Dr Chantal Donovan
School of Biomedical Sciences and Pharmacy
- Phone:(02) 4042 0509
Opening up an interest in airways
An undergraduate job in a lab over winter sparked a career focus on lung disease Dr Chantal Donovan’s move to a world-leading respiratory medicine research centre in Newcastle.
Chantal can pinpoint her interest in science as being sparked in high school so she decided to enrol in a Bachelor of Science at the University of Melbourne to help hone her focus. It was while studying pharmacology in her second year, that Chantal found her passion.
Not just content with knowing that drugs worked, Chantal ended up majoring in pharmacology and biochemistry because “I wanted to fully understand how the drugs worked,” Chantal says.
It was during her third year of study that Chantal met a pivotal force in her research: Dr Jane Bourke. “Jane took me on as a winter student and we did a great deal of work into asthma models that really set me on my research path.” Chantal ended up doing honours, and then a PhD with Jane looking at novel therapies for asthma and COPD.
When Jane moved universities, Chantal found a new supervisor, Associate Professor Ross Vlahos who was working with COPD research and smoke models. “I ended up moving what I’d learnt with Jane into Ross’s models and the two ended up combining nicely.”
And this research has continued to inspire Chantal’s work. “We were looking at two different drugs and their impact on airways. The first was rosiglitazone, a drug used for treating type II diabetes which we found actually had an effect relaxing the airways. The second was working with the bitter taste receptors on the tongue. We found that not only are these receptors in the airways, but the drugs that work on them can work to relax the muscle too.
Chantal has already published a substantial body of work, with 18 peer reviewed publications and 25 abstracts as 1st/last author. Her work on understanding the pathogenesis of lung disease, identifying novel targets and therapeutics has been recognised by at the Thoracic Society of Australia and New Zealand and the Australasian Society of Clinical Pharmacologists and Toxicologists society meetings.
A prestigious British Pharmacological Society/ASCEPT Outstanding Young Investigator Award and an array of competitive grants, visiting fellowships and travel awards are testament to Chantal’s standing in the field. Chantal was invited to session chair at the 2016 European Respiratory Society Annual Scientific Meeting in London, and has been a reviewer for a range of journals.
Finding world class facilities in Newcastle
An early career researcher, Chantal has been extremely busy since submitting her PhD in August 2015. The move to Newcastle was considered: Chantal knew she wanted to work with a lung-research lab – so she set about researching the best. And this search led her to the renowned work of Professor Phil Hansbro and his research team. “Of all the labs I’ve looked at in the world, none compares to Phil’s,” Chantal enthuses. “It was quite an easy decision to come here to be honest.”
Before moving from Melbourne, Chantal applied for an NHMRC Early Career Fellowship to work with Phil’s team exploring lung diseases and potential new treatments and preventions. Lung diseases are a major burden on the Australian population and economy. With this work, the team will assess the potential of a new target (IL-33) and therapy (anti-IL-33) in suppressing remodelling in experimental models and human tissues.
Thanks to the success of this application, this work will be a continuation of some of the work that Chantal explored for her PhD “It’s a nice trajectory really,” she adds.
Chantal’s work into IL-33 will explore the role that this protein plays in a number of viral infections and inflammation of the lung. “We know it’s involved, but what’s unknown is how it affects ‘airway remodelling’ which is the scarring of the tissue that you get over time with lung disease.”
“We do know that when you have reduced remodelling you also have reduced IL-33, so what we’re trying to do is understand how and why this happens and whether we can use this information to target the remodelling.”
This work has potential applications for a whole range of lung diseases such as asthma, COPD and IPF. “Remodelling is currently untreated in a whole range of different diseases, so hopefully we can find a link that we can then target.”
Sharing science with parliament
Passionate about raising the profile of science, Chantal attended Science Meets Parliament in Canberra in March 2017. This bi-partisan annual event has been held since 1999 with the aim of urging “all political parties to recognise the importance of science to the nation’s future; economically, socially, culturally and environmentally”.
