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Pawan Sharma


I am a Chancellors Fellow at SoLS in the Molecular Biosciences Team and a Research Leader at the Woolcock Institute. I bring both industry (Pharma) and academic research experience from India and North America. My laboratory (Chronic Airways Disease Lab) focuses on discovering and identifying novel mechanisms that may act as first in class targets for treating chronic lung diseases such as asthma and COPD. We utilizes variety of translational model systems involving human airway cells from healthy and patient donors in conjunction with mouse models to test new therapies. One such process is autophagy; a highly conserved protective mechanism within the cell, which we have found to be dysregulated or impaired in asthma. We are trying to understand how this fundamental protective mechanism can be exploited to achieve clinical benefit in patients who do not respond to standard therapy while their lungs are constantly remodeled with chronic inflammation.

We are also interested in identifying novel and improving existing bronchodilators that target GPCRs to relax the airways. I have one PhD student and two will start later this month. I actively collaborate locally at UTS (SoLS, GSH, CHT), within Australia (Woolcock and Sydney Hospitals) and also with some of the leading researchers in North America.

Image of Pawan Sharma
Chancellor's Post Doctoral Research Fellow, School of Life Sciences
Core Member, CHT - Centre for Health Technologies
GMP, Pharmacy, Pharmacy:Pharmacology, PhD
Member, The Thoracic Society of Australia and New Zealand
Member, European Respiratory Society
Member, American Thoracic Society
+61 2 9514 3815

Research Interests

  • Chronic Lung Diseases (Asthma, COPD, IPF)
  • New Targets and Disease Mechanisms
  • Animal models of disease
  • Airway Remodeling, Airway Hyperresponsiveness, Inflammation
  • Autophagy, ER Stress, Mitochondrial Dysfunction
  • GPCRs (bronchodilators), calcium homeostatis
Can supervise: Yes

  • Pharmacology of Airways Disease
  • Respiratory Pathophysiology
  • Human Physiology


Halayko, A.J. & Sharma, P. 2011, 'Airway Smooth Muscle Cells' in Inflammation and Allergy Drug Design, pp. 163-171.
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McAlinden, K., Chan, Y., Kota, A., Chen, H., Oliver, B. & Sharma, P. 2017, 'Maternal E-cigarette Vaping Enhances Development of Allergic Asthma In the Offspring', American Journal of Respiratory and Critical Care Medicine, American Thoracic Society.
Rationale: E-cigarettes (eCig) are being considered as an alternative to quit cigarette smoking (CS) while their long-term safety and effect on lung patho-physiology are not known. Maternal eCig-vaping may be considered as a safer CS-replacement during pregnancy. Thus the effect of maternal eCig vaping needs further assessment, particularly the effect this has on offspring and development of allergic asthma later in life. Combining mouse models of maternal vaping and allergic asthma and human airway smooth muscle cells (ASM) in vitro we tested whether maternal eCig vaping enhances features of allergic asthma in the offspring. Methods: Female BALB/c mice were vaped with either eCig vapour (± nicotine) or CS+eCig (+nicotine) or room air (control group). The eCig vaping was started prior to mating and continued during gestation and lactation while CS-exposure was used prior to mating and replaced with eCig during gestation and mating. The female offspring from these mothers were subjected to an ovalbumin (OVA)-induced allergic asthma model. 24 hours after the last aerosolized OVA or saline challenge, lung function measurements were performed using flexiVent (Scireq, Canada) to increasing concentration of methacholine (MCh). Airway inflammation was assessed by counting total immune cell influx in BAL fluid. Human ASM cells were treated with varying concentrations of eCig liquid condensate and key parameters of mitochondrial function were measured with a Seahorse XF analyzer. Results: Repeated allergen-exposure induced Th2-driven inflammation in OVA-exposed mice, characterized by massive influx of leukocytes predominantly eosinophils (OVA: 3x105±8.3x104 vs Saline: 1.1x102±1x102) and to some extent neutrophils (OVA: 1.3x104±4.4x103 vs Saline: 1.3x102±1.1x102) into the airways. The effect of allergen on airway eosinophilia was significantly enhanced in the offsprings from eCig OVA (+Nic)-exposed mothers when compared with eCig OVA (-Nic) or CS+eCig animals. OVA-exposed ...
