Dr David Chapman is a translational physiologist with extensive expertise in airways diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Dr Chapman completed his PhD in Medicine at the Woolcock Institute of Medical Research in 2011. David was awarded an NHMRC Early Career Fellowship for 2013 to expand his research at the University of Vermont, USA. He continued at the University of Vermont for a subsequent two years in which he integrated new lung function tests into the Centre’s animal models of respiratory disease and helped initiate an ongoing research program understanding the effect of obesity for patients with asthma. Dr Chapman returned to Australia in December 2016 to lead the Translational Airways Group at the University of Technology Sydney with a joint position in the Airway Physiology Group at the Woolcock Institute of Medical Research. He has an international reputation in lung function measurement, particularly in relation to small airway dysfunction, airway hyperresponsiveness and obesity. His main research interests lie in understanding the way in which interventions such as obesity and tobacco use alter lung function and contribute to respiratory disease. David’s work has been recognised by multiple awards including the 2018 Ann Woolcock Award from the American Thoracic Society for “outstanding contributions and future promise in asthma research”.
Member, Program Committee, Respiratory Structure and Function Assembly, American Thoracic Society, 2018 - present
Member, Working Group, Thoracic Society of Australia and New Zealand (TSANZ) position paper on Electronic Nicotine Delivery Systems, 2018 - present
2018 Ann Woolcock Memorial Award, Assembly on Respiratory Structure & Function, American Thoracic Society
2018 John Read Prize for Sleep and Physiology, TSANZ national annual scientific meeting
2017 Best Poster Presentation, TSANZ NSW annual scientific meeting
2017 Best Poster Presentation, TSANZ national annual scientific meeting
2013-2017 NHMRC CJ Martin Post-doctoral Fellowship
2011 John Read Prize for Sleep and Physiology, TSANZ national annual scientific meeting
Can supervise: YES
The link between lung function and co-morbidities in Chronic Obstructive Lung Disease
In COPD, the destruction of lung tissue leads to gas trapping and hyperinflation, a condition in which patients breathe at abnormally high lung volumes. Hyperinflation is central to the reduced quality of life in patients with COPD, being correlated with increased symptoms, reduced exercise capacity, reduced cardiac function and worse sleep quality. We are currently investigating novel interventions to reduce hyperinflation in patients with COPD in order to improve exercise capacity, cardiac function and sleep quality.
The effect of Obesity on Respiratory Disease
Obesity is an important co-morbidity in patients with asthma and Chronic Obstructive Pulmonary Disease (COPD). Obesity is associated with increased respiratory symptoms, a reduced response to therapy and increased frequency of exacerbations. Although the mechanisms are not well understood, it is well know that obesity alters lung function in healthy people and that lung function in patients with respiratory disease is a net result of the effects of obesity and the effects of lung disease. We are currently trying to understand the complex relationship between obesity, respiratory disease and lung function in order to understand the contribution of obesity to the clinical management of obese patients with respiratory disease.
The effect of novel nicotine delivery systems on lung development and respiratory disease
Tobacco smoking is a major contributor to a multitude of diseases, including contributions to the development and severity of respiratory disease. Despite ample access to Nicotine Replacement Therapy and other smoking cessation tools, many smokers are not successful with long-term quit attempts. Therefore, several new nicotine delivery systems have been introduced in an attempt to reduce the harm due to tobacco smoking, including electronic cigarettes, heat-not-burn tobacco products and low nicotine cigarettes. However, it is unknown whether these are actually safer than tobacco cigarettes and if they are, to what extent. We are currently determining the potential for novel nicotine delivery systems to contribute to respiratory disease using mouse models of in utero exposure and mouse models of allergic airways disease.
Respiratory Physiology (MED1000)
Bozier, J, Chivers, EK, Chapman, DG, Larcombe, AN, Bastian, NA, Masso-Silva, JA, Byun, MK, McDonald, CF, Alexander, LEC & Ween, MP 2020, 'The Evolving Landscape of e-Cigarettes A Systematic Review of Recent Evidence', CHEST, vol. 157, no. 5, pp. 1362-1390.View/Download from: Publisher's site
Chapman, DG, King, GG, Robinson, PD, Farah, CS & Thamrin, C 2020, 'The need for physiological phenotyping to develop new drugs for airways disease.', Pharmacological research, vol. 159, p. 105029.View/Download from: Publisher's site
Asthma and COPD make up the majority of obstructive airways diseases (OADs), which affects ∼11 % of the population. The main drugs used to treat OADs have not changed in the past five decades, with advancements mainly comprising variations on existing treatments. The recent biologics are beneficial to only specific subsets of patients. Part of this may lie in our inability to adequately characterise the tremendous heterogeneity in every aspect of OAD. The field is currently moving towards the concept of personalised medicine, based on a focus on treatable traits that are objective, measurable and modifiable. We propose extending this concept via the use of emerging clinical tools for comprehensive physiological phenotyping. We describe, based on published data, the evidence for the use of functional imaging, gas washout techniques and oscillometry, as well as potential future applications, to more comprehensively assess and predict treatment response in OADs. In this way, we hope to demonstrate how physiological phenotyping tools will improve the way in which drugs are prescribed, but most importantly, will facilitate development of new drugs for OADs.
Rutting, S, Mahadev, S, Tonga, KO, Bailey, DL, Dame Carroll, JR, Farrow, CE, Thamrin, C, Chapman, DG & King, GG 2020, 'Obesity alters the topographical distribution of ventilation and the regional response to bronchoconstriction.', Journal of applied physiology (Bethesda, Md. : 1985).View/Download from: Publisher's site
Obesity is associated with reduced operating lung volumes that may contribute to increased airway closure during tidal breathing and abnormalities in ventilation distribution. We investigated the effect of obesity on the topographical distribution of ventilation before and after methacholine-induced bronchoconstriction using single-photon emission computed tomography (SPECT)-CT in healthy subjects. Nine obese and 10 non-obese subjects underwent baseline and post-bronchoprovocation SPECT-CT imaging, in which Technegas was inhaled upright followed by supine scanning. Lung regions that were non-ventilated (Ventnon), low-ventilated (Ventlow) or well-ventilated (Ventwell) were calculated using an adaptive threshold method and were expressed as a percentage of total lung volume. To determine regional ventilation, lungs were divided into upper, middle and lower thirds of axial length derived from CT. At baseline, Ventnon and Ventlow for the entire lung, were similar in obese and non-obese subjects. However, in the upper lung zone, Ventnon (17.5±10.6% vs. 34.7±7.8%, p<0.001) and Ventlow (25.7±6.3% vs. 33.6±5.1%, p<0.05) were decreased in obese subjects with a consequent increase in Ventwell (56.8±9.2% vs. 31.7±10.1%, p<0.001). The greater diversion of ventilation to the upper zone was correlated with BMI (rs=0.74, p<0.001), Rrs (rs=0.72, p<0.001), and Xrs (rs=-0.64, p=0.003), but not with lung volumes or basal airway closure. Following bronchoprovocation overall Ventnon increased similarly in both groups, however in non-obese subjects Ventnon only increased in the lower zone, whereas in obese subjects Ventnon increased more evenly across all lung zones. In conclusion, obesity is associated with altered ventilation distribution during baseline and following bronchoprovocation that are independent of reduced lung volumes.