Chantal was thrilled to have the opportunity to put her respiratory research before the nation’s political leaders. “This event showcases scientific research across all aspects of STEM and provides opportunities to raise issues about the future of research in Australia.”
“By bringing together scientists and politicians, it provides a platform to bridge the gap in knowledge, in particular the needs and concerns of scientists at a government level, with the ultimate goal raising the profile of science in Australia.
“During the meeting I had the honour of meeting the Australian of the Year Emeritus Professor Alan Mackay-Sim and the Honorable Bill Shorten and this two day meeting really provided an eye-opening experience.”
Ensuring that research into lung diseases is effectively funded is a focus on Chantal’s, who acknowledges that science communications and outreach is just another item on a researcher’s to-do list.
Australia has one of the highest rates of lung disease in the world, with one in ten Australians living with a respiratory illness. Chantal’s aim is to help identify gaps in our knowledge which will start to help us identify new therapeutic targets and biomarkers. Watch this space.
Dr Donovan is an NHMRC Early Career Post-doctoral Fellow (Peter Doherty Biomedical Fellow) for the Priority Centre for Healthy Lungs and School of Biomedical Science and Pharmacy. She is a member of Professor Phil Hansbro's research team based at the Hunter Medical Research Institute. She completed her PhD (January 2012-April 2015) in the Department of Pharmacology and Therapeutics at the University of Melbourne and Bachelor of Science (Honours) with first class at the University of Melbourne. She completed her first postdoctoral training (April 2015-December 2016) in the Department of Pharmacology at Monash University, with additional training under precision cut lung slice expert Professor Michael Sanderson at the University of Massachusetts Medical School in the USA.
Dr Donovan has 19 peer reviewed publications (13 manuscripts, 6 reviews). She has presented 25 abstracts as 1st/last author and 15 co-author at 13 national & 7 international conferences.
Her research on understanding the pathogenesis of lung disease, identifying novel targets and new therapeutics, is recognised by prestigious oral (x7) and poster (x7) awards at the national respiratory (Thoracic Society of Australia and New Zealand) and pharmacological (Australasian Society of Clinical Pharmacologists and Toxicologist) society meetings. Including the prestigious British Pharmacological Society/ASCEPT Outstanding Young Investigator Award (2016), finalist in the Young Investigator Award (TSANZ, 2014), and the Garth McQueen oral presentation prize for best PhD student (ASCEPT, 2012).
She has obtained over $500k in competitive grants/fellowships, including equipment grants, visiting fellowships, prestigious national (University of Melbourne, UoN) and international (American Thoracic Society, ATS) travel awards, and an international trainee scholarship from the ATS (2016).
Dr Donovan is an expert in a range of mouse models (allergic, bacterial, viral, cigarette smoke) of respiratory disease, assessment of lung function (whole lung mechanics, DLCO, large airway organ bath, small airway myography, precision cut lung slices), and molecular biology (PCR, Western blot, ELISA). She played an integral role in extending the standard outcomes of PCLS in Australia including integrated assessment of molecular signaling pathways and cytokine release.
- Doctor of Philosophy, University of Melbourne
- Bachelor of Science (Honours), University of Melbourne
- airway remodelling
- precision cut lung slices
Fields of Research
For publications that are currently unpublished or in-press, details are shown in italics.