Kota, A., Xenaki, D., Deshpande, D., Oliver, B. & Sharma, P. 2017, 'ASK1 Inhibition Prevented Mitogen-Induced Human Airway Smooth Muscle Growth in Chronic Obstructive Pulmonary Disease', American Journal of Respiratory and Critical Care Medicine, American Thoracic Society.

Journal articles

Sharma, P., Yi, R., Nayak, A., Wang, N., Knight, M.J., Pan, S., Oliver, B. & Deshpande, D.A. 2017, 'Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice.', Scientific Reports, vol. 7, pp. 1-14.
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Kota, A., Deshpande, D., Haghi, M., Oliver, B. & Sharma, P. 2017, 'Autophagy and airway fibrosis: Is there a link?', F1000 Research, vol. 6, no. 409, pp. 1-10.
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In the past decade, an emerging process named 'autophagy has generated intense interest in many chronic lung diseases. Tissue remodeling and fibrosis is a common feature of many airway diseases, and current therapies do not prevent or reverse these structural changes. Autophagy has evolved as a conserved process for bulk degradation and recycling of cytoplasmic components to maintain basal cellular homeostasis and healthy organelle populations in the cell. Furthermore, autophagy serves as a cell survival mechanism and can also be induced by chemical and physical stress to the cell. Accumulating evidence demonstrates that autophagy plays an essential role in vital cellular processes, including tissue remodeling. This review will discuss some of the recent advancements made in understanding the role of this fundamental process in airway fibrosis with emphasis on airway remodeling, and how autophagy can be exploited as a target for airway remodeling in asthma and chronic obstructive pulmonary disease.
Pan, S., Sharma, P., Shah, S. & Deshpande, D. 2017, 'Bitter Taste Receptor Agonists Alter Mitochondrial Function and Induce Autophagy in Airway Smooth Muscle Cells', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 313, no. 1, pp. L154-L165.
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Sukjamnong, S., Chan, Y.L., Zakarya, R., Saad, S., Sharma, P., Santiyanont, R., Chen, H. & Oliver, B.G. 2017, 'Effect of long-term maternal smoking on the offspring's lung health.', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 313, no. 2, pp. L416-L423.
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Maternal smoking during pregnancy contributes to long-term health problems in offspring, especially respiratory disorders that can manifest in either childhood or adulthood. Receptors for advanced glycation end products (RAGE) are multiligand receptors abundantly localized in the lung, capable of responding to by-products of reactive oxygen species and proinflammatory responses. RAGE signaling is a key regulator of inflammation in cigarette smoking-related pulmonary diseases. However, the impact of maternal cigarette smoke exposure on lung RAGE signaling in the offspring is unclear. This study aims to investigate the effect of maternal cigarette smoke exposure (SE), as well as mitochondria-targeted antioxidant [mitoquinone mesylate (MitoQ)] treatment, during pregnancy on the RAGE-mediated signaling pathway in the lung of male offspring. Female Balb/c mice (8 wk) were divided into a sham group (exposed to air), an SE group (exposed to cigarette smoke), and an SE + MQ group (exposed to cigarette smoke with MitoQ supplement from mating). The lungs from male offspring were collected at 13 wk. RAGE and its downstream signaling, including nuclear factor-B and mitogen-activated protein kinase family consisting of extracellular signal-regulated kinase 1, ERK2, c-JUN NH2-terminal kinase (JNK), and phosphorylated JNK, in the lung were significantly increased in the SE offspring. Mitochondrial antioxidant manganese superoxide dismutase was reduced, whereas IL-1 and oxidative stress response nuclear factor (erythroid-derived 2)-like 2 were significantly increased in the SE offspring. Maternal MitoQ treatment normalized RAGE, IL-1, and Nrf-2 levels in the SE + MQ offspring. Maternal SE increased RAGE and its signaling elements associated with increased oxidative stress and inflammatory cytokines in offspring lungs, whereas maternal MitoQ treatment can partially normalize these changes.
Sharma, P., Panebra, A., Pera, T., Tiegs, B.C., Hershfeld, A., Kenyon, L.C. & Deshpande, D.A. 2016, 'Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells.', American journal of physiology. Lung cellular and molecular physiology, vol. 310, no. 4, pp. L365-L376.