Tang, FSM, Rutting, S, Farrow, CE, Tonga, KO, Watts, J, Dame-Carrol, JR, Bertolin, A, King, GG, Thamrin, C & Chapman, DG 2020, 'Ventilation heterogeneity and oscillometry predict asthma control improvement following step-up inhaled therapy in uncontrolled asthma', RESPIROLOGY.View/Download from: Publisher's site
Tonga, KO, Chapman, DG, Farah, CS, Oliver, BG, Zimmermann, SC, Milne, S, Sanai, F, Jetmalani, K, Berend, N, Thamrin, C & King, GG 2020, 'Reduced lung elastic recoil and fixed airflow obstruction in asthma', RESPIROLOGY, vol. 25, no. 6, pp. 613-619.View/Download from: Publisher's site
van der Velden, JL, Alcorn, JF, Chapman, DG, Lundblad, LKA, Irvin, CG, Davis, RJ, Butnor, K & Janssen-Heininger, YMW 2020, 'Airway epithelial specific deletion of Jun-N-terminal kinase 1 attenuates pulmonary fibrosis in two independent mouse models', PLOS ONE, vol. 15, no. 1.View/Download from: Publisher's site
Zimmermann, SC, Thamrin, C, Chan, ASL, Bertolin, A, Chapman, DG & King, GG 2020, 'Relationships Between Forced Oscillatory Impedance and 6-minute Walk Distance After Pulmonary Rehabilitation in COPD', INTERNATIONAL JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE, vol. 15, pp. 157-166.View/Download from: Publisher's site
Bozier, J, Zakarya, R, Chapman, DG & Oliver, BGG 2020, 'How harmless are E-cigarettes? Effects in the pulmonary system.', Current Opinion in Pulmonary Medicine, vol. 26, no. 1, pp. 97-102.View/Download from: Publisher's site
PURPOSE OF REVIEW:Electronic cigarettes have quickly risen to be the leading alternative nicotine source to tobacco. E-cigarette use is hard to research and regulate because of the novelty and rapid evolution of the devices and E-liquids. Epidemiological data on long-term usage is currently lacking, but in smaller cohort studies we are starting to understand the usage patterns and demographics of users, which differ depending on where the study takes place and the regulatory environment. The present review describes the current knowledge of the effects of E-cigarettes on the pulmonary system and knowledge of their usage patterns worldwide. RECENT FINDINGS:E-cigarette use is continuing to rise in young adults in United States and Canada, but not in United Kingdom. These suggest that regulation is influencing uptake in young adults. If E-cigarettes are to be considered as a harm minimisation smoking cessation product, use in young never smokers must be factored into the risk assessment. A recent surge in cases of lung injury associated with vaping in America has resulted in the definition of vaping associated pulmonary injury, although the exact cause remains unknown. SUMMARY:It is our opinion that E-cigarettes can no longer be defined as harmless. Further studies are needed to determine the risks for all populations as it is evident that a large proportion of E-cigarette users are never-smokers, meaning they cannot only be considered from a harm reduction perspective.
Chamberlain, N, Korwin-Mihavics, BR, Nakada, EM, Bruno, SR, Heppner, DE, Chapman, DG, Hoffman, SM, van der Vliet, A, Suratt, BT, Dienz, O, Alcorn, JF & Anathy, V 2019, 'Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics.', Redox biology, vol. 22.View/Download from: Publisher's site
Protein disulfide isomerases (PDI) are a family of redox chaperones that catalyze formation or isomerization of disulfide bonds in proteins. Previous studies have shown that one member, PDIA3, interacts with influenza A virus (IAV) hemagglutinin (HA), and this interaction is required for efficient oxidative folding of HA in vitro. However, it is unknown whether these host-viral protein interactions occur during active infection and whether such interactions represent a putative target for the treatment of influenza infection. Here we show that PDIA3 is specifically upregulated in IAV-infected mouse or human lung epithelial cells and PDIA3 directly interacts with IAV-HA. Treatment with a PDI inhibitor, LOC14 inhibited PDIA3 activity in lung epithelial cells, decreased intramolecular disulfide bonds and subsequent oligomerization (maturation) of HA in both H1N1 (A/PR8/34) and H3N2 (X31, A/Aichi/68) infected lung epithelial cells. These reduced disulfide bond formation significantly decreased viral burden, and also pro-inflammatory responses from lung epithelial cells. Lung epithelial-specific deletion of PDIA3 in mice resulted in a significant decrease in viral burden and lung inflammatory-immune markers upon IAV infection, as well as significantly improved airway mechanics. Taken together, these results indicate that PDIA3 is required for effective influenza pathogenesis in vivo, and pharmacological inhibition of PDIs represents a promising new anti-influenza therapeutic strategy during pandemic and severe influenza seasons.
Chapman, DG, Casey, DT, Ather, JL, Aliyeva, M, Daphtary, N, Lahue, KG, van der Velden, JL, Janssen-Heininger, YMW & Irvin, CG 2019, 'The Effect of Flavored E-cigarettes on Murine Allergic Airways Disease.', Scientific reports, vol. 9, no. 1.View/Download from: Publisher's site
Flavored e-cigarettes are preferred by the majority of users yet their potential toxicity is unknown. Therefore our aim was to determine the effect of selected flavored e-cigarettes, with or without nicotine, on allergic airways disease in mice. Balb/c mice were challenged with PBS or house dust mite (HDM) (Days 0, 7, 14-18) and exposed to room air or e-cigarette aerosol for 30 min twice daily, 6 days/week from Days 0-18 (n = 8-12/group). Mice were exposed to Room Air, vehicle control (50%VG/%50PG), Black Licorice, Kola, Banana Pudding or Cinnacide without or with 12 mg/mL nicotine. Mice were assessed at 72 hours after the final HDM challenge. Compared to mice challenged with HDM and exposed to Room Air, nicotine-free Cinnacide reduced airway inflammation (p = 0.045) and increased peripheral airway hyperresponsiveness (p = 0.02), nicotine-free Banana Pudding increased soluble lung collagen (p = 0.049), with a trend towards increased airway inflammation with nicotine-free Black Licorice exposure (p = 0.089). In contrast, all e-cigarettes containing nicotine suppressed airway inflammation (p < 0.001 for all) but did not alter airway hyperresponsiveness or airway remodeling. Flavored e-cigarettes without nicotine had significant but heterogeneous effects on features of allergic airways disease. This suggests that some flavored e-cigarettes may alter asthma pathophysiology even when used without nicotine.
