Can supervise: YES
Li, J, Xu, X, Jiang, Y, Hansbro, NG, Hansbro, PM, Xu, J & Liu, G 2020, 'Elastin is a key factor of tumor development in colorectal cancer', BMC CANCER, vol. 20, no. 1.View/Download from: Publisher's site
Prasher, P, Sharma, M, Mehta, M, Paudel, KR, Satija, S, Chellappan, DK, Dureja, H, Gupta, G, Tambuwala, MM, Negi, P, Wich, PR, Hansbro, NG, Hansbro, PM & Dua, K 2020, 'Plants derived therapeutic strategies targeting chronic respiratory diseases: Chemical and immunological perspective', Chemico-Biological Interactions, vol. 325.View/Download from: Publisher's site
© 2020 Elsevier B.V. The apparent predicament of the representative chemotherapy for managing respiratory distress calls for an obligatory deliberation for identifying the pharmaceuticals that effectively counter the contemporary intricacies associated with target disease. Multiple, complex regulatory pathways manifest chronic pulmonary disorders, which require chemotherapeutics that produce composite inhibitory effect. The cost effective natural product based molecules hold a high fervor to meet the prospects posed by current respiratory-distress therapy by sparing the tedious drug design and development archetypes, present a robust standing for the possible replacement of the fading practice of poly-pharmacology, and ensure the subversion of a potential disease relapse. This study summarizes the experimental evidences on natural products moieties and their components that illustrates therapeutic efficacy on respiratory disorders.
Yong, DOC, Saker, SR, Chellappan, DK, Madheswaran, T, Panneerselvam, J, Choudhury, H, Pandey, M, Chan, YL, Collet, T, Gupta, G, Oliver, BG, Wark, P, Hansbro, N, Hsu, A, Hansbro, PM, Dua, K & Zeeshan, F 2020, 'Molecular and Immunological Mechanisms Underlying the Various Pharmacological Properties of the Potent Bioflavonoid, Rutin.', Endocrine, metabolic & immune disorders drug targets.View/Download from: Publisher's site
The application of medicinal plants has captured the interest of researchers in recent times due to their potent therapeutic properties and a better safety profile. The prominent role of herbal products in treating and preventing multiple diseases dates back to ancient history and most of the modern drugs today originated from its significant sources owing to their ability to control multiple targets via different signalling pathways. Among them, flavonoids consist of a large group of polyphenols, which are well known for their various therapeutic benefits. Rutin is considered one of the attractive phytochemicals and important flavonoid in the pharmaceutical industry due to its diverse pharmacological activities via various underlying molecular mechanisms. It is usually prescribed for various disease conditions such as varicosities, haemorrhoids and internal haemorrhage. In this review, we have discussed and highlighted the different molecular mechanisms attributed to the various pharmacological activities of rutin such as antioxidant, anti-inflammatory, anticancer, anti-allergic and anti-diabetic. This review will be beneficial to herbal, biological and molecular scientists in understanding the pharmacological relevance of rutin at the molecular level.
Chan, Y, Ng, SW, Chellappan, DK, Madheswaran, T, Zeeshan, F, Kumar, P, Pillay, V, Gupta, G, Wadhwa, R, Mehta, M, Wark, P, Hsu, A, Hansbro, NG, Hansbro, PM, Dua, K & Panneerselvam, J 2020, 'Celastrol-loaded liquid crystalline nanoparticles as an anti-inflammatory intervention for the treatment of asthma', INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS.View/Download from: Publisher's site
Hadjigol, S, Netto, KG, Maltby, S, Tay, HL, Nguyen, TH, Hansbro, NG, Eyers, F, Hansbro, PM, Yang, M & Foster, PS 2020, 'Lipopolysaccharide induces steroid-resistant exacerbations in a mouse model of allergic airway disease collectively through IL-13 and pulmonary macrophage activation.', Clinical and Experimental Allergy, vol. 50, no. 1.View/Download from: Publisher's site
BACKGROUND:Acute exacerbations of asthma represent a major burden of disease and are often caused by respiratory infections. Viral infections are recognized as significant triggers of exacerbations; however, less is understood about the how microbial bioproducts such as the endotoxin (lipopolysaccharide (LPS)) trigger episodes. Indeed, increased levels of LPS have been linked to asthma onset, severity and steroid resistance. OBJECTIVE:The goal of this study was to identify mechanisms underlying bacterial-induced exacerbations by employing LPS as a surrogate for infection. METHODS:We developed a mouse model of LPS-induced exacerbation on the background of pre-existing type-2 allergic airway disease (AAD). RESULTS:LPS-induced exacerbation was characterized by steroid-resistant airway hyperresponsiveness (AHR) and an exaggerated inflammatory response distinguished by increased numbers of infiltrating neutrophils/macrophages and elevated production of lung inflammatory cytokines, including TNFα, IFNγ, IL-27 and MCP-1. Expression of the type-2 associated inflammatory factors such as IL-5 and IL-13 were elevated in AAD but not altered by LPS exposure. Furthermore, AHR and airway inflammation were no longer suppressed by corticosteroid (dexamethasone) treatment after LPS exposure. Depletion of pulmonary macrophages by administration of 2-chloroadenosine into the lungs suppressed AHR and reduced IL-13, TNFα and IFNγ expression. Blocking IL-13 function, through either IL-13-deficiency or administration of specific blocking antibodies, also suppressed AHR and airway inflammation. CONCLUSIONS & CLINICAL RELEVANCE:We present evidence that IL-13 and innate immune pathways (in particular pulmonary macrophages) contribute to LPS-induced exacerbation of pre-existing AAD and provide insight into the complex molecular processes potentially underlying microbial-induced exacerbations.