Journal article (34 outputs)
Ali MK, Kim RY, Brown AC, Donovan C, Vanka KS, Mayall JR, et al., 'Critical role for iron accumulation in the pathogenesis of fibrotic lung disease.', J Pathol, 251 49-62 (2020)
Lo Bello F, Hansbro PM, Donovan C, Coppolino I, Mumby S, Adcock IM, Caramori G, 'New drugs under development for COPD.', Expert Opin Emerg Drugs, (2020)
Ali MK, Kim RY, Brown AC, Mayall JR, Karim R, Pinkerton JW, et al., 'Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma.', Eur Respir J, 55 (2020)
Donovan C, Liu G, Shen S, Marshall JE, Kim RY, Alemao CA, et al., 'The role of the microbiome and the NLRP3 inflammasome in the gut and lung', Journal of Leukocyte Biology, 108 925-935 (2020)
©2020 Society for Leukocyte Biology The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, is one ... [more]
©2020 Society for Leukocyte Biology The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, is one of the most well-characterized inflammasomes, activated by pathogen-associated molecular patterns and damage-associated molecular patterns, including from commensal or pathogenic bacterial and viral infections. The NLRP3 inflammasome promotes inflammatory cell recruitment and regulates immune responses in tissues such as the gastrointestinal tract and the lung, and is involved in many diseases that affect the gut and lung. Recently, the microbiome in the gut and the lung, and the crosstalk between these organs (gut¿lung axis), has been identified as a potential mechanism that may influence disease in a bidirectional manner. In this review, we focus on themes presented in this area at the 2019 World Congress on Inflammation. We discuss recent evidence on how the microbiome can affect NLRP3 inflammasome responses in the gut and lung, the role of this inflammasome in regulating gut and lung inflammation in disease, and its potential role in the gut¿lung axis. We highlight the exponential increase in our understanding of the NLRP3 inflammasome due to the synthesis of the NLRP3 inflammasome inhibitor, MCC950, and propose future studies that may further elucidate the roles of the NLRP3 inflammasome in gut and lung diseases.
Donovan C, Hansbro PM, 'IL-33 in Chronic Respiratory Disease: From Preclinical to Clinical Studies', ACS Pharmacology and Translational Science, 3 56-62 (2020) [C1]
Copyright © 2019 American Chemical Society. IL-33 has been deorphanized as a member of the IL-1 family and has key roles as an alarmin and cytokine with potent capacity to drive t... [more]
Copyright © 2019 American Chemical Society. IL-33 has been deorphanized as a member of the IL-1 family and has key roles as an alarmin and cytokine with potent capacity to drive type 2 inflammation. This has led to a plethora of studies surrounding its role in chronic diseases with a type 2 inflammatory component. Here, we review the roles of IL-33 in two chronic respiratory diseases, asthma and chronic obstructive pulmonary disease (COPD). We discuss the hallmark and paradigm-shifting studies that have contributed to our understanding of IL-33 biology. We cover animal studies that have elucidated the mechanisms of IL-33 and assessed the role of anti-IL-33 treatment and immunization against IL-33. We highlight key clinical evidence for the potential of targeting increased IL-33 in respiratory diseases including exacerbations, and we outline current clinical trials using an anti-IL-33 monoclonal antibody in asthma patients. Finally, we discuss some of the challenges that have arisen in IL-33 biology and highlight potential future directions in targeting this cytokine in chronic respiratory diseases.