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Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediate-conductance calcium-activated K(+) channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as bronchoc...
Sharma, P., Jha, A., Stelmack, G.L., Detillieux, K., Basu, S., Klonisch, T., Unruh, H. & Halayko, A.J. 2015, 'Characterization of the dystrophin-glycoprotein complex in airway smooth muscle: role of -sarcoglycan in airway responsiveness.', Canadian journal of physiology and pharmacology, vol. 93, no. 3, pp. 195-202.
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The dystrophin-glycoprotein complex (DGC) is an integral part of caveolae microdomains, and its interaction with caveolin-1 is essential for the phenotype and functional properties of airway smooth muscle (ASM). The sarcoglycan complex provides stability to the dystroglycan complex, but its role in ASM contraction and lung physiology in not understood. We tested whether -sarcoglycan (-SG), through its interaction with the DGC, is a determinant of ASM contraction ex vivo and airway mechanics in vivo. We measured methacholine (MCh)-induced isometric contraction and airway mechanics in -SG KO and wild-type mice. Last, we performed immunoblotting and transmission electron microscopy to assess DGC protein expression and the ultrastructural features of tracheal smooth muscle. Our results reveal an age-dependent reduction in the MCh-induced tracheal isometric force and significant reduction in airway resistance at high concentrations of MCh (50.0 mg/mL) in -SG KO mice. The changes in contraction and lung function correlated with decreased caveolin-1 and -dystroglycan abundance, as well as an age-dependent loss of caveolae in the cell membrane of tracheal smooth muscle in -SG KO mice. Collectively, these results confirm and extend understanding of a functional role for the DGC in the contractile properties of ASM and demonstrate that this results in altered lung function in vivo.
Jha, A., Sharma, P., Anaparti, V., Ryu, M.H. & Halayko, A.J. 2015, 'A role for transient receptor potential ankyrin 1 cation channel (TRPA1) in airway hyper-responsiveness?', Canadian journal of physiology and pharmacology, vol. 93, no. 3, pp. 171-176.
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Airway smooth muscle (ASM) contraction controls the airway caliber. Airway narrowing is exaggerated in obstructive lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The mechanism by which ASM tone is dysregulated in disease is not clearly understood. Recent research on ion channels, particularly transient receptor potential cation channel, subfamily A, member 1 (TRPA1), is uncovering new understanding of altered airway function. TRPA1, a member of the TRP channel superfamily, is a chemo-sensitive cation channel that can be activated by a variety of external and internal stimuli, leading to the influx of Ca(2+). Functional TRPA1 channels have been identified in neuronal and non-neuronal tissues of the lung, including ASM. In the airways, these channels can regulate the release of mediators that are markers of airway inflammation in asthma and COPD. For, example, TRPA1 controls cigarette-smoke-induced inflammatory mediator release and Ca(2+) mobilization in vitro and in vivo, a response tied to disease pathology in COPD. Recent work has revealed that pharmacological or genetic inhibition of TRPA1 inhibits the allergen-induced airway inflammation in vitro and airway hyper-responsiveness (AHR) in vivo. Collectively, it appears that TRPA1 channels may be determinants of ASM contractility and local inflammation control, positioning them as part of novel mechanisms that control (patho)physiological function of airways and ASM.
Boardman, C., Chachi, L., Gavrila, A., Keenan, C.R., Perry, M.M., Xia, Y.C., Meurs, H. & Sharma, P. 2014, 'Mechanisms of glucocorticoid action and insensitivity in airways disease.', Pulmonary pharmacology & therapeutics, vol. 29, no. 2, pp. 129-143.
Glucocorticoids are the mainstay for the treatment of chronic inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, it has been recognized that glucocorticoids do not work well in certain patient populations suggesting reduced sensitivity. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors. Studies are emerging to understand these mechanisms in detail, which would help in increasing glucocorticoid sensitivity in patients with chronic airways disease. This review aims to highlight both classical and emerging concepts of the anti-inflammatory mechanisms of glucocorticoids and also review some novel strategies to overcome steroid insensitivity in airways disease.
