Can supervise: YES
Starkey, MR, Plank, MW, Casolari, P, Papi, A, Pavlidis, S, Guo, Y, Cameron, GJM, Haw, TJ, Tam, A, Obiedat, M, Donovan, C, Hansbro, NG, Nguyen, DH, Nair, PM, Kim, RY, Horvat, JC, Kaiko, GE, Durum, SK, Wark, PA, Sin, DD, Caramori, G, Adcock, IM, Foster, PS & Hansbro, PM 2019, 'IL-22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis', EUROPEAN RESPIRATORY JOURNAL, vol. 54, no. 1.View/Download from: UTS OPUS or Publisher's site
Caramori, G, Ruggeri, P, Mumby, S, Ieni, A, Lo Bello, F, Chimankar, V, Donovan, C, Andò, F, Nucera, F, Coppolino, I, Tuccari, G, Hansbro, PM & Adcock, IM 2019, 'Molecular links between COPD and lung cancer: new targets for drug discovery?', Expert opinion on therapeutic targets, vol. 23, no. 6, pp. 539-553.View/Download from: UTS OPUS or Publisher's site
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.
Donovan, C, Starkey, MR, Kim, RY, Rana, BMJ, Barlow, JL, Jones, B, Haw, TJ, Mono Nair, P, Budden, K, Cameron, GJM, Horvat, JC, Wark, PA, Foster, PS, McKenzie, ANJ & Hansbro, PM 2019, 'Roles for T/B lymphocytes and ILC2s in experimental chronic obstructive pulmonary disease.', Journal of leukocyte biology, vol. 105, no. 1, pp. 143-150.View/Download from: UTS OPUS or Publisher's site
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 Rorafl/fl Il7rCre [ILC2-deficient] mice). Wild-type (WT) C57BL/6 mice, Rag1-/- , and Rorafl/fl Il7rCre 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 Rorafl/fl Il7rCre 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.
Schofield, ZV, Croker, D, Robertson, AAB, Massey, NL, Donovan, C, Tee, E, Edwards, D, Woodruff, TM, Halai, R, Hansbro, PM & Cooper, MA 2018, 'Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling.', Scientific reports, vol. 8, no. 1.View/Download from: UTS OPUS or Publisher's site
Short chain fatty acids (SCFAs) are protective against inflammatory diseases. Free fatty acid receptor 2 (FFA2), is a target of SCFAs however, their selectivity for FFA2 over other FFA receptors is limited. This study aimed to functionally characterise 2-(4-chlorophenyl)-3-methyl-N-(thiazole-2-yl)butanamide (4CMTB) and 4-((4-(2-chlorophenyl)thiazole-2-yl)amino)-4oxo-3-phenylbutanoic acid (2CTAP), and their enantiomers, in modulating FFA2 activity. The racemic mixture (R/S) and its constituents (R-) and (S-) 4CMTB or 2CTAP were used to stimulate human (h)FFA2 in the absence or presence of acetate. Calcium ions (Ca2+), phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) and cyclic adenosine monophosphate (cAMP) were measured. R/S-4CMTB is a functionally selective ago-allosteric ligand that enhances Ca2+ response to acetate. Both R/S-4CMTB and S-4CMTB are more potent activators of pERK1/2 and inhibitors of forskolin-induced cAMP than acetate. S-4CMTB increased neutrophil infiltration in intestinal ischemia reperfusion injury (IRI). 2CTAP inhibited constitutive Ca2+ levels, antagonised acetate-induced pERK1/2 and prevented damage following IRI. This study characterises enantiomers of functionally selective ligands for FFA2 in cells stably expressing hFFA2. It highlights the novel roles of selective FFA2 enantiomers 4CMTB and 2CTAP on Ca2+, pERK1/2 and cAMP and their roles as allosteric modulators which, may assist in efforts to design novel therapeutic agents for FFA2-driven inflammatory diseases.