Mehta, M, Chellappan, DK, Wich, PR, Hansbro, NG, Hansbro, PM & Dua, K 2020, 'miRNA nanotherapeutics: potential and challenges in respiratory disorders.', Future Medicinal Chemistry, vol. 12, no. 11, pp. 987-990.View/Download from: Publisher's site
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: Publisher's site
Liu, G, Cooley, MA, Jarnicki, AG, Borghuis, T, Nair, PM, Tjin, G, Hsu, AC, Haw, TJ, Fricker, M, Harrison, CL, Jones, B, Hansbro, NG, Wark, PA, Horvat, JC, Argraves, WS, Oliver, BG, Knight, DA, Burgess, JK & Hansbro, PM 2019, 'Fibulin-1c regulates transforming growth factor-beta activation in pulmonary tissue fibrosis', JCI INSIGHT, vol. 4, no. 16.View/Download from: Publisher's site
Ng, SW, Chan, Y, Chellappan, DK, Madheswaran, T, Zeeshan, F, Chan, YL, Collet, T, Gupta, G, Oliver, BG, Wark, P, Hansbro, N, Hsu, A, Hansbro, PM, Dua, K & Panneerselvam, J 2019, 'Molecular modulators of celastrol as the keystones for its diverse pharmacological activities.', Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, vol. 109, pp. 1785-1792.View/Download from: Publisher's site
In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their potent pharmacological actions and better toxicological profile. One such example that has come into the light with considerable interest is the pentacyclic triterpenoid, celastrol, which has been found to provide substantial therapeutic properties in a variety of diseases. In an effort to further accelerate its potential to be utilized in clinical practice in the future; along with advancing technologies in the field of drug discovery and development, different researchers have been investigating on the various mechanisms and immunological targets of celastrol that underlie its broad spectrum of pharmacological properties. In this review, we have collated the various research findings related to the molecular modulators responsible for different pharmacological activities shown by celastrol. Our review will be of interest to the herbal, biological, molecular scientist and by providing a quick snapshot about celastrol giving a new direction in the area of herbal drug discovery and development.
Dua, K, Malyla, V, Singhvi, G, Wadhwa, R, Krishna, RV, Shukla, SD, Shastri, MD, Chellappan, DK, Maurya, PK, Satija, S, Mehta, M, Gulati, M, Hansbro, N, Collet, T, Awasthi, R, Gupta, G, Hsu, A & Hansbro, PM 2019, 'Increasing complexity and interactions of oxidative stress in chronic respiratory diseases: An emerging need for novel drug delivery systems.', Chemico-biological interactions, vol. 299, pp. 168-178.View/Download from: Publisher's site
Oxidative stress is intensely involved in enhancing the severity of various chronic respiratory diseases (CRDs) including asthma, chronic obstructive pulmonary disease (COPD), infections and lung cancer. Even though there are various existing anti-inflammatory therapies, which are not enough to control the inflammation caused due to various contributing factors such as anti-inflammatory genes and antioxidant enzymes. This leads to an urgent need of novel drug delivery systems to combat the oxidative stress. This review gives a brief insight into the biological factors involved in causing oxidative stress, one of the emerging hallmark feature in CRDs and particularly, highlighting recent trends in various novel drug delivery carriers including microparticles, microemulsions, microspheres, nanoparticles, liposomes, dendrimers, solid lipid nanocarriers etc which can help in combating the oxidative stress in CRDs and ultimately reducing the disease burden and improving the quality of life with CRDs patients. These carriers improve the pharmacokinetics and bioavailability to the target site. However, there is an urgent need for translational studies to validate the drug delivery carriers for clinical administration in the pulmonary clinic.