Alemao CA, Budden KF, Gomez HM, Rehman SF, Marshall JE, Shukla SD, et al., 'Impact of diet and the bacterial microbiome on the mucous barrier and immune disorders.', Allergy, (2020)
Johansen MD, Irving A, Montagutelli X, Tate MD, Rudloff I, Nold MF, et al., 'Animal and translational models of SARS-CoV-2 infection and COVID-19.', Mucosal Immunol, (2020)
Prihandoko R, Kaur D, Wiegman CH, Alvarez-Curto E, Donovan C, Chachi L, et al., 'Pathophysiological regulation of lung function by the free fatty acid receptor FFA4.', Sci Transl Med, 12 (2020)
Donovan C, Starkey MR, Kim RY, Rana BMJ, Barlow JL, Jones B, et al., 'Roles for T/B lymphocytes and ILC2s in experimental chronic obstructive pulmonary disease', Journal of Leukocyte Biology, 105 143-150 (2019) [C1]
©2018 Society for Leukocyte Biology Pulmonary inflammation in chronic obstructive pulmonary disease (COPD) is characterized by both innate and adaptive immune responses; however,... [more]
©2018 Society for Leukocyte Biology Pulmonary inflammation in chronic obstructive pulmonary disease (COPD) is characterized by both innate and adaptive immune responses; however, their specific roles in the pathogenesis of COPD are unclear. Therefore, we investigated the roles of T and B lymphocytes and group 2 innate lymphoid cells (ILC2s) in airway inflammation and remodelling, and lung function in an experimental model of COPD using mice that specifically lack these cells (Rag1 -/- and Rora fl/fl Il7r Cre [ILC2-deficient] mice). Wild-type (WT) C57BL/6 mice, Rag1 -/- , and Rora fl/fl Il7r Cre mice were exposed to cigarette smoke (CS; 12 cigarettes twice a day, 5 days a week) for up to 12¿weeks, and airway inflammation, airway remodelling (collagen deposition and alveolar enlargement), and lung function were assessed. WT, Rag1 -/- , and ILC2-deficient mice exposed to CS had similar levels of airway inflammation and impaired lung function. CS exposure increased small airway collagen deposition in WT mice. Rag1 -/- normal air- and CS-exposed mice had significantly increased collagen deposition compared to similarly exposed WT mice, which was associated with increases in IL-33, IL-13, and ILC2 numbers. CS-exposed Rora fl/fl Il7r Cre mice were protected from emphysema, but had increased IL-33/IL-13 expression and collagen deposition compared to WT CS-exposed mice. T/B lymphocytes and ILC2s play roles in airway collagen deposition/fibrosis, but not inflammation, in experimental COPD.
Caramori G, Ruggeri P, Mumby S, Ieni A, Lo Bello F, Chaminka V, et al., 'Molecular links between COPD and lung cancer: new targets for drug discovery?', Expert Opinion on Therapeutic Targets, 23 539-553 (2019) [C1]
© 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group. Introduction: COPD and lung cancer are leading causes of morbidity and mortality worldwide, and they sh... [more]
© 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group. Introduction: COPD and lung cancer are leading causes of morbidity and mortality worldwide, and they share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by their incidence in only a fraction of smokers. This reflects the ability of cigarette smoke to induce an inflammatory response in the airways of susceptible smokers. Moreover, COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage and repression of the DNA repair mechanisms, chronic exposure to pro-inflammatory cytokines, repression of innate immunity and increased cellular proliferation. Areas covered: We have focused our review on the potential pathogenic molecular links between tobacco smoking-related COPD and lung cancer and the potential molecular targets for new drug development by understanding the common signaling pathways involved in COPD and lung cancer. Expert commentary: Research in this field is mostly limited to animal models or small clinical trials. Large clinical trials are needed but mostly combined models of COPD and lung cancer are necessary to investigate the processes caused by chronic inflammation, including genetic and epigenetic alteration, and the expression of inflammatory mediators that link COPD and lung cancer, to identify new molecular therapeutic targets.
