. The let-7 family of microRNAs has previously been linked to fibrosis. HDM exposure in WT mice and primary lung epithelial cells resulted in striking decreases in let-7g miRNA that were not observed in mice or primary lung epithelial cells lacking JNK1-/- mice. Overexpression of let-7g in lung epithelial cells reversed the HDM-induced increases in -SMA. Collectively, these findings demonstrate an important requirement for JNK1 in promoting HDM-induced fibrotic airway remodeling.
Hulme, K.M., Salome, C.M., Brown, N.J., Berend, N., Agus, H.M., Horlyck, K.R., King, G.G. & Chapman, D.G. 2013, 'Deep inspiration volume and the impaired reversal of bronchoconstriction in asthma.', Respir Physiol Neurobiol, vol. 189, no. 3, pp. 506-512.
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It is unclear whether the failure to reverse bronchoconstriction with deep inspiration (DI) in asthma is due to reduced maximal dilatation of the DI. We compared the effect of different DI volumes on maximal dilatation and reversal of bronchoconstriction in nine asthmatics and ten non-asthmatics. During bronchoconstriction, subjects took DI to 40%, 70% and 100% inspiratory capacity, on separate days. Maximal dilatation was measured as respiratory system resistance (Rrs) at end-inspiration and residual dilatation as Rrs at end-expiration, both expressed as percent of Rrs at end-tidal expiration prior to DI. DI volume was positively associated with maximal dilatation in non-asthmatics (ANOVA p=0.055) and asthmatics (p=0.023). DI volume was positively associated with residual dilatation in non-asthmatics (p=0.004) but not in asthmatics (p=0.53). The degree of maximal dilatation independently predicted residual dilatation in non-asthmatics but not asthmatics. These findings suggest that the failure to reverse bronchoconstriction with DI in asthma is not due to reduced maximal dilatation, but rather due to increased airway narrowing during expiration.
Chapman, D.G. & Salome, C.M. 2013, 'Lifestyles of the fat and lazy.', Clin Exp Allergy, vol. 43, no. 1, pp. 2-4.
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Chapman, D. & Farah, C.S. 2013, 'Understanding the effects of obesity on asthma', Salud(i)Ciencia, vol. 20, no. 1, pp. 61-64.
Asthma is a chronic inflammatory disease of the airways characterised by airways that narrow too easily and too much to stimuli. These episodes of airway narrowing present symptomatically as periods of wheezing, breathlessness, chest tightness and/or coughing In obese patients with asthma, symptoms appear to be less responsive to inhaled corticosteroids compared to non-obese asthmatics. It is unclear as to whether obesity "up-regulates" the normal asthma disease pathway or directly increases asthma symptoms without altering asthma pathophysiology. Recent evidence from our laboratory suggests that obesity detrimentally affects asthma control independently of any effect on the normal asthma disease pathophysiology. Furthermore, obesity increases the amount of airway closure during bronchoconstriction, although it is unknown as to whether this leads to worse asthma control in obese asthmatics. Nonetheless, our research suggests that, in obese asthmatics, consideration should be given to the role of obesity-related factors that are not responsive to inhaled corticosteroid treatment in the manifestation of asthma-like symptoms. Copyright &copy; Sociedad Iberoamericana de Informaci&oacute;n Cient&iacute;fica (SIIC), 2013.
Janssen-Heininger, Y.M.W., Nolin, J.D., Hoffman, S.M., van der Velden, J.L., Tully, J.E., Lahue, K.G., Abdalla, S.T., Chapman, D.G., Reynaert, N.L., van der Vliet, A. & Anathy, V. 2013, 'Emerging mechanisms of glutathione-dependent chemistry in biology and disease.', J Cell Biochem, vol. 114, no. 9, pp. 1962-1968.
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Glutathione has traditionally been considered as an antioxidant that protects cells against oxidative stress. Hence, the loss of reduced glutathione and formation of glutathione disulfide is considered a classical parameter of oxidative stress that is increased in diseases. Recent studies have emerged that demonstrate that glutathione plays a more direct role in biological and pathophysiological processes through covalent modification to reactive cysteines within proteins, a process known as S-glutathionylation. The formation of an S-glutathionylated moiety within the protein can lead to structural and functional modifications. Activation, inactivation, loss of function, and gain of function have all been attributed to S-glutathionylation. In pathophysiological settings, S-glutathionylation is tightly regulated. This perspective offers a concise overview of the emerging field of protein thiol redox modifications. We will also cover newly developed methodology to detect S-glutathionylation in situ, which will enable further discovery into the role of S-glutathionylation in biology and disease.
Chapman, D.G., Berend, N., Horlyck, K.R., King, G.G. & Salome, C.M. 2012, 'Does increased baseline ventilation heterogeneity following chest wall strapping predispose to airway hyperresponsiveness?', J Appl Physiol (1985), vol. 113, no. 1, pp. 25-30.