Terlizzi, M, Molino, A, Colarusso, C, Donovan, C, Imitazione, P, Somma, P, Aquino, RP, Hansbro, PM, Pinto, A & Sorrentino, R 2018, '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, vol. 9.View/Download from: UTS OPUS or Publisher's site
Faiz, A, Donovan, C, Nieuwenhuis, MAE, van den Berge, M, Postma, DS, Yao, S, Park, CY, Hirsch, R, Fredberg, JJ, Tjin, G, Halayko, AJ, Rempel, KL, Ward, JPT, Lee, T, Bossé, Y, Nickle, DC, Obeidat, M, Vonk, JM, Black, JL, Oliver, BG, Krishnan, R, McParland, B, Bourke, JE & Burgess, JK 2017, 'Latrophilin receptors: Novel bronchodilator targets in asthma', Thorax, vol. 72, pp. 74-82.View/Download from: UTS OPUS or Publisher's site
© 2016 BMJ Publishing Group Ltd & British Thoracic Society.Background Asthma affects 300 million people worldwide. In asthma, the major cause of morbidity and mortality is acute airway narrowing, due to airway smooth muscle (ASM) hypercontraction, associated with airway remodelling. However, little is known about the transcriptional differences between healthy and asthmatic ASM cells. Objectives To investigate the transcriptional differences between asthmatic and healthy airway smooth muscle cells (ASMC) in culture and investigate the identified targets using in vitro and ex vivo techniques. Methods Human asthmatic and healthy ASMC grown in culture were run on Affymetrix_Hugene_1.0_ST microarrays. Identified candidates were confirmed by PCR, and immunohistochemistry. Functional analysis was conducted using in vitro ASMC proliferation, attachment and contraction assays and ex vivo contraction of mouse airways. Results We suggest a novel role for latrophilin (LPHN) receptors, finding increased expression on ASMC from asthmatics, compared with non-asthmatics in vivo and in vitro, suggesting a role in mediating airway function. A single nucleotide polymorphism in LPHN1 was associated with asthma and with increased LPHN1 expression in lung tissue. When activated, LPHNs regulated ASMC adhesion and proliferation in vitro, and promoted contraction of mouse airways and ASMC. Conclusions Given the need for novel inhibitors of airway remodelling and bronchodilators in asthma, the LPHN family may represent promising novel targets for future dual therapeutic intervention.
Hansbro, PM, Kim, RY, Starkey, MR, Donovan, C, Dua, K, Mayall, JR, Liu, G, Hansbro, NG, Simpson, JL, Wood, LG, Hirota, JA, Knight, DA, Foster, PS & Horvat, JC 2017, 'Mechanisms and treatments for severe, steroid-resistant allergic airway disease and asthma.', Immunological reviews, vol. 278, no. 1, pp. 41-62.View/Download from: UTS OPUS or Publisher's site
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.
Liu, G, Cooley, MA, Nair, PM, Donovan, C, Hsu, AC, Jarnicki, AG, Haw, TJ, Hansbro, NG, Ge, Q, Brown, AC, Tay, H, Foster, PS, Wark, PA, Horvat, JC, Bourke, JE, Grainge, CL, Argraves, WS, Oliver, BG, Knight, DA, Burgess, JK & Hansbro, PM 2017, 'Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c.', The Journal of Pathology, vol. 243, no. 4, pp. 510-523.View/Download from: UTS OPUS or Publisher's site
Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c-deficient (Fbln1c-/- ) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild-type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c-/- mice with AAD also had reduced numbers of α-smooth muscle actin-positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)-5, IL-13, IL-33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL-5, IL-33 and TNF levels in lung-draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3-positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL-5 and IL-13 from co-cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium-treated controls. Our data show that...
Jones, B, Donovan, C, Liu, G, Gomez, HM, Chimankar, V, Harrison, CL, Wiegman, CH, Adcock, IM, Knight, DA, Hirota, JA & Hansbro, PM 2017, 'Animal models of COPD: What do they tell us?', Respirology, vol. 22, no. 1, pp. 21-32.View/Download from: UTS OPUS or Publisher's site
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.
Donovan, C, Bourke, JE & Vlahos, R 2016, 'Targeting the IL-33/IL-13 Axis for Respiratory Viral Infections', Trends in Pharmacological Sciences, vol. 37, no. 4, pp. 252-261.View/Download from: Publisher's site
© 2016 Elsevier Ltd. Lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are highly prevalent worldwide. One of the major factors that limits the efficacy of current medication in these patients are viral infections, leading to exacerbations of symptoms and decreased quality of life. Current pharmacological strategies targeting virus-induced lung disease are problematic due to antiviral resistance and the requirement for strain-specific vaccination. Thus, new therapeutic strategies are urgently required. In this Opinion article, we provide state-of-the-art evidence from humans and preclinical animal models implicating the interleukin (IL)-33/IL-13 axis in virus-induced lung disease. Thus, targeting the IL-33/IL-13 axis may be a feasible way to overcome the limitations of current therapy used to treat virus-induced exacerbations of lung disease.