Starkey MR, Plank MW, Casolari P, Papi A, Pavlidis S, Guo Y, et al., 'IL-22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis', EUROPEAN RESPIRATORY JOURNAL, 54 (2019) [C1]
Terlizzi M, Molino A, Colarusso C, Donovan C, Imitazione P, Somma P, et al., 'Activation of the Absent in Melanoma 2 Inflammasome in Peripheral Blood Mononuclear Cells From Idiopathic Pulmonary Fibrosis Patients Leads to the Release of Pro-Fibrotic Mediators', FRONTIERS IN IMMUNOLOGY, 9 (2018) [C1]
Schofield ZV, Croker D, Robertson AAB, Massey NL, Donovan C, Tee E, et al., 'Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling', SCIENTIFIC REPORTS, 8 (2018) [C1]
Hansbro PM, Kim RY, Starkey MR, Donovan C, Dua K, Mayall JR, et al., 'Mechanisms and treatments for severe, steroid-resistant allergic airway disease and asthma', Immunological Reviews, 278 41-62 (2017) [C1]
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Severe, steroid-resistant asthma is clinically and economically important since affected individuals d... [more]
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Severe, steroid-resistant asthma is clinically and economically important since affected individuals do not respond to mainstay corticosteroid treatments for asthma. Patients with this disease experience more frequent exacerbations of asthma, are more likely to be hospitalized, and have a poorer quality of life. Effective therapies are urgently required, however, their development has been hampered by a lack of understanding of the pathological processes that underpin disease. A major obstacle to understanding the processes that drive severe, steroid-resistant asthma is that the several endotypes of the disease have been described that are characterized by different inflammatory and immunological phenotypes. This heterogeneity makes pinpointing processes that drive disease difficult in humans. Clinical studies strongly associate specific respiratory infections with severe, steroid-resistant asthma. In this review, we discuss key findings from our studies where we describe the development of representative experimental models to improve our understanding of the links between infection and severe, steroid-resistant forms of this disease. We also discuss their use in elucidating the mechanisms, and their potential for developing effective therapeutic strategies, for severe, steroid-resistant asthma. Finally, we highlight how the immune mechanisms and therapeutic targets we have identified may be applicable to obesity-or pollution-associated asthma.
Jones B, Donovan C, Liu G, Gomez HM, Chimankar V, Harrison CL, et al., 'Animal models of COPD: What do they tell us?', Respirology, 22 21-32 (2017) [C1]
© 2016 Asian Pacific Society of Respirology COPD is a major cause of global mortality and morbidity but current treatments are poorly effective. This is because the underlying mec... [more]
© 2016 Asian Pacific Society of Respirology COPD is a major cause of global mortality and morbidity but current treatments are poorly effective. This is because the underlying mechanisms that drive the development and progression of COPD are incompletely understood. Animal models of disease provide a valuable, ethically and economically viable experimental platform to examine these mechanisms and identify biomarkers that may be therapeutic targets that would facilitate the development of improved standard of care. Here, we review the different established animal models of COPD and the various aspects of disease pathophysiology that have been successfully recapitulated in these models including chronic lung inflammation, airway remodelling, emphysema and impaired lung function. Furthermore, some of the mechanistic features, and thus biomarkers and therapeutic targets of COPD identified in animal models are outlined. Some of the existing therapies that suppress some disease symptoms that were identified in animal models and are progressing towards therapeutic development have been outlined. Further studies of representative animal models of human COPD have the strong potential to identify new and effective therapeutic approaches for COPD.
Liu G, Cooley MA, Nair PM, Donovan C, Hsu AC, Jarnicki AG, et al., 'Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c', JOURNAL OF PATHOLOGY, 243 510-523 (2017) [C1]
Kim RY, Rae B, Neal R, Donovan C, Pinkerton J, Balachandran L, et al., 'Elucidating novel disease mechanisms in severe asthma', CLINICAL & TRANSLATIONAL IMMUNOLOGY, 5 (2016) [C1]
Thorburn AN, Tseng H-Y, Donovan C, Hansbro NG, Jarnicki AG, Foster PS, et al., 'TLR2, TLR4 AND MyD88 Mediate Allergic Airway Disease (AAD) and Streptococcus pneumoniae-Induced Suppression of AAD.', PLoS One, 11 e0156402 (2016) [C1]
Bourke JE, Bai Y, Donovan C, Esposito JG, Tan X, Sanderson MJ, 'Novel small airway bronchodilator responses to rosiglitazone in mouse lung slices', American Journal of Respiratory Cell and Molecular Biology, 50 748-756 (2014) [C1]