Shukla, SD, Shastri, MD, Chong, WC, Dua, K, Budden, KF, Mahmood, MQ, Hansbro, NG, Keely, S, Eri, R, Patel, RP, Peterson, GM & Hansbro, PM 2019, 'Microbiome-focused asthma management strategies.', Current opinion in pharmacology, vol. 46, pp. 143-149.View/Download from: Publisher's site
Asthma is a common, heterogeneous and serious disease with high prevalence globally. Poorly controlled, steroid-resistant asthma is particularly important as there are no effective therapies and it exerts substantial healthcare and societal burden. The role of microbiomes, particularly in chronic diseases has generated considerable interest in recent times. Existing evidence clearly demonstrates an association between asthma initiation and the microbiome, both respiratory and gastro-intestinal, although its' roles are poorly understood when assessing the asthma progression or heterogeneity (i.e. phenotypes/endotypes) across different geographical locations. Moreover, modulating microbiomes could be preventive and/or therapeutic in patients with asthma warrants urgent attention. Here, we review recent advances in assessing the role of microbiomes in asthma and present the challenges associated with the potential therapeutic utility of modifying microbiomes in management.
Soon, L, Ng, PQ, Chellian, J, Madheswaran, T, Panneerselvam, J, Gupta, G, Nammi, S, Hansbro, NG, Hsu, A, Dureja, H, Mehta, M, Satija, S, Hansbro, PM, Dua, K, Collet, T & Chellappan, DK 2019, 'Therapeutic potential of Artemisia vulgaris: An insight into underlying immunological mechanisms.', Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer, vol. 38, no. 3, pp. 205-216.View/Download from: Publisher's site
Artemisia vulgaris is a traditional Chinese herb believed to have a wide range of healing properties; it is traditionally used to treat numerous health ailments. The plant is commonly called mugwort or riverside wormwood. The plant is edible, and in addition to its medicinal properties, it is also used as a culinary herb in Asian cooking in the form of a vegetable or in soup. The plant has garnered the attention of researchers in the past few decades, and several research studies have investigated its biological effects, including antioxidant, anti-inflammatory, anticancer, hypolipidemic, and antimicrobial properties. In this review, various studies on these biological effects are discussed along with the tests conducted, compounds involved, and proposed mechanisms of action. This review will be of interest to the researchers working in the field of herbal medicine, pharmacology, medical sciences, and immunology.
Chellappan, DK, Ng, ZY, Wong, J-Y, Hsu, A, Wark, P, Hansbro, N, Taylor, J, Panneerselvam, J, Madheswaran, T, Gupta, G, Bebawy, M, Hansbro, PM & Dua, K 2018, 'Immunological axis of curcumin-loaded vesicular drug delivery systems.', Future medicinal chemistry, vol. 10, no. 8, pp. 839-844.View/Download from: Publisher's site
Several vesicular systems loaded with curcumin have found their way in the therapeutic applications of several diseases, primarily acting through their immunological pathways. Such systems use particles at a nanoscale range, bringing about their intended use through a range of complex mechanisms. Apart from delivering drug substances into target tissues, these vesicular systems also effectively overcome problems like insolubility and unequal drug distribution. Several mechanisms are explored lately by different workers, and interest over vesicular curcumin has been renewed in the past decade. This commentary discusses several immunological targets in which curcumin is employed in a vesicular form.
Dua, K, Hansbro, NG, Foster, PS & Hansbro, PM 2018, 'Targeting MicroRNAs: Promising Future Therapeutics in the Treatment of Allergic Airway Disease', CRITICAL REVIEWS IN EUKARYOTIC GENE EXPRESSION, vol. 28, no. 2, pp. 125-127.View/Download from: Publisher's site
Ng, ZY, Wong, J-Y, Panneerselvam, J, Madheswaran, T, Kumar, P, Pillay, V, Hsu, A, Hansbro, N, Bebawy, M, Wark, P, Hansbro, P, Dua, K & Chellappan, DK 2018, 'Assessing the potential of liposomes loaded with curcumin as a therapeutic intervention in asthma', COLLOIDS AND SURFACES B-BIOINTERFACES, vol. 172, pp. 51-59.View/Download from: Publisher's site
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: 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: 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...