Kaminsky, DA, Chapman, DG, Holbrook, JT, Henderson, RJ, Sugar, EA, Mastronarde, J, Teague, WG, Busk, M, Sumino, K, Dixon, AE, Wise, RA & Irvin, CG 2019, 'Older age and obesity are associated with increased airway closure in response to methacholine in patients with asthma', RESPIROLOGY, vol. 24, no. 7, pp. 638-645.View/Download from: Publisher's site
King, GG, Farrow, CE & Chapman, DG 2019, 'Dismantling the pathophysiology of asthma using imaging.', European respiratory review : an official journal of the European Respiratory Society, vol. 28, no. 152.View/Download from: Publisher's site
Asthma remains an important disease worldwide, causing high burden to patients and healthcare systems and presenting a need for better management and ultimately prevention and cure. Asthma is a very heterogeneous condition, with many different pathophysiological processes. Better measurement of those pathophysiological processes are needed to better phenotype disease, and to go beyond the current, highly limited measurements that are currently used: spirometry and symptoms. Sophisticated three-dimensional lung imaging using computed tomography and ventilation imaging (single photon emission computed tomography and positron emission tomography) and magnetic resonance imaging and methods of lung imaging applicable to asthma research are now highly developed. The body of current evidence suggests that abnormalities in structure and ventilatory function measured by imaging are clinically relevant, given their associations with disease severity, exacerbation risk and airflow obstruction. Therefore, lung imaging is ready for more widespread use in clinical trials and to become part of routine clinical assessment of asthma.
Milne, S, Huvanandana, J, Nguyen, C, Duncan, JM, Chapman, DG, Tonga, KO, Zimmermann, SC, Slattery, A, King, GG & Thamrin, C 2019, 'Time-based pulmonary features from electrical impedance tomography demonstrate ventilation heterogeneity in chronic obstructive pulmonary disease', JOURNAL OF APPLIED PHYSIOLOGY, vol. 127, no. 5, pp. 1441-1452.View/Download from: Publisher's site
Milne, S, Jetmalani, K, Chapman, DG, Duncan, JM, Farah, CS, Thamrin, C & King, GG 2019, 'Respiratory system reactance reflects communicating lung volume in chronic obstructive pulmonary disease.', Journal of applied physiology (Bethesda, Md. : 1985), vol. 126, no. 5, pp. 1223-1231.View/Download from: Publisher's site
Respiratory system reactance (Xrs) measured by the forced oscillation technique (FOT) is theoretically and experimentally related to lung volume. In chronic obstructive pulmonary disease (COPD), the absolute volume measured by body plethysmography includes a proportion that is inaccessible to pressure oscillations applied via the mouth, that is, a "noncommunicating" lung volume. We hypothesized that in COPD the presence of noncommunicating lung would disrupt the expected Xrs-volume relationship compared with plethysmographic functional residual capacity (FRCpleth). Instead, Xrs would relate to estimates of communicating volume, namely, expiratory reserve volume (ERV) and single-breath alveolar volume (VaSB). We examined FOT and lung function data from people with COPD (n = 51) and from healthy volunteers (n = 40). In healthy volunteers, we observed an expected inverse relationship between reactance at 5 Hz (X5) and FRCpleth. In contrast, there was no such relationship between X5 and FRCpleth in COPD subjects. However, there was an inverse relationship between X5 and both ERV and VaSB. Hence the theoretical Xrs-volume relationship is present in COPD but only when considering the communicating volume rather than the absolute lung volume. These findings confirm the role of reduced communicating lung volume as an important determinant of Xrs and therefore advance our understanding and interpretation of FOT measurements in COPD. NEW & NOTEWORTHY To investigate the determinants of respiratory system reactance (Xrs) measured by the forced oscillation technique (FOT) in chronic obstructive pulmonary disease (COPD), we examine the relationship between Xrs and lung volume. We show that Xrs does not relate to absolute lung volume (functional residual capacity) in COPD but instead relates only to the volume of lung in communication with the airway opening. This communicating volume may therefore be fundamental to our interpretation of FOT measurements in COPD and other pulmo...
Nakada, EM, Bhakta, NR, Korwin-Mihavics, BR, Kumar, A, Chamberlain, N, Bruno, SR, Chapman, DG, Hoffman, SM, Daphtary, N, Aliyeva, M, Irvin, CG, Dixon, AE, Woodruff, PG, Amin, S, Poynter, ME, Desai, DH & Anathy, V 2019, 'Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresponsiveness by inhibiting UPR transducers.', JCI insight, vol. 4, no. 9.View/Download from: Publisher's site
Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma. Whether CBAs exert their beneficial effects on allergic airway responses via 1 arm or several arms of the UPR, or alternatively through the signaling pathways for conserved bile acid receptor, remains largely unknown. We used a house dust mite-induced (HDM-induced) murine model of asthma to evaluate and compare the effects of 5 CBAs and 1 unconjugated bile acid in attenuating allergen-induced UPR and airway responses. Expression of UPR-associated transcripts was assessed in airway brushings from human patients with asthma and healthy subjects. Here we show that CBAs, such as alanyl β-muricholic acid (AβM) and TUDCA, significantly decreased inflammatory, immune, and cytokine responses; mucus metaplasia; and airway hyperresponsiveness, as compared with other CBAs in a model of allergic airway disease. CBAs predominantly bind to activating transcription factor 6α (ATF6α) compared with the other canonical transducers of the UPR, subsequently decreasing allergen-induced UPR activation and resolving allergic airway disease, without significant activation of the bile acid receptors. TUDCA and AβM also attenuated other HDM-induced ER stress markers in the lungs of allergic mice. Quantitative mRNA analysis of airway epithelial brushings from human subjects demonstrated that several ATF6α-related transcripts were significantly upregulated in patients with asthma compared with healthy subjects. Collectively, these results demonstrate that CBA-based therapy potently inhibits the allergen-induced UPR and allergic airway disease in mice via preferential binding of the canonical transducer of the UPR, ATF6α. These results potentially suggest a novel avenue to treat allergic asthma using select CBAs.