There is a need to identify novel agents that elicit small airway relaxation when ß2-adrenoceptor agonists become ineffective in difficult-to-treat asthma. Because chronic treatme... [more]
There is a need to identify novel agents that elicit small airway relaxation when ß2-adrenoceptor agonists become ineffective in difficult-to-treat asthma. Because chronic treatment with the synthetic peroxisome proliferator activated receptor (PPAR)¿ agonist rosiglitazone (RGZ) inhibits airway hyperresponsiveness in mouse models of allergic airways disease, we tested the hypothesis that RGZ causes acute airway relaxation by measuring changes in small airway size in mouse lung slices. Whereas the ß-adrenoceptor agonists albuterol (ALB) and isoproterenol induced partial airway relaxation, RGZ reversed submaximal and maximal contraction to methacholine (MCh) and was similarly effective after precontraction with serotonin or endothelin-1. Concentration-dependent relaxation to RGZ was not altered by the ß-adrenoceptor antagonist propranolol and was enhanced by ALB. RGZ-induced relaxation wasmimicked by other synthetic PPAR¿ agonists but not by the putative endogenous agonist 15-deoxy-PGJ2 and was not prevented by the PPAR¿ antagonist GW9662. To induce airway relaxation, RGZ inhibited the amplitude and frequency of MCh-induced Ca2+ oscillations of airway smooth muscle cells (ASMCs). In addition, RGZ reduced MCh-induced Ca2+ sensitivity of the ASMCs. Collectively, these findings demonstrate that acute bronchodilator responses induced by RGZ are PPAR¿ independent, additive with ALB, and occur by the inhibition of ASMC Ca2+ signaling and Ca2+ sensitivity. Because RGZ continues to elicit relaxation when ß-adrenoceptor agonists have a limited effect, RGZ or related compounds may have potential as bronchodilators for the treatment of difficult asthma. Copyright © 2014 by the American Thoracic Society.
FitzPatrick M, Donovan C, Bourke JE, 'Prostaglandin E
Background: Current asthma therapy may not adequately target contraction of smaller intrapulmonary airways, which are a major site of airway obstruction and inflammation. The aim ... [more]
Background: Current asthma therapy may not adequately target contraction of smaller intrapulmonary airways, which are a major site of airway obstruction and inflammation. The aim of this study was to characterise responses of mouse intrapulmonary airways to prostaglandin E2 (PGE2) and compare its dilator efficacy with the ß2-adrenoceptor agonist salbutamol in situ, using lung slices. Methods: Lung slices (150 µm) were prepared from male Balb/C mice. Changes in intrapulmonary airway lumen area were recorded and analysed by phase-contrast microscopy. Relaxation to PGE2 and salbutamol were assessed following various levels of pre-contraction with methacholine, serotonin or endothelin-1, as well as following overnight incubation with PGE2 or salbutamol. The mechanism of PGE2-mediated relaxation was explored using selective EP antagonists (EP1/2 AH6809; EP4 L-161982) and Ca2+-permeabilized slices, where airway responses are due to regulation of Ca2+-sensitivity alone. Results: PGE2 elicited EP1/2-mediated relaxation of intrapulmonary airways. PGE2 was more potent than salbutamol in opposing submaximal pre-contraction to all constrictors tested, and only PGE2 opposed maximal pre-contraction with endothelin-1. Relaxation to PGE2 was maintained when contraction to methacholine was mediated via increased Ca2+-sensitivity alone. PGE2 was less sensitive to homologous or heterologous desensitization of its receptors than salbutamol. Conclusion: The greater efficacy and potency of PGE2 compared to salbutamol in mouse intrapulmonary airways supports further investigation of the mechanisms underlying this improved dilator responsiveness for the treatment of severe asthma. © 2013.
Baker KE, Bonvini SJ, Donovan C, Foong RE, Han B, Jha A, et al., 'Novel drug targets for asthma and COPD: Lessons learned from invitro and invivo models', Pulmonary Pharmacology and Therapeutics, 29 181-198 (2014) [C1]
© 2014. Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent respiratory diseases characterized by airway inflammation, airway obstruction and airway hyper... [more]
© 2014. Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent respiratory diseases characterized by airway inflammation, airway obstruction and airway hyperresponsiveness. Whilst current therapies, such as ß-agonists and glucocorticoids, may be effective at reducing symptoms, they do not reduce disease progression. Thus, there is a need to identify new therapeutic targets. In this review, we summarize the potential of novel targets or tools, including anti-inflammatories, phosphodiesterase inhibitors, kinase inhibitors, transient receptor potential channels, vitamin D and protease inhibitors, for the treatment of asthma and COPD.