Dua, K, Hansbro, NG & Hansbro, PM 2017, 'Steroid resistance and concomitant respiratory infections: A challenging battle in pulmonary clinic.', EXCLI journal, vol. 16, pp. 981-985.View/Download from: Publisher's site
Dua, K, Hansbro, NG, Foster, PS & Hansbro, PM 2017, 'MicroRNAs as therapeutics for future drug delivery systems in treatment of lung diseases', DRUG DELIVERY AND TRANSLATIONAL RESEARCH, vol. 7, no. 1, pp. 168-178.View/Download from: Publisher's site
Kim, RY, Horvat, JC, Pinkerton, JW, Starkey, MR, Essilfie, AT, Mayall, JR, Nair, PM, Hansbro, NG, Jones, B, Haw, TJ, Sunkara, KP, Nguyen, TH, Jarnicki, AG, Keely, S, Mattes, J, Adcock, IM, Foster, PS & Hansbro, PM 2017, 'MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase-mediated suppression of histone deacetylase 2.', Journal of Allergy and Clinical Immunology, vol. 139, no. 2, pp. 519-532.View/Download from: Publisher's site
Severe steroid-insensitive asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is hampered by a lack of understanding of the mechanisms of disease pathogenesis. Steroid-insensitive asthma is associated with respiratory tract infections and noneosinophilic endotypes, including neutrophilic forms of disease. However, steroid-insensitive patients with eosinophil-enriched inflammation have also been described. The mechanisms that underpin infection-induced, severe steroid-insensitive asthma can be elucidated by using mouse models of disease.We sought to develop representative mouse models of severe, steroid-insensitive asthma and to use them to identify pathogenic mechanisms and investigate new treatment approaches.Novel mouse models of Chlamydia, Haemophilus influenzae, influenza, and respiratory syncytial virus respiratory tract infections and ovalbumin-induced, severe, steroid-insensitive allergic airway disease (SSIAAD) in BALB/c mice were developed and interrogated.Infection induced increases in the levels of microRNA (miRNA)-21 (miR-21) expression in the lung during SSIAAD, whereas expression of the miR-21 target phosphatase and tensin homolog was reduced. This was associated with an increase in levels of phosphorylated Akt, an indicator of phosphoinositide 3-kinase (PI3K) activity, and decreased nuclear histone deacetylase (HDAC)2 levels. Treatment with an miR-21-specific antagomir (Ant-21) increased phosphatase and tensin homolog levels. Treatment with Ant-21, or the pan-PI3K inhibitor LY294002, reduced PI3K activity and restored HDAC2 levels. This led to suppression of airway hyperresponsiveness and restored steroid sensitivity to allergic airway disease. These observations were replicated with SSIAAD associated with 4 different pathogens.We identify a previously unrecognized role for an miR-21/PI3K/HDAC2 axis in SSIAAD. Our data highlight miR-21 as a novel therapeutic target for the treatment of t...
Kim, RY, Pinkerton, JW, Essilfie, AT, Robertson, AAB, Baines, KJ, Brown, AC, Mayall, JR, Ali, MK, Starkey, MR, Hansbro, NG, Hirota, JA, Wood, LG, Simpson, JL, Knight, DA, Wark, PA, Gibson, PG, O'Neill, LAJ, Cooper, MA, Horvat, JC & Hansbro, PM 2017, 'Role for NLRP3 Inflammasome-mediated, IL-1β-Dependent Responses in Severe, Steroid-Resistant Asthma.', American Journal of Respiratory and Critical Care Medicine, vol. 196, no. 3, pp. 283-297.View/Download from: Publisher's site
Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and concomitant IL-1β responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma.To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1β in severe, steroid-resistant asthma.We developed mouse models of Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1β responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1β responses in experimental severe, steroid-resistant asthma were examined using a highly selective NLRP3 inhibitor, MCC950; the specific caspase-1 inhibitor Ac-YVAD-cho; and neutralizing anti-IL-1β antibody. Roles for IL-1β-induced neutrophilic inflammation were examined using IL-1β and anti-Ly6G.Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1β responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1β expression. Treatment with anti-IL-1β, Ac-YVAD-cho, and MCC950 suppressed IL-1β responses and the important steroid-resistant features of disease in mice, whereas IL-1β administration recapitulated these features. Neutrophil depletion suppressed IL-1β-induced steroid-res...
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: Publisher's site
Grafton, K, Moir, L, Black, J, Hansbro, N, Hansbro, P, Burgess, J & Oliver, BG 2014, 'LF-15 & T7, Synthetic Peptides Derived from Tumstatin, Attenuate Aspects of Airway Remodelling in a Murine Model of Chronic OVA-Induced Allergic Airway Disease', PLoS ONE, vol. 9, no. 1, pp. 1-6.View/Download from: Publisher's site
Background: Tumstatin is a segment of the collagen-IV protein that is markedly reduced in the airways of asthmatics. Tumstatin can play an important role in the development of airway remodelling associated with asthma due to its anti-angiogenic propertie
Maltby, S, Hansbro, NG, Tay, HL, Stewart, J, Plank, M, Donges, B, Rosenberg, HF & Foster, PS 2014, 'Production and Differentiation of Myeloid Cells Driven by Proinflammatory Cytokines in Response to Acute Pneumovirus Infection in Mice', JOURNAL OF IMMUNOLOGY, vol. 193, no. 8, pp. 4072-4082.View/Download from: Publisher's site
Beckett, EL, Stevens, RL, Jarnicki, AG, Kim, RY, Hanish, I, Hansbro, NG, Deane, A, Keely, S, Horvat, JC, Yang, M, Oliver, BG, van Rooijen, N, Inman, MD, Adachi, R, Soberman, RJ, Hamadi, S, Wark, PA, Foster, PS & Hansbro, PM 2013, 'A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 131, no. 3, pp. 752-+.View/Download from: Publisher's site
Collison, A, Siegle, JS, Hansbro, NG, Kwok, C-T, Herbert, C, Mattes, J, Hitchins, M, Foster, PS & Kumar, RK 2013, 'Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma', DISEASE MODELS & MECHANISMS, vol. 6, no. 4, pp. 993-1000.View/Download from: Publisher's site
Eftekhari, P, Hajizadeh, S, Reza Raoufy, M, Reza Masjedi, M, Yang, M, Hansbro, N, Li, JJ & Foster, PS 2013, 'Preventive effect of N-acetylcysteine in a mouse model of steroid resistant acute exacerbation of asthma', EXCLI Journal, vol. 12, pp. 184-192.