Peters, U, Subramanian, M, Chapman, DG, Kaminsky, DA, Irvin, CG, Wise, RA, Skloot, GS, Bates, JHT & Dixon, AE 2019, 'BMI but not central obesity predisposes to airway closure during bronchoconstriction.', Respirology (Carlton, Vic.), vol. 24, no. 6, pp. 543-550.View/Download from: Publisher's site
BACKGROUND AND OBJECTIVE:Obesity produces restrictive effects on lung function. We previously reported that obese patients with asthma exhibit a propensity towards small airway closure during methacholine challenge which improved with weight loss. We hypothesized that increased abdominal adiposity, a key contributor to the restrictive effects of obesity on the lung, mediates this response. This study investigates the effect of body mass index (BMI) versus waist circumference (WC) on spirometric lung function, sensitivity to airway narrowing and closure, and airway closure during bronchoconstriction in patients with asthma. METHODS:Participants underwent spirometry and methacholine challenge. Sensitivity to airway closure and narrowing was assessed from the dose-response slopes of the forced vital capacity (FVC) and the ratio of forced expiratory volume in 1 s (FEV1 ) to FVC, respectively. Airway closure during bronchoconstriction (closing index) was computed as the percent reduction in FVC divided by the percent reduction in FEV1 at maximal bronchoconstriction. RESULTS:A total of 116 asthmatic patients (56 obese) underwent methacholine challenge. Spirometric lung function was inversely related to WC (P < 0.05), rather than BMI. Closing index increased significantly during bronchoconstriction in obese patients and was related to increasing BMI (P = 0.01), but not to WC. Sensitivity to airway closure and narrowing was not associated with BMI or WC. CONCLUSION:Although WC is associated with restrictive effects on baseline lung function, increased BMI, rather than WC, predisposes to airway closure during bronchoconstriction. These findings suggest that obesity predisposes to airway closure during bronchoconstriction through mechanisms other than simple mass loading.
Tonga, KO, Berend, N, Thamrin, C, Farah, CS, Jetmalani, K, Chapman, DG & King, GG 2019, 'Lung elastic recoil and ventilation heterogeneity of diffusion-dependent airways in older people with asthma and fixed airflow obstruction.', European Respiratory Journal, vol. 53.View/Download from: Publisher's site
Small airways are abnormal in asthma . One measurement of small airway function is Sacin, derived from the multiple-breath nitrogen washout (MBNW) test. Sacin reflects ventilation heterogeneity in diffusion-dependent airways, and is correlated with airway hyperresponsiveness  and asthma control . Theoretically, heterogeneity of diffusion-dependent ventilation can arise due to the heterogeneity of cross-sectional areas of airway openings in terminal airways and the acini . Therefore, Sacin may be affected by structural changes in those airways. The elastic properties of the lung may also affect Sacin, as the phase III slope, a marker of ventilation heterogeneity derived from the single-breath nitrogen washout, correlates with lung compliance in explanted lungs of smokers and in healthy lungs .
Tonga, KO, King, GG, Farah, CS, Thamrin, C, Tang, FS, Santos, J, Sharma, P, Chapman, DG & Oliver, BG 2018, 'Steroid insensitive fixed airflow obstruction is not related to airway inflammation in older non-smokers with asthma.', Respiratory research, vol. 19, no. 1, pp. 176-176.View/Download from: Publisher's site
There is limited evidence linking airway inflammation and lung function impairment in older non-smoking asthmatics with fixed airflow obstruction (FAO), which can develop despite treatment with inhaled corticosteroids (ICS). We assessed lung function (spirometry, forced oscillation technique (FOT)), lung elastic recoil and airway inflammation using bronchoalveolar lavage (BAL) in non-smoking adult asthmatics with FAO, following 2 months treatment with high-dose ICS/long-acting beta-agonist. Subjects demonstrated moderate FAO, abnormal FOT indices and loss of lung elastic recoil. This cross-sectional study showed a lack of a relationship between BAL neutrophils, eosinophils, inflammatory cytokines and lung function impairment. Other inflammatory pathways or the effect of inflammation on lung function over time may explain FAO development.
Anathy, V, Lahue, KG, Chapman, DG, Chia, SB, Casey, DT, Aboushousha, R, van der Velden, JLJ, Elko, E, Hoffman, SM, McMillan, DH, Jones, JT, Nolin, JD, Abdalla, S, Schneider, R, Seward, DJ, Roberson, EC, Liptak, MD, Cousins, ME, Butnor, KJ, Taatjes, DJ, Budd, RC, Irvin, CG, Ho, Y-S, Hakem, R, Brown, KK, Matsui, R, Bachschmid, MM, Gomez, JL, Kaminski, N, van der Vliet, A & Janssen-Heininger, YMW 2018, 'Reducing protein oxidation reverses lung fibrosis.', Nature medicine, vol. 24, no. 8, pp. 1128-1135.View/Download from: Publisher's site
Idiopathic pulmonary fibrosis is characterized by excessive deposition of collagen in the lung, leading to chronically impaired gas exchange and death1-3. Oxidative stress is believed to be critical in this disease pathogenesis4-6, although the exact mechanisms remain enigmatic. Protein S-glutathionylation (PSSG) is a post-translational modification of proteins that can be reversed by glutaredoxin-1 (GLRX)7. It remains unknown whether GLRX and PSSG play a role in lung fibrosis. Here, we explored the impact of GLRX and PSSG status on the pathogenesis of pulmonary fibrosis, using lung tissues from subjects with idiopathic pulmonary fibrosis, transgenic mouse models and direct administration of recombinant Glrx to airways of mice with existing fibrosis. We demonstrate that GLRX enzymatic activity was strongly decreased in fibrotic lungs, in accordance with increases in PSSG. Mice lacking Glrx were far more susceptible to bleomycin- or adenovirus encoding active transforming growth factor beta-1 (AdTGFB1)-induced pulmonary fibrosis, whereas transgenic overexpression of Glrx in the lung epithelium attenuated fibrosis. We furthermore show that endogenous GLRX was inactivated through an oxidative mechanism and that direct administration of the Glrx protein into airways augmented Glrx activity and reversed increases in collagen in mice with TGFB1- or bleomycin-induced fibrosis, even when administered to fibrotic, aged animals. Collectively, these findings suggest the therapeutic potential of exogenous GLRX in treating lung fibrosis.