Sharma, P., Basu, S., Mitchell, R.W., Stelmack, G.L., Anderson, J.E. & Halayko, A.J. 2014, 'Role of dystrophin in airway smooth muscle phenotype, contraction and lung function.', PloS one, vol. 9, no. 7, p. e102737.
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Dystrophin links the transmembrane dystrophin-glycoprotein complex to the actin cytoskeleton. We have shown that dystrophin-glycoprotein complex subunits are markers for airway smooth muscle phenotype maturation and together with caveolin-1, play an important role in calcium homeostasis. We tested if dystrophin affects phenotype maturation, tracheal contraction and lung physiology. We used dystrophin deficient Golden Retriever dogs (GRMD) and mdx mice vs healthy control animals in our approach. We found significant reduction of contractile protein markers: smooth muscle myosin heavy chain (smMHC) and calponin and reduced Ca2+ response to contractile agonist in dystrophin deficient cells. Immunocytochemistry revealed reduced stress fibers and number of smMHC positive cells in dystrophin-deficient cells, when compared to control. Immunoblot analysis of Akt1, GSK3 and mTOR phosphorylation further revealed that downstream PI3K signaling, which is essential for phenotype maturation, was suppressed in dystrophin deficient cell cultures. Tracheal rings from mdx mice showed significant reduction in the isometric contraction to methacholine (MCh) when compared to genetic control BL10ScSnJ mice (wild-type). In vivo lung function studies using a small animal ventilator revealed a significant reduction in peak airway resistance induced by maximum concentrations of inhaled MCh in mdx mice, while there was no change in other lung function parameters. These data show that the lack of dystrophin is associated with a concomitant suppression of ASM cell phenotype maturation in vitro, ASM contraction ex vivo and lung function in vivo, indicating that a linkage between the DGC and the actin cytoskeleton via dystrophin is a determinant of the phenotype and functional properties of ASM.
Ghavami, S., Sharma, P., Yeganeh, B., Ojo, O.O., Jha, A., Mutawe, M.M., Kashani, H.H., Los, M.J., Klonisch, T., Unruh, H. & Halayko, A.J. 2014, 'Airway mesenchymal cell death by mevalonate cascade inhibition: integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins.', Biochimica et biophysica acta, vol. 1843, no. 7, pp. 1259-1271.
HMG-CoA reductase, the proximal rate-limiting enzyme in the mevalonate pathway, is inhibited by statins. Beyond their cholesterol lowering impact, statins have pleiotropic effects and their use is linked to improved lung health. We have shown that mevalonate cascade inhibition induces apoptosis and autophagy in cultured human airway mesenchymal cells. Here, we show that simvastatin also induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in these cells. We tested whether coordination of ER stress, autophagy and apoptosis determines survival or demise of human lung mesenchymal cells exposed to statin. We observed that simvastatin exposure activates UPR (activated transcription factor 4, activated transcription factor 6 and IRE1) and caspase-4 in primary human airway fibroblasts and smooth muscle cells. Exogenous mevalonate inhibited apoptosis, autophagy and UPR, but exogenous cholesterol was without impact, indicating that sterol intermediates are involved with mechanisms mediating statin effects. Caspase-4 inhibition decreased simvastatin-induced apoptosis, whereas inhibition of autophagy by ATG7 or ATG3 knockdown significantly increased cell death. In BAX(-/-)/BAK(-/-) murine embryonic fibroblasts, simvastatin-triggered apoptotic and UPR events were abrogated, but autophagy flux was increased leading to cell death via necrosis. Our data indicate that mevalonate cascade inhibition, likely associated with depletion of sterol intermediates, can lead to cell death via coordinated apoptosis, autophagy, and ER stress. The interplay between these pathways appears to be principally regulated by autophagy and Bcl-2-family pro-apoptotic proteins. These findings uncover multiple mechanisms of action of statins that could contribute to refining the use of such agent in treatment of lung disease.
Yeganeh, B., Wiechec, E., Ande, S.R., Sharma, P., Moghadam, A.R., Post, M., Freed, D.H., Hashemi, M., Shojaei, S., Zeki, A.A. & Ghavami, S. 2014, 'Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease.', Pharmacology & therapeutics, vol. 143, no. 1, pp. 87-110.