Oxidative stress appears to have an important role in glucocorticoid insensitivity, as a crucial problem in asthma therapy. We studied the preventive effect of antioxidant N-acetylcysteine (NAC) on the airway hyper-responsiveness (AHR) and the accumulation of inflammatory cells in the airways in an animal model of steroid resistant acute exacerbation of asthma. Systemically sensitized Balb/C mice were exposed to Ovalbumin aerosol on days 13, 14, 15 and 16, followed by intratracheal lipopolysaccharide (LPS) to induce acute exacerbation. NAC (intraperitoneal, 320 mg/kg 30 min before and 12 hours after each challenge) reduced hyperresponsiveness with/out dexamethasone. LPS application caused neutrophilia in bronchoalveolar lavage fluid (BALF) and eosinophil count was higher than respective control in BALF as well as neutrophils after dexamethasone treatment. NAC significantly decreased neutrophil and eosinophil count in BALF as well as inflammatory cytokines (IL-13 and IL-5).We concluded that addition of NAC to asthma therapy has beneficial preventive effects in an animal model of steroid resistant acute exacerbation of asthma.
Herbert, C, Siegle, JS, Shadie, AM, Nikolaysen, S, Garthwaite, L, Hansbro, NG, Foster, PS & Kumar, RK 2013, 'Development of asthmatic inflammation in mice following early-life exposure to ambient environmental particulates and chronic allergen challenge', DISEASE MODELS & MECHANISMS, vol. 6, no. 2, pp. 479-488.View/Download from: Publisher's site
Davidson, S, Kaiko, G, Loh, Z, Lalwani, A, Zhang, V, Spann, K, Foo, SY, Hansbro, N, Uematsu, S, Akira, S, Matthaei, KI, Rosenberg, HF, Foster, PS & Phipps, S 2011, 'Plasmacytoid dendritic cells promote host defense against acute pneumovirus infection via the TLR7-MyD88-dependent signaling pathway', Journal of Immunology, vol. 186, no. 10, pp. 5938-5948.View/Download from: Publisher's site
Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants. In human infants, plasmacytoid dendritic cells (pDC) are recruited to the nasal compartment during infection and initiate host defense through the secretion of type I IFN, IL-12, and IL-6. However, RSV-infected pDC are refractory to TLR7-mediated activation. In this study, we used the rodent-specific pathogen, pneumonia virus of mice (PVM), to determine the contribution of pDC and TLR7 signaling to the development of the innate inflammatory and early adaptive immune response. In wild-type, but not TLR7- or MyD88-deficient mice, PVM inoculation led to a marked infiltration of pDC and increased expression of type I, II, and III IFNs. The delayed induction of IFNs in the absence of TLR7 or MyD88 was associated with a diminished innate inflammatory response and augmented virus recovery from lung tissue. In the absence of TLR7, PVM-specific CD8+ T cell cytokine production was abrogated. The adoptive transfer of TLR7-sufficient, but not TLR7-deficient pDC to TLR7 gene-deleted mice recapitulated the antiviral responses observed in wild-type mice and promoted virus clearance. In summary, TLR7-mediated signaling by pDC is required for appropriate innate responses to acute pneumovirus infection. It is conceivable that as-yet-unidentified defects in the TLR7 signaling pathway may be associated with elevated levels of RSV-associated morbidity and mortality among otherwise healthy human infants. Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved.
Siegle, JS, Hansbro, N, Dong, C, Angkasekwinai, P, Foster, PS & Kumar, RK 2011, 'Blocking induction of T helper type 2 responses prevents development of disease in a model of childhood asthma', Clinical and Experimental Immunology, vol. 165, no. 1, pp. 19-28.View/Download from: Publisher's site
Early-life respiratory viral infections are linked to subsequent development of allergic asthma in children. We assessed the underlying immunological mechanisms in a novel model of the induction phase of childhood asthma. BALB/c mice were infected neonatally with pneumonia virus of mice, then sensitized intranasally with ovalbumin following recovery. Animals were challenged with low levels of aerosolized ovalbumin for 4 weeks to induce changes of chronic asthma, then received a single moderate-level challenge to elicit mild acute allergic inflammation. To inhibit the initial induction of a T helper type 2 (Th2) response, we administered neutralizing antibodies against interleukin (IL)-4 or IL-25, then assessed development of airway inflammation and remodelling. Anti-IL-4 administered during chronic challenge prevented development of chronic and acute allergic inflammation, as well as goblet cell hyperplasia/metaplasia, but features of remodelling such as subepithelial fibrosis and epithelial hypertrophy were unaffected. In contrast, anti-IL-25 had limited effects on the airway inflammatory response but prevented key changes of remodelling, although it had no effect on goblet cells. Both antibodies suppressed development of a Th2 response, while anti-IL-25 also promoted a Th17 response. In further experiments, anti-IL-25 was administered in early life alone, and again had limited effects on airway inflammation, but prevented development of airway wall remodelling. We conclude that in this murine model of childhood asthma, administration of anti-IL-4 or anti-IL-25 prevents development of some key features of asthma, suggesting that suppression of development of a Th2 response during the neonatal period or later in childhood could be effective for primary prevention. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.