Donovan, C, Seow, HJ, Bourke, JE & Vlahos, R 2016, 'Influenza A virus infection and cigarette smoke impair bronchodilator responsiveness to β-adrenoceptor agonists in mouse lung', Clinical Science, vol. 130, no. 10, pp. 829-837.View/Download from: Publisher's site
© 2016 The Author(s). β2-adrenoceptor agonists are the mainstay therapy for patients with asthma but their effectiveness in cigarette smoke (CS)-induced lung disease such as chronic obstructive pulmonary disease (COPD) is limited. In addition, bronchodilator efficacy of β2-adrenoceptor agonists is decreased during acute exacerbations of COPD (AECOPD), caused by respiratory viruses including influenza A. Therefore, the aim of the present study was to assess the effects of the β2-adrenoceptor agonist salbutamol (SALB) on small airway reactivity using mouse precision cut lung slices (PCLS) prepared from CS-exposed mice and from CS-exposed mice treated with influenza A virus (Mem71, H3N1). CS exposure alone reduced SALB potency and efficacy associated with decreased β2-adrenoceptor mRNA expression, and increased tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) expression. This impaired relaxation was restored by day 12 in the absence of further CS exposure. In PCLS prepared after Mem71 infection alone, responses to SALB were transient and were not well maintained. CS exposure prior to Mem71 infection almost completely abolished relaxation, although β2-adrenoceptor and TNFα and IL-1β expression were unaltered. The present study has shown decreased sensitivity to SALB after CS or a combination of CS and Mem71 occurs by different mechanisms. In addition, the PCLS technique and our models of CS and influenza infection provide a novel setting for assessment of alternative bronchodilators.
Lam, M, Royce, SG, Donovan, C, Jelinic, M, Parry, LJ, Samuel, CS & Bourke, JE 2016, 'Serelaxin elicits bronchodilation and enhances β-adrenoceptor-mediated airway relaxation', Frontiers in Pharmacology, vol. 7, no. OCT.View/Download from: Publisher's site
© 2016 Lam, Royce, Donovan, Jelinic, Parry, Samuel and Bourke. Treatment with β-adrenoceptor agonists does not fully overcome the symptoms associated with severe asthma. Serelaxin elicits potent uterine and vascular relaxation via its cognate receptor, RXFP1, and nitric oxide (NO) signaling, and is being clinically evaluated for the treatment of acute heart failure. However, its direct bronchodilator efficacy has yet to be explored. Tracheal rings were prepared from male Sprague-Dawley rats (250-350 g) and tricolor guinea pigs, and precision cut lung slices (PCLSs) containing intrapulmonary airways were prepared from rats only. Recombinant human serelaxin (rhRLX) alone and in combination with rosiglitazone (PPARγ agonist; recently described as a novel dilator) or β-adrenoceptor agonists (isoprenaline, salbutamol) were added either to pre-contracted airways, or before contraction with methacholine or endothelin-1. Regulation of rhRLX responses by epithelial removal, indomethacin (cyclooxygenase inhibitor), L-NAME (nitric oxide synthase inhibitor), SQ22536 (adenylate cyclase inhibitor) and ODQ (guanylate cyclase inhibitor) were also evaluated. Immunohistochemistry was used to localize RXFP1 to airway epithelium and smooth muscle. rhRLX elicited relaxation in rat trachea and PCLS, more slowly than rosiglitazone or isoprenaline, but potentiated relaxation to both these dilators. It markedly increased β-adrenoceptor agonist potency in guinea pig trachea. rhRLX, rosiglitazone, and isoprenaline pretreatment also inhibited the development of rat tracheal contraction. Bronchoprotection by rhRLX increased with longer pre-incubation time, and was partially reduced by epithelial removal, indomethacin and/or L-NAME. SQ22536 and ODQ also partially inhibited rhRLX-mediated relaxation in both intact and epithelial-denuded trachea. RXFP1 expression in the airways was at higher levels in epithelium than smooth muscle. In summary, rhRLX elicits large and small airway relaxation via...