Chamberlain, N, Mihavics, B, Nakada, E, Bruno, S, Heppner, D, Chapman, D, Hoffman, S, van der Vliet, A, Suratt, B, Dienz, O, Alcorn, J & Anathy, V 2018, 'Lung epithelial PDIA3 plays a critical role in influenza infection', Free Radical Biology and Medicine, vol. 128, pp. S101-S101.View/Download from: Publisher's site
Jetmalani, K, Thamrin, C, Farah, CS, Bertolin, A, Chapman, DG, Berend, N, Salome, CM & King, GG 2018, 'Peripheral airway dysfunction and relationship with symptoms in smokers with preserved spirometry.', Respirology, vol. 23, no. 5, pp. 512-518.View/Download from: Publisher's site
Smokers develop respiratory symptoms and peripheral airway dysfunction even when spirometry is preserved. Multiple breath nitrogen washout (MBNW) and impulse oscillometry system (IOS) are potentially useful measures of peripheral airway function but they have not been compared in such subjects. We hypothesized that MBNW and IOS are jointly abnormal in smokers with normal spirometry and that these abnormalities relate to respiratory symptoms.Eighty smokers with normal spirometry completed a symptom questionnaire, had ventilation heterogeneity in diffusion (Sacin) and convection-dependent (Scond) airways and trapped gas volume at functional residual capacity as a percentage of vital capacity (%VtrFRC/VC) measured by MBNW. Respiratory resistance and reactance at 5 and 20 Hz were measured using IOS.Respiratory symptoms were reported in 55 (68%) subjects. Forty (50%) subjects had at least one abnormal MBNW parameter, predominantly in Sacin. Forty-one (51%) subjects had at least one abnormal IOS parameter, predominantly in resistance. Sixty-one (76%) subjects had an abnormality in either MBNW or IOS. Chronic bronchitis symptoms were associated with an increased Scond, while wheeze was associated with lower spirometry and an increased resistance. Abnormalities in MBNW and IOS parameters were unrelated to each other.Respiratory symptoms and peripheral airway dysfunction are common in smokers with normal spirometry. Symptoms of chronic bronchitis related to conductive airway abnormalities, while wheeze was related to spirometry and IOS. The clinical significance of abnormalities in peripheral airway function in smokers remains undetermined.
Qian, X, Aboushousha, R, van de Wetering, C, Chia, SB, Amiel, E, Schneider, RW, van der Velden, JLJ, Lahue, KG, Hoagland, DA, Casey, DT, Daphtary, N, Ather, JL, Randall, MJ, Aliyeva, M, Black, KE, Chapman, DG, Lundblad, LKA, McMillan, DH, Dixon, AE, Anathy, V, Irvin, CG, Poynter, ME, Wouters, EFM, Vacek, PM, Henket, M, Schleich, F, Louis, R, van der Vliet, A & Janssen-Heininger, YMW 2018, 'IL-1/inhibitory κB kinase ε-induced glycolysis augment epithelial effector function and promote allergic airways disease.', Journal of Allergy and Clinical Immunology, vol. 142, no. 2.View/Download from: Publisher's site
Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma.We sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma.We examined alterations in glycolysis in sputum samples from asthmatic patients and primary human nasal cells and used murine models of allergic asthma, as well as primary mouse tracheal epithelial cells, to evaluate the relevance of glycolysis.In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1-dependent manner. Furthermore, administration of IL-1β into the airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1β or IL-1α resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1β- or IL-1α-mediated proinflammatory responses and the stimulatory effects of IL-1β on house dust mite (HDM)-induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of HDM or IL-1β and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate levels and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatic patients intrinsically produced more lactate compared with cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils. A positive correlation was observed between sputum lactate and IL-1β levels, and lactate content correlated negatively with lun...
Chen, H, Li, G, Chan, YL, Chapman, DG, Sukjamnong, S, Nguyen, T, Annissa, T, McGrath, KC, Sharma, P & Oliver, BG 2018, 'Maternal E-Cigarette Exposure in Mice Alters DNA Methylation and Lung Cytokine Expression in Offspring.', American Journal of Respiratory Cell and Molecular Biology, vol. 58, no. 3, pp. 366-377.View/Download from: Publisher's site
E-cigarette usage is increasing, especially among the young, with both the general population and physicians perceiving them as a safe alternative to tobacco smoking. Worryingly, e-cigarettes are commonly used by pregnant women. As nicotine is known to adversely affect children in utero, we hypothesized that nicotine delivered via e-cigarettes would negatively affect lung development. To test this, we developed a mouse model of maternal e-vapor (nicotine and nicotine-free) exposure and investigated the impact on the growth and lung inflammation in both offspring and mothers. Female Balb/c mice were exposed to e-fluid vapor containing nicotine (18 mg/ml nicotine E-cigarette [E-cig18], equivalent to two cigarettes per treatment, twice daily,) or nicotine free (E-cig0 mg/ml) from 6 weeks before mating until pups weaned. Male offspring were studied at Postnatal Day (P) 1, P20, and at 13 weeks. The mothers were studied when the pups weaned. In the mothers' lungs, e-cigarette exposure with and without nicotine increased the proinflammatory cytokines IL-1β, IL-6, and TNF-α. In adult offspring, TNF-α protein levels were increased in both E-cig18 and E-cig0 groups, whereas IL-1β was suppressed. This was accompanied by global changes in DNA methylation. In this study, we found that e-cigarette exposure during pregnancy adversely affected maternal and offspring lung health. As this occurred with both nicotine-free and nicotine-containing e-vapor, the effects are likely due to by-products of vaporization rather than nicotine.