Burgess, J, Boustany, S, Moir, L, Weckmann, M, Lau, J, Grafton, K, Baraket, M, Hansbro, P, Hansbro, N, Foster, P, Black, J & Oliver, BG 2010, 'Reduction of Tumstatin in Asthmatic Airways Contributes to Angiogenesis, Inflammation, and Hyperresponsiveness', American Journal Of Respiratory And Critical Care Medicine, vol. 181, no. 2, pp. 106-115.View/Download from: Publisher's site
Rationale Angiogenesis is a prominent feature of remodeling in asthma. Many proangiogenic factors are up-regulated in asthma, but little is known about levels of endogenous antiangiogenic agents. Collagen IV is decreased in the airway basement membrane i
Lau, J, Oliver, BG, Baraket, M, Beckett, E, Hansbro, N, Moir, L, Wilton, S, Williams, C, Foster, P, Hansbro, P, Black, J & Burgess, J 2010, 'Fibulin-1 Is Increased in Asthma - A Novel Mediator of Airway Remodeling?', Plos One, vol. 5, no. 10.View/Download from: Publisher's site
Background: The extracellular matrix is a dynamic and complex network of macromolecules responsible for maintaining and influencing cellular functions of the airway. The role of fibronectin, an extracellular matrix protein, is well documented in asthma.
Siegle, JS, Hansbro, N, Herbert, C, Rosenberg, HF, Domachowske, JB, Asquith, KL, Foster, PS & Kumar, RK 2010, 'Early-life viral infection and allergen exposure interact to induce an asthmatic phenotype in mice', Respiratory Research, vol. 11.View/Download from: Publisher's site
Background: Early-life respiratory viral infections, notably with respiratory syncytial virus (RSV), increase the risk of subsequent development of childhood asthma. The purpose of this study was to assess whether early-life infection with a species-specific model of RSV and subsequent allergen exposure predisposed to the development of features of asthma.Methods: We employed a unique combination of animal models in which BALB/c mice were neonatally infected with pneumonia virus of mice (PVM, which replicates severe RSV disease in human infants) and following recovery, were intranasally sensitised with ovalbumin. Animals received low-level challenge with aerosolised antigen for 4 weeks to elicit changes of chronic asthma, followed by a single moderate-level challenge to induce an exacerbation of inflammation. We then assessed airway inflammation, epithelial changes characteristic of remodelling, airway hyperresponsiveness (AHR) and host immunological responses.Results: Allergic airway inflammation, including recruitment of eosinophils, was prominent only in animals that had recovered from neonatal infection with PVM and then been sensitised and chronically challenged with antigen. Furthermore, only these mice exhibited an augmented Th2-biased immune response, including elevated serum levels of anti-ovalbumin IgE and IgG1 as well as increased relative expression of Th2-associated cytokines IL-4, IL-5 and IL-13. By comparison, development of AHR and mucous cell change were associated with recovery from PVM infection, regardless of subsequent allergen challenge. Increased expression of IL-25, which could contribute to induction of a Th2 response, was demonstrable in the lung following PVM infection. Signalling via the IL-4 receptor α chain was crucial to the development of allergic inflammation, mucous cell change and AHR, because all of these were absent in receptor-deficient mice. In contrast, changes of remodelling were evident in mice that received chronic aller...
Phipps, S, Hansbro, N, Lam, CE, Foo, SY, Matthaei, KI & Foster, PS 2009, 'Allergic sensitization is enhanced in early life through toll-like receptor 7 activation', Clinical and Experimental Allergy, vol. 39, no. 12, pp. 1920-1928.View/Download from: Publisher's site
Background Prospective cohort studies suggest that children hospitalized in early life with severe infections are significantly more likely to develop recurrent wheezing and asthma. Objective Using an inhalational mouse model of allergic airways inflammation, we sought to determine the effect of viral and bacterial-associated molecular patterns on the magnitude of the allergic inflammatory response and whether this effect was age dependent. Methods BALB/c mice were sensitized by intranasal administration of endotoxinlow ovalbumin (OVA) in the absence or presence of viral single-stranded (ss)RNA, lipoteichoic acid or flagellin as neonates (within the first 24 h of life) or as weanlings (4 weeks of age). Mice were challenged four times with OVA at 6 weeks of age and end-points (bronchoalveolar lavage cytology, histology, antigen-specific T and B cell responses) determined at 7 weeks of age. Results Inhalational sensitization (<24 h or 4 weeks of age) and challenge with OVA induced a mild allergic inflammatory response in the airways as indicated by increased numbers of eosinophils and mucus cells, elevated serum OVA-specific IgG1, and production of T helper 2 (Th2) cytokines. Mice sensitized to endotoxinlow OVA at birth in the presence of ssRNA or lipoteichoic acid, but not flagellin, showed an increase in the numbers of airway and tissue eosinophils, mucus producing cells and antigen-specific production of IL-13 as compared with mice exposed only to endotoxinlow OVA. By contrast, all three TLR ligands failed to increase the magnitude of OVA-induced allergic inflammation in mice sensitized as weanlings. Conclusions Recognition of distinct microbial-associated patterns in early life may preferentially promote the de novo differentiation of bystander, antigen-specific CD4+ T cells toward a Th2 phenotype, and promote an asthma-like phenotype upon cognate antigen exposure in later life. © 2009 Blackwell Publishing Ltd.