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Baseline ventilation heterogeneity is associated with airway hyperresponsiveness (AHR) in asthma; however, it is unknown whether increased baseline ventilation heterogeneity leads to AHR or both are independent effects of similar disease pathophysiology. Reducing functional residual capacity (FRC) in healthy subjects increases baseline ventilation heterogeneity and airway responsiveness, but the relationship between the two is unclear. The aim was to determine whether an increase in baseline ventilation heterogeneity due to a reduction in FRC correlated with the increase in response to methacholine. In 13 healthy male subjects, ventilation heterogeneity was measured by multiple-breath N(2) washout before a cumulative high-dose (0.79-200 mol) methacholine challenge. On a separate day, the protocol was performed with chest wall strapping (CWS) to reduce FRC. Indexes of ventilation heterogeneity in the convection-dependent (Scond) and diffusion-convection-dependent (Sacin) airways were calculated from the multiple-breath N(2) washout. CWS decreased FRC by 15.6 &plusmn; 2.7% (P < 0.0001). CWS increased the percent fall in forced expiratory volume in 1 s during bronchial challenge (P = 0.006), and the magnitude of this effect was independently determined by the effect of CWS on Sacin and FRC (r(adj)(2) = 0.55, P = 0.02). This suggests that changes in baseline ventilation heterogeneity in healthy subjects are sufficient to increase airway responsiveness, independent of the presence of disease pathology.
Bossé, Y., Chapman, D.G., Paré, P.D., King, G.G. & Salome, C.M. 2011, 'A 'Good' muscle in a 'Bad' environment: the importance of airway smooth muscle force adaptation to airway hyperresponsiveness.', Respir Physiol Neurobiol, vol. 179, no. 2-3, pp. 269-275.
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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" [Boss&eacute;, Y., Chin, L.Y., Par&eacute;, 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.
Chapman, D.G., Berend, N., King, G.G. & Salome, C.M. 2011, 'Effect of deep inspiration avoidance on ventilation heterogeneity and airway responsiveness in healthy adults.', J Appl Physiol (1985), vol. 110, no. 5, pp. 1400-1405.
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The mechanisms by which deep inspiration (DI) avoidance increases airway responsiveness in healthy subjects are not known. DI avoidance does not alter respiratory mechanics directly; however, computational modeling has predicted that DI avoidance would increase baseline ventilation heterogeneity. The aim was to determine if DI avoidance increased baseline ventilation heterogeneity and whether this correlated with the increase in airway responsiveness. Twelve healthy subjects had ventilation heterogeneity measured by multiple-breath nitrogen washout (MBNW) before and after 20 min of DI avoidance. This was followed by another 20-min period of DI avoidance before the inhalation of a single methacholine dose. The protocol was repeated on a separate day with the addition of five DIs at the end of each of the two periods of DI avoidance. Baseline ventilation heterogeneity in convection-dependent and diffusion-convection-dependent airways was calculated from MBNW. The response to methacholine was measured by the percent fall in forced expiratory volume in 1 s/forced vital capacity (FVC) (airway narrowing) and percent fall in FVC (airway closure). DI avoidance increased baseline diffusion-convection-dependent airways (P = 0.02) but did not affect convection-dependent airways (P = 0.9). DI avoidance increased both airway closure (P = 0.002) and airway narrowing (P = 0.02) during bronchial challenge. The increase in diffusion-convection-dependent airways due to DI avoidance did not correlate with the increase in either airway narrowing (r(s) = 0.14) or airway closure (r(s) = 0.12). These findings suggest that DI avoidance increases diffusion-convection-dependent ventilation heterogeneity that is not associated with the increase in airway responsiveness. We speculate that DI avoidance reduces surfactant release, which increases peripheral ventilation heterogeneity and also predisposes to peripheral airway closure.
Chapman, D.G., Brown, N.J. & Salome, C.M. 2011, 'The dynamic face of respiratory research: understanding the effect of airway disease on a lung in constant motion.', Pulm Pharmacol Ther, vol. 24, no. 5, pp. 505-512.
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The lungs are in a constant state of motion. The dynamic nature of tidal breathing, whereby cycles of pressure changes across the lungs cause the chest wall, lung tissue and airways to repeatedly expand and contract, ventilates the lung tissue and allows respiration to occur. However, these regular cycles of tidal inspirations and expirations are punctuated by breaths of differing volumes, most particularly periodic deep inspirations. In normal, healthy subjects, these deep inspirations have a dual effect in reducing airway responsiveness. Firstly, deep inspirations taken under baseline conditions protect the airways against subsequent bronchoconstriction, termed DI bronchoprotection. Secondly, deep inspirations are able to dramatically reverse bronchoconstriction. The ability for deep inspirations to reverse bronchoconstriction appears to be due to both the ability to dilate the airways with a full inspiration to total lung capacity (TLC) and the rate at which the airways re-narrow once tidal breathing is resumed. Deep inspiration reversal is reduced in subjects with asthma and is due both to a reduced ability to dilate the airways as well as an increase in the rate of re-narrowing. On the other hand, DI bronchoprotection is completely absent in asthma. Although the mechanisms behind these abnormalities remain unclear, the inability for deep inspirations to both protect against and fully reverse bronchoconstriction in patients with asthma appears critical in the development of airway hyperresponsiveness. As such, determining the pathophysiology responsible for the malfunction of deep inspirations in asthma remains critical to understanding the disease and is likely to pave the way for novel therapeutic targets.