Royce, SG, Nold, MF, Bui, C, Donovan, C, Lam, M, Lamanna, E, Rudloff, I, Bourke, JE & Nold-Petry, CA 2016, 'Airway remodeling and hyperreactivity in a model of Bronchopulmonary dysplasia and their modulation by IL-1 receptor antagonist', American Journal of Respiratory Cell and Molecular Biology, vol. 55, no. 6, pp. 858-868.View/Download from: Publisher's site
© Copyright 2016 by the American Thoracic Society. Bronchopulmonary dysplasia (BPD) is a chronic disease of extreme prematurity that has serious long-term consequences including increased asthma risk. We earlier identified IL-1 receptor antagonist (IL-1Ra) as a potent inhibitor of murine BPD induced by combining perinatal inflammation (intraperitoneal LPS to pregnant dams) and exposure of pups to hyperoxia (fraction of inspired oxygen = 0.65). In this study, we determined whether airway remodeling and hyperresponsiveness similar to asthma are evident in this model, and whether IL-1Ra is protective. During 28-day exposure to air or hyperoxia, pups received vehicle or 10 mg/kg IL-1Ra by daily subcutaneous injection. Lungs were then prepared for histology and morphometry of alveoli and airways, or for real-time PCR, or inflated with agarose to prepare precision-cut lung slices to visualize ex vivo intrapulmonary airway contraction and relaxation by phase-contrast microscopy. In pups reared under normoxic conditions, IL-1Ra treatment did not affect alveolar or airway structure or airway responses. Pups reared in hyperoxia developed a severe BPD-like lung disease, with fewer, larger alveoli, increased subepithelial collagen, and increased expression of α-smooth muscle actin and cyclin D1. After hyperoxia, methacholine elicited contraction with similar potency but with an increased maximum reduction in lumen area (air, 44%; hyperoxia, 89%), whereas dilator responses to salbutamol were maintained. IL-1Ra treatment prevented hyperoxia-induced alveolar disruption and airway fibrosis but, surprisingly, not the increase in methacholine-induced airway contraction. The current study is the first to demonstrate ex vivo airway hyperreactivity caused by systemic maternal inflammation and postnatal hyperoxia, and it reveals further preclinical mechanistic insights into IL-1Ra as a treatment targeting key pathophysiological features of BPD.
Thorburn, AN, Tseng, H-Y, Donovan, C, Hansbro, NG, Jarnicki, AG, Foster, PS, Gibson, PG & Hansbro, PM 2016, 'TLR2, TLR4 AND MyD88 Mediate Allergic Airway Disease (AAD) and Streptococcus pneumoniae-Induced Suppression of AAD', PLOS ONE, vol. 11, no. 6.View/Download from: UTS OPUS or Publisher's site
Donovan, C, Bailey, SR, Tran, J, Haitsma, G, Ibrahim, ZA, Foster, SR, Tang, MLK, Royce, SG & Bourke, JE 2015, 'Rosiglitazone elicits in vitro relaxation in airways and precision cut lung slices from a mouse model of chronic allergic airways disease', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 309, no. 10, pp. L1219-L1228.View/Download from: Publisher's site
© 2015 the American Physiological Society. Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor-γ (PPAR γ) ligand, is a novel dilator of small airways in mouse precision cut lung slices (PCLS). In this study, relaxation to RGZ and ẞ-adrenoceptor agonists were compared in trachea from naïve mice and guinea pigs and trachea and PCLS from a mouse model of chronic allergic airways disease (AAD). Airways were precontracted with methacholine before addition of PPAR γ ligands [RGZ, ciglitazone (CGZ), or 15-deoxy-Δ12,14-prostaglandin J2 (15-deoxy-PGJ2)] or ẞ-adrenoceptor agonists (isoprenaline and salbutamol). The effects of T0070907 and GW9662 (PPAR γ antagonists) or epithelial removal on relaxation were assessed. Changes in force of trachea and lumen area in PCLS were measured using preparations from saline-challenged mice and mice sensitized (days 0 and 14) and challenged with ovalbumin (3 times/wk, 6 wk). RGZ and CGZ elicited complete relaxation with greater efficacy than y-adrenoceptor agonists in mouse airways but not guinea pig trachea, while 15-deoxy-PGJ2 did not mediate bronchodilation. Relaxation to RGZ was not prevented by T0070907 or GW9662 or by epithelial removal. RGZ-induced relaxation was preserved in the trachea and increased in PCLS after ovalbumin-challenge. Although RGZ was less potent than y-adrenoceptor agonists, its effects were additive with salbutamol and isoprenaline and only RGZ maintained potency and full efficacy in maximally contracted airways or after allergen challenge. Acute PPAR γ-independent, epithelial-independent airway relaxation to RGZ is resistant to functional antagonism and maintained in both trachea and PCLS from a model of chronic AAD. These novel efficacious actions of RGZ support its therapeutic potential in asthma when responsiveness to ẞ-adrenoceptor agonists is limited.