Donovan C, Simoons M, Esposito J, Ni Cheong J, FitzPatrick M, Bourke JE, 'Rosiglitazone is a superior bronchodilator compared to chloroquine and ß-adrenoceptor agonists in mouse lung slices', Respiratory Research, 15 (2014) [C1]
Background: Current therapy for relieving bronchoconstriction may be ineffective in severe asthma, particularly in the small airways. The aim of this study was to further characte... [more]
Background: Current therapy for relieving bronchoconstriction may be ineffective in severe asthma, particularly in the small airways. The aim of this study was to further characterise responses to the recently identified novel bronchodilators rosiglitazone (RGZ) and chloroquine (CQ) under conditions where ß-adrenoceptor agonist efficacy was limited or impaired in mouse small airways within lung slices.Methods: Relaxation to RGZ and CQ was assessed following submaximal methacholine (MCh) pre-contraction, in slices treated overnight with either RGZ, CQ or albuterol (ALB) (to induce ß-adrenoceptor desensitization), and in slices treated with caffeine/ryanodine in which contraction is associated with increases in Ca2+ sensitivity in the absence of contractile agonist-induced Ca2+ oscillations. Furthermore, the effects of RGZ, CQ, ALB and isoproterenol (ISO) on the initiation and development of methacholine-induced contraction were also compared.Results: RGZ and CQ, but not ALB or ISO, elicited complete relaxation with increasing MCh pre-contraction and maintained their potency and efficacy following ß-adrenoceptor desensitization. RGZ, CQ and ALB maintained efficacy following overnight incubation with RGZ or CQ. Relaxation responses to all dilators were generally maintained but delayed after caffeine/ryanodine. Pre-treatment with RGZ, but not CQ, ALB or ISO, reduced MCh potency.Conclusions: This study demonstrates the superior effectiveness of RGZ in comparison to CQ and ß-adrenoceptor agonists as a dilator of mouse small airways. Further investigation of the mechanisms underlying the relatively greater efficacy of RGZ under these conditions are warranted and should be extended to include studies in human asthmatic airways. © 2014 Donovan et al.; licensee BioMed Central Ltd.
Donovan C, Royce SG, Esposito J, Tran J, Ibrahim ZA, Tang MLK, et al., 'Differential Effects of Allergen Challenge on Large and Small Airway Reactivity in Mice', PLoS ONE, 8 (2013) [C1]
The relative contributions of large and small airways to hyperresponsiveness in asthma have yet to be fully assessed. This study used a mouse model of chronic allergic airways dis... [more]
The relative contributions of large and small airways to hyperresponsiveness in asthma have yet to be fully assessed. This study used a mouse model of chronic allergic airways disease to induce inflammation and remodelling and determine whether in vivo hyperresponsiveness to methacholine is consistent with in vitro reactivity of trachea and small airways. Balb/C mice were sensitised (days 0, 14) and challenged (3 times/week, 6 weeks) with ovalbumin. Airway reactivity was compared with saline-challenged controls in vivo assessing whole lung resistance, and in vitro measuring the force of tracheal contraction and the magnitude/rate of small airway narrowing within lung slices. Increased airway inflammation, epithelial remodelling and fibrosis were evident following allergen challenge. In vivo hyperresponsiveness to methacholine was maintained in isolated trachea. In contrast, methacholine induced slower narrowing, with reduced potency in small airways compared to controls. In vitro incubation with IL-1/TNFa did not alter reactivity. The hyporesponsiveness to methacholine in small airways within lung slices following chronic ovalbumin challenge was unexpected, given hyperresponsiveness to the same agonist both in vivo and in vitro in tracheal preparations. This finding may reflect the altered interactions of small airways with surrounding parenchymal tissue after allergen challenge to oppose airway narrowing and closure. © 2013 Donovan et al.