Chapman, D.G., King, G.G., Berend, N., Diba, C. & Salome, C.M. 2010, 'Avoiding deep inspirations increases the maximal response to methacholine without altering sensitivity in non-asthmatics.', Respir Physiol Neurobiol, vol. 173, no. 2, pp. 157-163.
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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 FEV(1) DRC to methacholine. Thirteen non-asthmatic and ten asthmatic subjects underwent a standard cumulative high-dose methacholine challenge (0.1-200mol). 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 , the position constant, as a measure of sensitivity. The fall in FEV(1) 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 (V40m) and partial (V40p) curves were calculated from the first manoeuvre after methacholine and the ratio of the values for V40m and V40p was calculated as a measure of the bronchodilator effect of DI (BD(DI)). In non-asthmatic subjects, avoiding DI increased the maximum fall in FEV(1) at the highest common dose (p=0.0001) but did not alter (p=0.75). Avoiding DI before challenge did not alter BD(DI) (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.
Chapman, D.G., Berend, N., King, G.G. & Salome, C.M. 2010, 'Can we cure airway hyperresponsiveness with a gym membership?', J Appl Physiol (1985), vol. 109, no. 2, pp. 267-268.
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Chapman, D.G., Berend, N., King, G.G., McParland, B.E. & Salome, C.M. 2009, 'Deep inspirations protect against airway closure in nonasthmatic subjects.', J Appl Physiol (1985), vol. 107, no. 2, pp. 564-569.
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The mechanism by which deep inspirations protect against increased airway responsiveness in nonasthmatic subjects is not known. The aim was to investigate the role of airway closure and airway narrowing in deep inspiration bronchoprotection. Twelve nonasthmatic and nine asthmatic subjects avoided deep inspirations (DI) for 20 min, then took five DI expired to functional residual capaciy (DI-FRC) or, on a separate day, no DI (no DI) before inhaling a single dose of methacholine. On another day, eight nonasthmatic subjects took five DI expired to residual volume (DI-RV). Peripheral airway function was measured by respiratory system reactance (Xrs), using the forced oscillation technique, and by forced vital capacity (FVC) as an index of airway closure. Respiratory system resistance (Rrs) and forced expiratory volume in 1 s (FEV1)/FVC were measured as indexes of airway narrowing. In nonasthmatic subjects, DI-FRC reduced the response measured by FEV1 (P=0.019), Xrs (P=0.02), and FVC (P=0.0005) but not by Rrs (P=0.15) or FEV1/FVC (P=0.52) compared with no DI. DI-RV had a less protective effect than DI-FRC on response measured by FEV1 (P=0.04) and FVC (P=0.016). There was no difference between all protocols when the response was measured by Xrs (P=0.20), Rrs (P=0.88), or FEV1/FVC (P=0.88). DI had no effect on methacholine response in asthmatic subjects. DI protect against airway responsiveness through an effect on peripheral airways involving reduced airway closure. The protective effect of DI on FEV1 and FVC was abolished by expiration to residual volume. We speculate that the reduced airway closure is due to reduced baseline ventilation heterogeneity and/or reduced airway surface tension.
Chapman, D.G., Berend, N., King, G.G. & Salome, C.M. 2008, 'Increased airway closure is a determinant of airway hyperresponsiveness.', Eur Respir J, vol. 32, no. 6, pp. 1563-1569.
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In order to investigate whether increased airway closure is a component of airway hyperresponsiveness (AHR), airway closure was compared during induced bronchoconstriction in 62 asthmatic, 41 nonasthmatic nonobese (control) and 20 nonasthmatic obese (obese) subjects. Airway closure and airway narrowing were measured by spirometry as percentage change in forced vital capacity (%DeltaFVC) and change in forced expiratory ratio (DeltaFER), respectively. Multiple regression analyses were used to assess the determinants of AHR, assessed by the dose response slope (DRS). The DRS was significantly increased in asthmatics compared with controls but did not differ between obese and controls. The spirometric predictors of logDRS were baseline FER, DeltaFER, body mass index (BMI) and %DeltaFVC. There was a negative relationship between BMI and logDRS in the regression, suggesting a protective effect. The present findings suggest that the extent of airway closure during induced bronchoconstriction is a determinant of airway hyperresponsiveness, independent of the level of airway narrowing. However, after adjusting for airway closure, obesity appears to protect against airway hyperresponsiveness.
My active collaborations include:
Professor Charles Irvin (University of Vermont, USA)
Professor Yvonne Janssen-Heininger (University of Vermont, USA)
Professor David Kaminsky (University of Vermont, USA)
A/Prof Vikas Anathy (University of Vermont, USA)
A/Prof Ynuk Bosse (University of Laval,  Canada)