Hansbro, NG, Horvat, JC, Wark, PA & Hansbro, PM 2008, 'Understanding the mechanisms of viral induced asthma: New therapeutic directions', PHARMACOLOGY & THERAPEUTICS, vol. 117, no. 3, pp. 313-353.View/Download from: Publisher's site
Ito, K, Herbert, C, Siegle, JS, Vuppusetty, C, Hansbro, N, Thomas, PS, Foster, PS, Barnes, PJ & Kumar, RK 2008, 'Steroid-resistant neutrophilic inflammation in a mouse model of an acute exacerbation of asthma', American Journal of Respiratory Cell and Molecular Biology, vol. 39, no. 5, pp. 543-550.View/Download from: Publisher's site
Neutrophilic inflammation in acute exacerbations of asthma tends to be resistant to treatment with glucocorticoids. This may be related to decreased activity and expression of histone deacetylase-2 (HDAC2), which down-regulates expression of proinflammatory genes via recruitment to the glucocorticoid receptor complex. We assessed airway inflammation and response to steroid treatment in a novel mouse model of an acute exacerbation of chronic asthma. Systemically sensitized mice received low-level challenge with aerosolized ovalbumin for 4 weeks, followed by a single moderate-level challenge to induce enhanced inflammation in distal airways. We assessed the effects of pre-treatment with dexamethasone on the accumulation of inflammatory cells in the airways, airway responsiveness to methacholine, expression and enzymatic activity of nuclear proteins including histone acetyl transferase (HAT) and HDAC2, and levels of transcripts for neutrophil chemoattractant and survival cytokines. Dexamethasone suppressed inflammation associated with eosinophil and T-lymphocyte recruitment, but did not prevent neutrophil accumulation or development of airway hyperresponsiveness. Increased activity of HAT was suppressed by steroid treatment, but the marked diminution of HDAC2 activity and increased activity of nuclear factor-κB were not reversed. Correspondingly, elevated expression of mRNA for TNF-α, granulocyte macrophage colony-stimulating factor, IL-8, and p21waf were also not suppressed by dexamethasone. Levels of lipid peroxidation and protein nitration products were elevated in the acute exacerbation model. We conclude that impaired nuclear recruitment of HDAC2 could be an important mechanism of steroid resistance of the neutrophilic inflammation in exacerbations of asthma. Oxidative stress may contribute to decreased HDAC2 activity.
Su, Y-C, Rolph, MS, Hansbro, NG, Mackay, CR & Sewell, WA 2008, 'Granulocyte-macrophage colony-stimulating factor is required for bronchial eosinophilia in a murine model of allergic airway inflammation', JOURNAL OF IMMUNOLOGY, vol. 180, no. 4, pp. 2600-2607.View/Download from: Publisher's site
Horvat, JC, Beagley, KW, Wade, MA, Preston, JA, Hansbro, NG, Hickey, DK, Kaiko, GE, Gibson, PG, Foster, PS & Hansbro, PM 2007, 'Neonatal chlamydial infection induces mixed T-Cell responses that drive allergic airway disease', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 176, no. 6, pp. 556-564.View/Download from: Publisher's site
Weckmann, M, Collison, A, Simpson, JL, Kopp, MV, Wark, PAB, Smyth, MJ, Yagita, H, Matthaei, KI, Hansbro, N, Whitehead, B, Gibson, PG, Foster, PS & Mattes, J 2007, 'Critical link between TRAIL and CCL20 for the activation of TH2 cells and the expression of allergic airway disease', Nature Medicine, vol. 13, no. 11, pp. 1308-1315.View/Download from: Publisher's site
The role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in immune responses mediated by T-helper 2 (TH2) lymphocytes is unknown. Here we characterize the development of allergic airway disease in TRAIL-deficient (Tnfsf10-/-) mice and in mice exposed to short interfering RNA targeting TRAIL. We show that TRAIL is abundantly expressed in the airway epithelium of allergic mice and that inhibition of signaling impairs production of the chemokine CCL20 and homing of myeloid dendritic cells and T cells expressing CCR6 and CD4 to the airways. Attenuated homing limits T H2 cytokine release, inflammation, airway hyperreactivity and expression of the transcriptional activator STAT6. Activation of STAT6 by interleukin-13 restores airway hyperreactivity in Tnfsf10-/- mice. Recombinant TRAIL induces pathognomic features of asthma and stimulates the production of CCL20 in primary human bronchial epithelium cells. TRAIL is also increased in sputum of asthmatics. The function of TRAIL in the airway epithelium identifies this molecule as a target for the treatment of asthma. © 2007 Nature Publishing Group.