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Conference (4 outputs)
Budden K, Shukla S, Rehman SF, Sahu P, Donovan C, Bowerman KL, et al., 'The Role of the Gastrointestinal Microbiome in Lung Cancer Pathogenesis', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2019)
Horvat JC, Alit M, Johnstone D, Essilfie A-T, Mayall J, Pinkerton JW, et al., 'Role Of Increased Iron Levels In The Pathogenesis Of Lung Disease', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Washington, DC (2017)
Tay HL, Hsu A, Nguyen T, Donovan C, Collison A, Mattes J, et al., 'Interleukin-36 gamma: Roles in lungs innate immunity, inflammation and allergy', CYTOKINE, Int Cytokine & Interferon Soc, Kanazawa, JAPAN (2017)
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Grants and Funding
|Number of grants||5|
Click on a grant title below to expand the full details for that specific grant.
20182 grants / $416,411
Targeting remodelling in chronic obstructive pulmonary disease (COPD), chronic asthma and idiopathic pulmonary fibrosis (IPF)$396,411
Funding body: NHMRC (National Health & Medical Research Council)
|Funding body||NHMRC (National Health & Medical Research Council)|
|Project Team||Doctor Chantal Donovan|
|Type Of Funding||Aust Competitive - Commonwealth|
Funding body: Hunter Medical Research Institute
|Funding body||Hunter Medical Research Institute|
|Project Team||Miss Vrushali Chimankar, Associate Professor Jay Horvat, Doctor Chantal Donovan, Professor Philip Hansbro|
|Scheme||Emlyn and Jennie Thomas Postgraduate Medical Research Scholarship|
|Type Of Funding||C3120 - Aust Philanthropy|
20173 grants / $234,080
Targeting IL-33 in chronic obstructive pulmonary disease (COPD), chronic asthma and idiopathic pulmonary fibrosis (IPF)$213,007
Funding body: NHMRC (National Health & Medical Research Council)
|Funding body||NHMRC (National Health & Medical Research Council)|
|Project Team||Doctor Chantal Donovan|
|Scheme||Early Career Fellowships|
|Type Of Funding||Aust Competitive - Commonwealth|
Funding body: University of Newcastle
|Funding body||University of Newcastle|
|Project Team||Doctor Chantal Donovan|
|Scheme||NHMRC ECF Support|
|Type Of Funding||Internal|
Funding body: NSW Ministry of Health
|Funding body||NSW Ministry of Health|
|Project Team||Associate Professor Jay Horvat, Doctor Chantal Donovan, Doctor Richard Kim, Doctor Shakti Shukla, Doctor Atiqur Rahman|
|Scheme||Medical Research Support Program (MRSP)|
|Type Of Funding||C2220 - Aust StateTerritoryLocal - Other|
Number of supervisions
|Commenced||Level of Study||Research Title||Program||Supervisor Type|
|2018||PhD||Developing New Treatments in COPD||PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle||Co-Supervisor|
|2018||PhD||Understand the Roles and Therapeutic Targeting of Macrophages in COPD||PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle||Co-Supervisor|
|2018||PhD||Investigating Asthma-COPD Overlap Using Mouse Models||PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle||Co-Supervisor|
|2017||PhD||Understanding the Molecular Basis of Chronic Respiratory Diseases through Multi-Omics Approaches||PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle||Co-Supervisor|
|2017||PhD||Investigating the Development of New Treatments for Lung Cancer||PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle||Co-Supervisor|
|2017||PhD||Elucidating and Targeting Genomic and Epigenetic Changes in the Development and Progression of Lung Cancer||PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle||Co-Supervisor|
|2016||PhD||Investigating the Genetics and Epigenetics of the Development of Lung Cancer||PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle||Co-Supervisor|
|2016||PhD||Mechanisms and Therapeutic Targeting of Immunometabolism in Lung Disease||PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle||Co-Supervisor|