© 2015 Donovan et al. The bacterial endotoxin, lipopolysaccharide (LPS) has been associated with occupational airway diseases with asthma-like symptoms and in acute exacerbations of COPD. The direct and indirect effects of LPS on small airway reactivity have not been fully elucidated. We tested the hypothesis that both in vitro and in vivo LPS treatment would increase contraction and impair relaxation of mouse small airways. Lung slices were prepared from naï ve Balb/C mice and cultured in the absence or presence of LPS (10 μg/ml) for up to 48 h for measurement of TNFα levels in conditioned media. Alternatively, mice were challenged with PBS or LPS in vivo once a day for 4 days for preparation of lung slices or for harvest of lungs for Q-PCR analysis of gene expression of pro-inflammatory cytokines and receptors involved in airway contraction. Reactivity of small airways to contractile agonists, methacholine and serotonin, and bronchodilator agents, salbutamol, isoprenaline and rosiglitazone, were assessed using phase-contrast microscopy. In vitro LPS treatment of slices increased TNFα release 6-fold but did not alter contraction or relaxation to any agonists tested. In vivo LPS treatment increased lung gene expression of TNFα, IL-1β and ryanodine receptor isoform 2 more than 5-fold. However there were no changes in reactivity in lung slices from these mice, even when also incubated with LPS ex vivo. Despite evidence of LPS-induced inflammation, neither airway hyperresponsiveness or impaired dilator reactivity were evident. The increase in ryanodine receptor isoform 2, known to regulate calcium signaling in vascular smooth muscle, warrants investigation. Since LPS failed to elicit changes in small airway reactivity in mouse lung slices following in vitro or in vivo treatment, alternative approaches are required to define the potential contribution of this endotoxin to altered small airway reactivity in human lung diseases.
Donovan, C, Seow, HJ, Royce, SG, Bourke, JE & Vlahos, R 2015, 'Alteration of airway reactivity and reduction of ryanodine receptor expression by cigarette smoke in mice', American Journal of Respiratory Cell and Molecular Biology, vol. 53, no. 4, pp. 471-478.View/Download from: Publisher's site
Copyright © 2015 by the American Thoracic SocietyGrant: This work was supported by grants 1041575 and 1027112 from the National Health and Medical Research Council of Australia. Small airways are a major site of airflow limitation in chronic obstructive pulmonary disease (COPD). Despite the detrimental effects of long-term smoking in COPD, the effects of acute cigarette smoke (CS) exposure on small airway reactivity have not been fully elucidated. Balb/C mice were exposed to room air (sham) or CS for 4 days to cause airway inflammation. Changes in small airway lumen area in response to contractile agents were measured in lung slices in situ using phase-contrast microscopy. Separate slices were pharmacologically maintained at constant intracellular Ca2+ using caffeine/ryanodine before contractile measurements. Gene and protein analysis of contractile signaling pathways were performed on separate lungs. Monophasic contraction to serotonin became biphasic after CS exposure, whereas contraction to methacholine was unaltered. This altered pattern of contraction was normalized by caffeine/ryanodine. Expression of contractile agonist-specific receptors was unaltered; however, all isoforms of the ryanodine receptor were down-regulated. This is the first study to show that acute CS exposure selectively alters small airway contraction to serotonin and down-regulates ryanodine receptors involved in maintaining Ca2+ oscillations in airway smooth muscle. Understanding the contribution of ryanodine receptors to altered airway reactivity may inform the development of novel treatment strategies for COPD.