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The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs ('statins') directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD)), and cancer.
Moodley, T., Wilson, S.M., Joshi, T., Rider, C.F., Sharma, P., Yan, D., Newton, R. & Giembycz, M.A. 2013, 'Phosphodiesterase 4 inhibitors augment the ability of formoterol to enhance glucocorticoid-dependent gene transcription in human airway epithelial cells: a novel mechanism for the clinical efficacy of roflumilast in severe chronic obstructive pulmonary disease.', Molecular pharmacology, vol. 83, no. 4, pp. 894-906.
Post-hoc analysis of two phase III clinical studies found that the phosphodiesterase 4 (PDE4) inhibitor, roflumilast, reduced exacerbation frequency in patients with severe chronic obstructive pulmonary disease (COPD) who were taking inhaled corticosteroids (ICS) concomitantly, whereas patients not taking ICS derived no such benefit. In contrast, in two different trials also performed in patients with severe COPD, roflumilast reduced exacerbation rates in the absence of ICS, indicating that PDE4 inhibition alone is sufficient for therapeutic activity to be realized. Given that roflumilast is recommended as an "add-on" medication to patients with severe disease who will inevitably be taking a long-acting 2-adrenoceptor agonist (LABA)/ICS combination therapy, we tested the hypothesis that roflumilast augments the ability of glucocorticoids to induce genes with anti-inflammatory activity. Using a glucocorticoid response element (GRE) luciferase reporter transfected into human airway epithelial cells [both bronchial epithelium + adenovirus 12 - SV40 hybrid (BEAS-2B) cells and primary cultures], roflumilast enhanced fluticasone propionate-induced GRE-dependent transcription. Roflumilast also produced a sinistral displacement of the concentration-response curves that described the augmentation of GRE-dependent transcription by the LABA formoterol. In BEAS-2B cells and primary airway epithelia, roflumilast interacted with formoterol in a positive cooperative manner to enhance the expression of several glucocorticoid-inducible genes that have anti-inflammatory potential. We suggest that the ability of roflumilast and formoterol to interact in this way supports the concept that these drugs together may impart clinical benefit beyond that achievable by an ICS alone, a PDE4 inhibitor alone, or an ICS/LABA combination therapy. Roflumilast may, therefore, be especially effective in patients with severe COPD.
Wright, D., Sharma, P., Ryu, M.-.H., Rissé, P.-.A., Ngo, M., Maarsingh, H., Koziol-White, C., Jha, A., Halayko, A.J. & West, A.R. 2013, 'Models to study airway smooth muscle contraction in vivo, ex vivo and in vitro: implications in understanding asthma.', Pulmonary pharmacology & therapeutics, vol. 26, no. 1, pp. 24-36.
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Asthma is a chronic obstructive airway disease characterised by airway hyperresponsiveness (AHR) and airway wall remodelling. The effector of airway narrowing is the contraction of airway smooth muscle (ASM), yet the question of whether an inherent or acquired dysfunction in ASM contractile function plays a significant role in the disease pathophysiology remains contentious. The difficulty in determining the role of ASM lies in limitations with the models used to assess contraction. In vivo models provide a fully integrated physiological response but ASM contraction cannot be directly measured. Ex vivo and in vitro models can provide more direct assessment of ASM contraction but the loss of factors that may modulate ASM responsiveness and AHR, including interaction between multiple cell types and disruption of the mechanical environment, precludes a complete understanding of the disease process. In this review we detail key advantages of common in vivo, ex vivo and in vitro models of ASM contraction, as well as emerging tissue engineered models of ASM and whole airways. We also highlight important findings from each model with respect to the pathophysiology of asthma.
Ghavami, S., Yeganeh, B., Stelmack, G.L., Kashani, H.H., Sharma, P., Cunnington, R., Rattan, S., Bathe, K., Klonisch, T., Dixon, I.M., Freed, D.H. & Halayko, A.J. 2012, 'Apoptosis, autophagy and ER stress in mevalonate cascade inhibition-induced cell death of human atrial fibroblasts.', Cell death & disease, vol. 3, p. e330.