Chapman, DG, Mougey, EB, Van der Velden, JL, Lahue, KG, Aliyeva, M, Daphtary, N, George, KL, Hoffman, SM, Schneider, RW, Tracy, RP, Worthen, GS, Poynter, ME, Peters, SP, Lima, JJ, Janssen-Heininger, YMW & Irvin, CG 2017, 'The Duffy antigen receptor for chemokines regulates asthma pathophysiology.', Clinical and Experimental Allergy, vol. 47, no. 9, pp. 1214-1222.View/Download from: Publisher's site
The Duffy antigen receptor for chemokines (DARC) is an atypical receptor that regulates pro-inflammatory cytokines. However, the role of DARC in asthma pathophysiology is unknown.To determine the role of DARC in allergic airways disease in mice, and the association between DARC single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with asthma.Mice with targeted disruption of the Darc gene (Darc∆E2 ) or WT mice were challenged over 3 weeks with house dust mite (HDM) antigen. Allergic airways disease was assessed 24 hours and 7 days following the final challenge. Additionally, associations between DARC SNPs and clinical outcomes were analysed in a cohort of poorly controlled asthmatics.Total airway inflammation following HDM did not differ between Darc∆E2 and WT mice. At 24 hours, Darc∆E2 mice had increased airway hyperresponsiveness; however, at 7 days airway hyperresponsiveness had completely resolved in Darc∆E2 but persisted in WT mice. In poorly controlled asthmatics, DARC SNPs were associated with worse asthma control at randomization and subsequent increased risk of healthcare utilization (odds ratio 3.13(1.37-7.27), P=.0062).Our animal model and human patient data suggest a novel role for DARC in the temporal regulation in asthma pathophysiology and symptoms.
Gazzola, M, Lortie, K, Henry, C, Mailhot-Larouche, S, Chapman, DG, Couture, C, Seow, CY, Paré, PD, King, GG, Boulet, L-P & Bossé, Y 2017, 'Airway smooth muscle tone increases airway responsiveness in healthy young adults.', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 312, no. 3, pp. L348-L357.View/Download from: Publisher's site
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.
Hoffman, SM, Chapman, DG, Lahue, KG, Cahoon, JM, Rattu, GK, Daphtary, N, Aliyeva, M, Fortner, KA, Erzurum, SC, Comhair, SAA, Woodruff, PG, Bhakta, N, Dixon, AE, Irvin, CG, Janssen-Heininger, YMW, Poynter, ME & Anathy, V 2016, 'Protein disulfide isomerase-endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 137, no. 3, pp. 822-+.View/Download from: Publisher's site
Hoffman, SM, Nolin, JD, Jones, JT, Lahue, KG, Chapman, DG, Aliyeva, M, Daphtary, N, Lundblad, LKA, Abdalla, S, Ather, JL, Ho, Y-S, Irvin, CG, Anathy, V, Wouters, EFM, Poynter, ME & Janssen-Heininger, YMW 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.', Annals of the American Thoracic Society, vol. 13 Suppl 1, p. S97.View/Download from: Publisher's site
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 μg 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.
Hoffman, SM, Qian, X, Nolin, JD, Chapman, DG, Chia, SB, Lahue, KG, Schneider, R, Ather, JL, Randall, MJ, McMillan, DH, Jones, JT, Taatjes, DJ, Aliyeva, M, Daphtary, N, Abdalla, S, Lundblad, LKA, Ho, Y-S, Anathy, V, Irvin, CG, Wouters, EFM, Reynaert, NL, Dixon, AE, van der Vliet, A, Poynter, ME & Janssen-Heininger, YMW 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.View/Download from: Publisher's site
Protein S-glutathionylation (PSSG) is an oxidant-induced post-translational 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 with HDM on 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 HDM-treated 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-γ and IL-17A was increased in Glrx1(-/-) HDM mice compared with WT littermates. Restimulation of single-cell suspensions isolated from lungs or spleens with HDM resulted 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-γ and IL-17A.
Jetmalani, K, Chapman, DG, Thamrin, C, Farah, CS, Berend, N, Salome, CM & King, GG 2016, 'Bronchodilator responsiveness of peripheral airways in smokers with normal spirometry', RESPIROLOGY, vol. 21, no. 7, pp. 1270-1276.View/Download from: Publisher's site
Jones, CA, Chapman, DG, Weimersheimer, P, Fernandez, L, Alejandro Mesa, O, Peters, C, Vanaudenaerde, BM, Norotsky, MC & 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.
Siddesha, JM, Nakada, EM, Mihavics, BR, Hoffman, SM, Rattu, GK, Chamberlain, N, Cahoon, JM, Lahue, KG, Daphtary, N, Aliyeva, M, Chapman, DG, Desai, DH, Poynter, ME & Anathy, V 2016, 'Effect of a chemical chaperone, tauroursodeoxycholic acid, on HDM-induced allergic airway disease', AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, vol. 310, no. 11, pp. L1243-L1259.View/Download from: Publisher's site
van der Velden, JLJ, Ye, Y, Nolin, JD, Hoffman, SM, Chapman, DG, Lahue, KG, Abdalla, S, Chen, P, Liu, Y, Bennett, B, Khalil, N, Sutherland, D, Smith, W, Horan, G, Assaf, M, Horowitz, Z, Chopra, R, Stevens, RM, Palmisano, M, Janssen-Heininger, YMW & Schafer, PH 2016, 'JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers.', Clin Transl Med, vol. 5, no. 36, pp. 1-18.View/Download from: Publisher's site
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 ...
Anathy, V, Hoffman, S, Chapman, D, Janssen-Heininger, Y & Poynter, M 2015, 'Protein Disulfide Isomerase-ERp57 Regulates Allergic Asthma Phenotype', Free Radical Biology and Medicine, vol. 87, pp. S38-S38.View/Download from: Publisher's site
Chapman, DG & Irvin, CG 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.View/Download from: Publisher's site
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.