Baker, KE, Bonvini, SJ, Donovan, C, Foong, RE, Han, B, Jha, A, Shaifta, Y, Smit, M, Johnson, JR & Moir, LM 2014, 'Novel drug targets for asthma and COPD: Lessons learned from in vitro and in vivo models', PULMONARY PHARMACOLOGY & THERAPEUTICS, vol. 29, no. 2, pp. 181-198.View/Download from: Publisher's site
Bourke, JE, Bai, Y, Donovan, C, Esposito, JG, Tan, X & Sanderson, MJ 2014, 'Novel small airway bronchodilator responses to rosiglitazone in mouse lung slices', American Journal of Respiratory Cell and Molecular Biology, vol. 50, no. 4, pp. 748-756.View/Download from: Publisher's site
There is a need to identify novel agents that elicit small airway relaxation when β2-adrenoceptor agonists become ineffective in difficult-to-treat asthma. Because chronic treatment with the synthetic peroxisome proliferator activated receptor (PPAR)γ 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 β-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 β-adrenoceptor antagonist propranolol and was enhanced by ALB. RGZ-induced relaxation wasmimicked by other synthetic PPARγ agonists but not by the putative endogenous agonist 15-deoxy-PGJ2 and was not prevented by the PPARγ 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 PPARγ independent, additive with ALB, and occur by the inhibition of ASMC Ca2+ signaling and Ca2+ sensitivity. Because RGZ continues to elicit relaxation when β-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.
Donovan, C, Simoons, M, Esposito, J, Cheong, JN, FitzPatrick, M & Bourke, JE 2014, 'Rosiglitazone is a superior bronchodilator compared to chloroquine and beta-adrenoceptor agonists in mouse lung slices', RESPIRATORY RESEARCH, vol. 15.View/Download from: Publisher's site
FitzPatrick, M, Donovan, C & Bourke, JE 2014, 'Prostaglandin E-2 elicits greater bronchodilation than salbutamol in mouse intrapulmonary airways in lung slices', PULMONARY PHARMACOLOGY & THERAPEUTICS, vol. 28, no. 1, pp. 68-76.View/Download from: Publisher's site
Donovan, C, Royce, SG, Esposito, J, Tran, J, Ibrahim, ZA, Tang, MLK, Bailey, S & Bourke, JE 2013, 'Differential Effects of Allergen Challenge on Large and Small Airway Reactivity in Mice', PLoS ONE, vol. 8, no. 9.View/Download from: Publisher's site
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/TNFα 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.
Donovan, C, Tan, X & Bourke, JE 2012, 'PPAR γ ligands regulate noncontractile and contractile functions of airway smooth muscle: Implications for asthma therapy', PPAR Research.View/Download from: Publisher's site
In asthma, the increase in airway smooth muscle (ASM) can contribute to inflammation, airway wall remodeling and airway hyperresponsiveness (AHR). Targetting peroxisome proliferator-activated receptor γ (PPARγ), a receptor upregulated in ASM in asthmatic airways, may provide a novel approach to regulate these contributions. This review summarises experimental evidence that PPARγ ligands, such as rosiglitazone (RGZ) and pioglitazone (PGZ), inhibit proliferation and inflammatory cytokine production from ASM in vitro. In addition, inhaled administration of these ligands reduces inflammatory cell infiltration and airway remodelling in mouse models of allergen-induced airways disease. PPARγ ligands can also regulate ASM contractility, with acute treatment eliciting relaxation of mouse trachea in vitro through a PPARγ-independent mechanism. Chronic treatment can protect against the loss of bronchodilator sensitivity to β 2-adrenoceptor agonists and inhibit the development of AHR associated with exposure to nicotine in utero or following allergen challenge. Of particular interest, a small clinical trial has shown that oral RGZ treatment improves lung function in smokers with asthma, a group that is generally unresponsive to conventional steroid treatment. These combined findings support further investigation of the potential for PPARγ agonists to target the noncontractile and contractile functions of ASM to improve outcomes for patients with poorly controlled asthma. © 2012 Chantal Donovan et al.
Donovan, C, Kim, R, Brown, A, Tu, X, Jones, B, Budden, K, Ali, M, Nair, MP, Nguyen, D, Horvat, J & Hansbro, P 2019, 'INVESTIGATING ASTHMA-COPD OVERLAP USING MOUSE MODELS', RESPIROLOGY, WILEY, pp. 129-129.
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