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3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) are cholesterol-lowering drugs that exert other cellular effects and underlie their beneficial health effects, including those associated with myocardial remodeling. We recently demonstrated that statins induces apoptosis and autophagy in human lung mesenchymal cells. Here, we extend our knowledge showing that statins simultaneously induces activation of the apoptosis, autophagy and the unfolded protein response (UPR) in primary human atrial fibroblasts (hATF). Thus we tested the degree to which coordination exists between signaling from mitochondria, endoplasmic reticulum and lysosomes during response to simvastatin exposure. Pharmacologic blockade of the activation of ER-dependent cysteine-dependent aspartate-directed protease (caspase)-4 and lysosomal cathepsin-B and -L significantly decreased simvastatin-induced cell death. Simvastatin altered total abundance and the mitochondrial fraction of proapoptotic and antiapoptotic proteins, while c-Jun N-terminal kinase/stress-activated protein kinase mediated effects on B-cell lymphoma 2 expression. Chemical inhibition of autophagy flux with bafilomycin-A1 augmented simvastatin-induced caspase activation, UPR and cell death. In mouse embryonic fibroblasts that are deficient in autophagy protein 5 and refractory to autophagy induction, caspase-7 and UPR were hyper-induced upon treatment with simvastatin. These data demonstrate that mevalonate cascade inhibition-induced death of hATF manifests from a complex mechanism involving co-regulation of apoptosis, autophagy and UPR. Furthermore, autophagy has a crucial role in determining the extent of ER stress, UPR and permissiveness of hATF to cell death induced by statins.
Sharma, P., Ryu, M.H., Basu, S., Maltby, S.A., Yeganeh, B., Mutawe, M.M., Mitchell, R.W. & Halayko, A.J. 2012, 'Epithelium-dependent modulation of responsiveness of airways from caveolin-1 knockout mice is mediated through cyclooxygenase-2 and 5-lipoxygenase.', British journal of pharmacology, vol. 167, no. 3, pp. 548-560.
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BACKGROUND AND PURPOSE: Acute silencing of caveolin-1 (Cav-1) modulates receptor-mediated contraction of airway smooth muscle. Moreover, COX-2- and 5-lipoxygenase (5-LO)-derived prostaglandin and leukotriene biosynthesis can influence smooth muscle reactivity. COX-2 half-life can be prolonged through association with Cav-1. We suggested that lack of Cav-1 modulated levels of COX-2 which in turn modulated tracheal contraction, when arachidonic acid signalling was disturbed by inhibition of COX-2. EXPERIMENTAL APPROACH: Using tracheal rings from Cav-1 knockout (KO) and wild-type mice (B6129SF2/J), we measured isometric contractions to methacholine and used PCR, immunoblotting and immunohistology to monitor expression of relevant proteins. KEY RESULTS: Tracheal rings from Cav-1 KO and wild-type mice exhibited similar responses, but the COX-2 inhibitor, indomethacin, increased responses of tracheal rings from Cav-1 KO mice to methacholine. The phospholipase A inhibitor, eicosatetraynoic acid, which inhibits formation of both COX-2 and 5-LO metabolites, had no effect on wild-type or Cav-1 KO tissues. Indomethacin-mediated hyperreactivity was ablated by the LTD receptor antagonist (montelukast) and 5-LO inhibitor (zileuton). The potentiating effect of indomethacin on Cav-1 KO responses to methacholine was blocked by epithelial denudation. Immunoprecipitation showed that COX-2 binds Cav-1 in wild-type lungs. Immunoblotting and qPCR revealed elevated levels of COX-2 and 5-LO protein, but not COX-1, in Cav-1 KO tracheas, a feature that was prevented by removal of the epithelium. CONCLUSION AND IMPLICATIONS: The indomethacin-induced hypercontractility observed in Cav-1 KO tracheas was linked to increased expression of COX-2 and 5-LO, which probably enhanced arachidonic acid shunting and generation of pro-contractile leukotrienes when COX-2 was inhibited.
Gerthoffer, W.T., Schaafsma, D., Sharma, P., Ghavami, S. & Halayko, A.J. 2012, 'Motility, survival, and proliferation.', Comprehensive Physiology, vol. 2, no. 1, pp. 255-281.