Al-Alwan, A, Bates, JHT, Chapman, DG, Kaminsky, DA, DeSarno, MJ, Irvin, CG & Dixon, AE 2014, 'The Nonallergic Asthma of Obesity A Matter of Distal Lung Compliance', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 189, no. 12, pp. 1494-1502.View/Download from: Publisher's site
Chapman, DG, Irvin, CG, Kaminsky, DA, Forgione, PM, Bates, JHT & Dixon, AE 2014, 'Influence of distinct asthma phenotypes on lung function following weight loss in the obese', RESPIROLOGY, vol. 19, no. 8, pp. 1170-1177.View/Download from: Publisher's site
Chapman, DG, Pascoe, CD, Lee-Gosselin, A, Couturee, C, Seow, CY, Pare, PD, Salome, CM, King, GG & Bosse, Y 2014, 'Smooth Muscle in the Maintenance of Increased Airway Resistance Elicited by Methacholine in Humans', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 190, no. 8, pp. 879-885.View/Download from: Publisher's site
Chapman, DG, Tully, JE, Nolin, JD, Janssen-Heininger, YM & Irvin, CG 2014, 'Animal Models of Allergic Airways Disease: Where Are We and Where to Next?', JOURNAL OF CELLULAR BIOCHEMISTRY, vol. 115, no. 12, pp. 2055-2064.View/Download from: Publisher's site
Kaminsky, DA, Daud, A & Chapman, DG 2014, 'Relationship between the baseline alveolar volume-to-total lung capacity ratio and airway responsiveness', RESPIROLOGY, vol. 19, no. 7, pp. 1046-1051.View/Download from: Publisher's site
McMillan, D, Lahue, K, Nolin, J, Hoffman, S, Abdalla, S, Chapman, D, van der Velden, J, Anathy, V & Janssen-Heininger, Y 2014, 'Attenuation of GSTP1 Decreases Fas SGlutathionylation-Mediated Lung Epithelial Cell Apoptosis and Fibrotic Remodeling', Free Radical Biology and Medicine, vol. 76, pp. S164-S164.View/Download from: Publisher's site
van der Velden, JLJ, Hoffman, SM, Alcorn, JF, Tully, JE, Chapman, DG, Lahue, KG, Guala, AS, Lundblad, LKA, Aliyeva, M, Daphtary, N, Irvin, CG & Janssen-Heininger, YMW 2014, 'Absence of c-Jun NH2-terminal kinase 1 protects against house dust mite-induced pulmonary remodeling but not airway hyperresponsiveness and inflammation', AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, vol. 306, no. 9, pp. L866-L875.View/Download from: Publisher's site
Chapman, D & Farah, CS 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 © Sociedad Iberoamericana de Información Científica (SIIC), 2013.
Hulme, KM, Salome, CM, Brown, NJ, Berend, N, Agus, HM, Horlyck, KR, King, GG & Chapman, DG 2013, 'Deep inspiration volume and the impaired reversal of bronchoconstriction in asthma', RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY, vol. 189, no. 3, pp. 506-512.View/Download from: Publisher's site
Janssen-Heininger, YMW, Nolin, JD, Hoffman, SM, van der Velden, JL, Tully, JE, Lahue, KG, Abdalla, ST, Chapman, DG, Reynaert, NL, van der Vliet, A & Anathy, V 2013, 'Emerging mechanisms of glutathione-dependent chemistry in biology and disease.', Journal of cellular biochemistry, vol. 114, no. 9, pp. 1962-1968.View/Download from: Publisher's site
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, DG, Berend, N, Horlyck, KR, King, GG & Salome, CM 2012, 'Does increased baseline ventilation heterogeneity following chest wall strapping predispose to airway hyperresponsiveness?', JOURNAL OF APPLIED PHYSIOLOGY, vol. 113, no. 1, pp. 25-30.View/Download from: Publisher's site
Bossé, Y, Chapman, DG, Paré, PD, King, GG & Salome, CM 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.View/Download from: Publisher's site
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.
Chapman, DG, Berend, N, King, GG & Salome, CM 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.View/Download from: Publisher's site
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, DG, Brown, NJ & Salome, CM 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.View/Download from: Publisher's site
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, DG, Berend, N, King, GG & Salome, CM 2010, 'Can we cure airway hyperresponsiveness with a gym membership?', JOURNAL OF APPLIED PHYSIOLOGY, vol. 109, no. 2, pp. 267-268.View/Download from: Publisher's site
Chapman, DG, King, GG, Berend, N, Diba, C & Salome, CM 2010, 'Avoiding deep inspirations increases the maximal response to methacholine without altering sensitivity in non-asthmatics', RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY, vol. 173, no. 2, pp. 157-163.View/Download from: Publisher's site
Chapman, DG, Berend, N, King, GG, McParland, BE & Salome, CM 2009, 'Deep inspirations protect against airway closure in nonasthmatic subjects', JOURNAL OF APPLIED PHYSIOLOGY, vol. 107, no. 2, pp. 564-569.View/Download from: Publisher's site
Chapman, D, King, G & Forno, E 2018, 'Obesity and lung function: From childhood to adulthood' in Mechanisms and Manifestations of Obesity in Lung Disease, pp. 45-65.View/Download from: Publisher's site
© 2019 Elsevier Inc. All rights reserved.. Research in the last few decades has shown that obesity and its metabolic complications have important effects on the respiratory system. There is ample and growing evidence that obesity affects lung function in otherwise healthy adults and children. Obesity exerts an additional load upon the respiratory system, changing the balance of pressures between the inward recoil of the lung and the outward pressure of the chest. This has major consequences on lung volumes, airway mechanics, airway closure, expiratory flow limitation, ventilation distribution, airway hyperresponsiveness, and exhaled nitric oxide levels. Many of the changes in lung function due to obesity are likely to contribute to respiratory symptoms; however, there are important differences in the effect of obesity on lung function between children, adolescents, and adults. Therefore understanding the effects of obesity on lung function throughout the lifespan is imperative to understanding present and future effects of obesity on respiratory health.
Chapman, DG, Suratt, BT & Dixon, AE 2014, 'Respiratory Diseases in Obesity' in Fantuzzi, G & Braunschweig, C (eds), Adipose Tissue and Adipokines in Health and Disease, Springer, Germany, pp. 296-314.View/Download from: Publisher's site
While it has long been recognized that obesity is a risk factor for diseases such as type II diabetes and steatohepatitis, it has only recently been appreciated that obesity is a major risk factor for lung diseases such as asthma, sleep apnea and likely also pulmonary hypertension. Obesity also dramatically alters the clinical course of other common lung diseases such as chronic obstructive pulmonary disease and acute lung injury. The purpose of this chapter will be first to review the effects of obesity on lung function, and then to discuss the effect of obesity on the aforementioned pulmonary diseases.
Gordon, IO, Dowell, M, Chapman, DG, Irvin, CG & Husain, AN 2014, 'Asthma' in Mitchell, RN & McManus, LM (eds), Pathobiology of Human Disease A Dynamic Encyclopedia of Disease Mechanisms, Elsevier, pp. 2588-2608.
The work spans more than 48 different biological and medical fields, in five basic sections: Human Organ Systems Molecular Pathology/Basic Mechanisms of Diseases Animal Models/Other Model Systems Experimental Pathology Clinical Pathology ...