Siegle, JS, Hansbro, N, Herbert, C, Yang, M, Foster, PS & Kumar, RK 2006, 'Airway hyperreactivity in exacerbation of chronic asthma is independent of eosinophilic inflammation', American Journal of Respiratory Cell and Molecular Biology, vol. 35, no. 5, pp. 565-570.View/Download from: Publisher's site
We have developed an animal model to investigate the mechanisms underlying an acute exacerbation of chronic asthma. Sensitized BALB/c mice were exposed to aerosolized ovalbumin, either as chronic low-level challenge (mass concentration ≈ 3 mg/m3) for 4 wk, a single moderate-level challenge (≈ 30 mg/m3), or chronic low-level followed by single moderate-level challenge (the acute exacerbation group). Compared with animals receiving chronic challenge alone, mice in the acute exacerbation group exhibited a more marked inflammatory response, with involvement of intrapulmonary airways and lung parenchyma, and increased numbers of lymphocytes and eosinophils in bronchoalveolar lavage fluid. They also developed airway hyperreactivity (AHR) to methacholine, demonstrable as increased transpulmonary resistance and decreased compliance. This pattern of AHR was absent in chronically challenged animals, but was also present in animals given single moderate-level challenge. However, compared with animals receiving a single moderate-level challenge, inflammation and AHR were induced more rapidly in the acute exacerbation group. Eosinophil-deficient GATA1 Δdbl mice exhibited undiminished AHR in the acute exacerbation model. We conclude that in mice with pre-existing airway lesions resembling mild chronic asthma, exposure to a moderately high concentration of inhaled antigen induces features of an acute exacerbation. The inflammatory response involves distal airways and is associated with a distinct pattern of AHR, which develops independent of the enhanced eosinophilic inflammation.
Wadhwa, R, Shukla, SD, Chellappan, DK, Gupta, G, Collet, T, Hansbro, N, Oliver, B, Williams, K, Hansbro, PM, Dua, K & Maurya, PK 2019, 'Phytotherapy in Inflammatory Lung Diseases: An Emerging Therapeutic Interventional Approach' in Phytochemistry: An in-silico and in-vitro Update, Springer, Singapore, pp. 331-347.View/Download from: Publisher's site
Chronic obstructive pulmonary disease (COPD) and asthma are the most common inflammatory respiratory diseases related to an increase in mortality and morbidity. Generally, bronchodilators, ß- agonists, anticholinergics and theophylline used for treatment in these conditions and administered by inhalation for delivery, have localized and systematic effects. The adverse effects are due to pharmacodynamic and pharmacokinetic changes and especially drug-drug and drug-disease interactions. However, phytotherapy is classical and widespread throughout the world for the treatment of ailments. This chapter highlights cellular and molecular mediators involved in COPD and asthma, the shortcomings of current therapies and the emerging need of phytomedicines. Phytomedicine supports respiratory physiology, bronchial action and possesses antioxidants to maintain homeostasis.
Pacitti, D, Brown, A, Torregrossa, R, Kumar, V, Balachandran, L, Wood, M, Jong Haw, T, Hansbro, N, Scotton, CJ, Hansbro, P & Whiteman, M 2020, 'Mitochondria-targeted H2S suppresses and reverses cigarette smoke-induced inflammasome activity and lung injury in experimental COPD', 05.01 - Airway pharmacology and treatment, ERS Lung Science Conference 2020 abstracts, European Respiratory Society.View/Download from: Publisher's site
Brown, AC, Essilfie, AT, Beckett, EL, Thorburn, AN, Hansbro, NG, Jarnicki, AG, Yagita, H, Foster, PS, Horvat, JC, Wark, PAB & Hansbro, PM 2016, 'The role of CD8 T-cells during anti-PD1 treatment of viral infection-induced secondary bacterial pneumonia', EUROPEAN JOURNAL OF IMMUNOLOGY, International Congress of Immunology (ICI), WILEY-BLACKWELL, Melbourne, AUSTRALIA, pp. 511-512.
Herbert, C, Siegle, JS, Shadie, AM, Nikolaysen, S, Garthwaite, L, Hansbro, NG, Foster, PS & Kumar, RK 2013, 'EARLY LIFE EXPOSURE TO ENVIRONMENTAL PARTICULATES PREDISPOSES TO DEVELOPMENT OF ASTHMATIC INFLAMMATION', RESPIROLOGY, WILEY-BLACKWELL, pp. 39-39.