Gordon, IO, Dowell, ML, Chapman, DG, Irvin, CG & Husain, AN 2014, 'Pathobiology of Human Disease: Asthma' in Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms, pp. 2588-2608.View/Download from: Publisher's site
© 2014 Elsevier Inc. All rights reserved. Asthma is an obstructive pulmonary disease affecting children and adults with increasing prevalence. The pathophysiology of asthma is complex, with both genes and the environment playing important roles. Inflammation is a key process, and interaction among the three T helper (Th) lymphocyte subsets, Th1, Th2, and Th17, as well as other inflammatory cells (mast cells, eosinophils, and neutrophils) and host parenchyma leads to cLinical symptoms. Airway wall remodeLing also contributes to cLinical symptoms and involves airway smooth muscle, angiogenesis, extracellular matrix, mucous cells, and epitheLium. Certain histological features that are seen in endobronchial biopsies of patients with asthma include submucosal eosinophiLia, prominent airway smooth muscle, thickening of the basement membrane, and goblet cell hyperplasia. Although there are defined cLinical asthma phenotypes and tissue asthma phenotypes, there is imperfect correlation between histological features and cLinical phenotype. Although biopsy is used in the research setting, it is impractical to biopsy asthma patients to confirm the diagnosis, and therefore, besides a purely cLinical diagnosis based on symptoms, there are biomarkers, such as exhaled nitric oxide and inflammation in sputum, which can be used to help diagnose and monitor the disease. Asthma therapy can be classified as short-term controllers for acute exacerbation, for example, short-acting beta-2-receptor agonists, or long-term controllers, such as corticosteroids. New adjunct therapies include biologics targeting specific types of cells and bronchial thermoplasty, a procedure to ablate the airway smooth muscle. Mouse models of asthma have mostly focused on isolating the roles of the different types of inflammation and how the inflammation relates to airway remodeLing in the setting of different environmental exposures.
Chapman, DG, Arnott, C, Puranik, R, Prael, G, Patel, K, Tonga, KO, Milne, S, Zimmermann, SC, Munoz, PA, Lake, CD, Kaminsky, DA, Lau, E & King, GG 2020, 'Elastic Chest Compression Reduced Hyperinflation in People with Chronic Obstructive Pulmonary Disease', D28. COPD: FROM PATHOGENESIS TO PROGNOSIS, American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA, American Thoracic Society.View/Download from: Publisher's site
Chapman, DG, Patel, K, Jeagal, E, Jetmalani, K, Milne, S, Nilsen, K, Thamrin, C & King, GG 2020, 'Supine Posture Worsens Respiratory Mechanics in Chronic Obstructive Pulmonary Disease', B30. ARTHUR DUBOIS MEMORIAL SESSION: THE SMALL AND LARGE OF AIRWAY AND LUNG FUNCTION, American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA, American Thoracic Society.View/Download from: Publisher's site
Rutting, S, Roche, N, Wallis, R, Sanai, F, Mascarenhas, S, Handley, B, Schoeffel, R, Thamrin, C, Chapman, D & King, G 2020, 'Long-Term Variability in Oscillatory Impedance in Stable Obstructive Airways Diseases', B30. ARTHUR DUBOIS MEMORIAL SESSION: THE SMALL AND LARGE OF AIRWAY AND LUNG FUNCTION, American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA, American Thoracic Society.View/Download from: Publisher's site
Sanai, F, Kermode, JA, Noble, PB, King, GG, Chapman, DG & McParland, BE 2020, 'Relationship Between Airway Size and In-Vitro Sensitivity to Cholinomimetics', B30. ARTHUR DUBOIS MEMORIAL SESSION: THE SMALL AND LARGE OF AIRWAY AND LUNG FUNCTION, American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA, American Thoracic Society.View/Download from: Publisher's site
Chamberlain, N, Korwin-Mihavics, B, Nakada, E, Bruno, S, Heppner, D, Chapman, DG, Hoffman, SM, Van Der Vliet, A, Suratt, BT, Dienz, O, Alcorn, JF & Anathy, V 2019, 'Lung Epithelial PDIA3 Plays a Critical Role in Influenza infection', A28. BACTERIAL AND VIRAL LUNG INFECTIONS AND PATHOGENESIS, American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX, American Thoracic Society.View/Download from: Publisher's site
Chapman, D, Jetmalani, K, Thamrin, C, Farah, CS, Grunstein, RR, Comas-Soberats, M, Young, PM, Phillips, CL & King, G 2019, 'Reduced Sleep Quality Correlates with Worse Hyperinflation in Patients with Chronic Obstructive Pulmonary Disease', B64. COPD: MECHANISM AND TREATMENT, American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX, American Thoracic Society.View/Download from: Publisher's site
Tonga, K, Berend, N, Thamrin, C, Farah, CS, Jetmalani, K, Chapman, D & King, GG 2019, 'Lung Elastic Recoil and Acinar Ventilation Heterogeneity in Older Non-Smokers with Asthma and Fixed Airflow Obstruction', A64. CLINICAL ASTHMA: ASSESSMENT AND TREATMENT, American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX, American Thoracic Society.View/Download from: Publisher's site
Nilsen, K, Chapman, DG, Tonga, KO, King, GG, Thompson, BR & Thamrin, C 2018, 'Late Breaking Abstract - Estimating elastic recoil via the forced oscillation technique (FOT).', Clinical respiratory physiology, exercise and functional imaging, ERS International Congress 2018 abstracts, European Respiratory Society.View/Download from: Publisher's site
Chapman, DG, Hulme, KM, Berend, N, King, G & Salome, C 2012, 'The Relationship Between The Volume Of A Deep Inspiration And The Extent Of Airway Dilatation', B29. THE LUNG ON THE BORDER BETWEEN ORDER AND CHAOS, American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California, American Thoracic Society.View/Download from: Publisher's site
Bossé, Y, Chapman, D, Paré, PD, King, G & Salome, C 2011, 'Adaptation To Increased Airway Smooth Muscle-Tone Increases Airway Responsiveness In Healthy Subjects', B71. CRAZY MUSCLES: AIRWAY AND LYMPHATIC SMOOTH MUSCLE AND LYMPHANGIOLEIOMYOMATOSIS (LAM), American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado, American Thoracic Society.View/Download from: Publisher's site
Kermode, JA, Chapman, DG, Brown, NJ, Berend, N, King, GG & Salome, CM 2011, 'Reduced Airway Distensibility Is Not Associated With Airway Re-Narrowing Following Deep Inspiration', A72. ADVANCES IN NON-INVASIVE PULMONARY FUNCTION TECHNOLOGY AND OUTCOMES ANALYSIS, American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado, American Thoracic Society.View/Download from: Publisher's site
Prof Greg King (Royal North Shore Hospital)
Dr Edmund Lau (RPA Hospital)
Dr Claude Farah (Concord Hospital)
A/Prof Rajesh Puranik (Cardiovasular Magnetic Resonance Sydney)
Dr Clare Arnott (Sydney Magnetic Resonance Imaging)
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)