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Airway smooth muscle has classically been of interest for its contractile response linked to bronchoconstriction. However, terminally differentiated smooth muscle cells are phenotypically plastic and have multifunctional capacity for proliferation, cellular hypertrophy, migration, and the synthesis of extracellular matrix and inflammatory mediators. These latter properties of airway smooth muscle are important in airway remodeling which is a structural alteration that compounds the impact of contractile responses on limiting airway conductance. In this overview, we describe the important signaling components and the functional evidence supporting a view of smooth muscle cells at the core of fibroproliferative remodeling of hollow organs. Signal transduction components and events are summarized that control the basic cellular processes of proliferation, cell survival, apoptosis, and cellular migration. We delineate known intracellular control mechanisms and suggest future areas of interest to pursue to more fully understand factors that regulate normal myocyte function and airway remodeling in obstructive lung diseases.
Gerthoffer, W.T., Schaafsma, D., Sharma, P., Ghavami, S. & Halayko, A.J. 2012, 'Motility, Survival, and Proliferation', COMPREHENSIVE PHYSIOLOGY, vol. 2, no. 1, pp. 255-281.
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Ghavami, S., Mutawe, M.M., Sharma, P., Yeganeh, B., McNeill, K.D., Klonisch, T., Unruh, H., Kashani, H.H., Schaafsma, D., Los, M. & Halayko, A.J. 2011, 'Mevalonate cascade regulation of airway mesenchymal cell autophagy and apoptosis: a dual role for p53.', PloS one, vol. 6, no. 1, p. e16523.
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Statins inhibit the proximal steps of cholesterol biosynthesis, and are linked to health benefits in various conditions, including cancer and lung disease. We have previously investigated apoptotic pathways triggered by statins in airway mesenchymal cells, and identified reduced prenylation of small GTPases as a primary effector mechanism leading to p53-mediated cell death. Here, we extend our studies of statin-induced cell death by assessing endpoints of both apoptosis and autophagy, and investigating their interplay and coincident regulation. Using primary cultured human airway smooth muscle (HASM) and human airway fibroblasts (HAF), autophagy, and autophagosome formation and flux were assessed by transmission electron microscopy, cytochemistry (lysosome number and co-localization with LC3) and immunoblotting (LC3 lipidation and Atg12-5 complex formation). Chemical inhibition of autophagy increased simvastatin-induced caspase activation and cell death. Similarly, Atg5 silencing with shRNA, thus preventing Atg5-12 complex formation, increased pro-apoptotic effects of simvastatin. Simvastatin concomitantly increased p53-dependent expression of p53 up-regulated modulator of apoptosis (PUMA), NOXA, and damage-regulated autophagy modulator (DRAM). Notably both mevalonate cascade inhibition-induced autophagy and apoptosis were p53 dependent: simvastatin increased nuclear p53 accumulation, and both cyclic pifithrin- and p53 shRNAi partially inhibited NOXA, PUMA expression and caspase-3/7 cleavage (apoptosis) and DRAM expression, Atg5-12 complex formation, LC3 lipidation, and autophagosome formation (autophagy). Furthermore, the autophagy response is induced rapidly, significantly delaying apoptosis, suggesting the existence of a temporally coordinated p53 regulation network. These findings are relevant for the development of statin-based therapeutic approaches in obstructive airway disease.
Sharma, P., Ghavami, S., Stelmack, G.L., McNeill, K.D., Mutawe, M.M., Klonisch, T., Unruh, H. & Halayko, A.J. 2010, 'beta-Dystroglycan binds caveolin-1 in smooth muscle: a functional role in caveolae distribution and Ca2+ release.', Journal of cell science, vol. 123, no. Pt 18, pp. 3061-3070.
The dystrophin-glycoprotein complex (DGC) links the extracellular matrix and actin cytoskeleton. Caveolae form membrane arrays on smooth muscle cells; we investigated the mechanism for this organization. Caveolin-1 and beta-dystroglycan, the core transmembrane DGC subunit, colocalize in airway smooth muscle. Immunoprecipitation revealed the association of caveolin-1 with beta-dystroglycan. Disruption of actin filaments disordered caveolae arrays, reduced association of beta-dystroglycan and caveolin-1 to lipid rafts, and suppressed the sensitivity and responsiveness of methacholine-induced intracellular Ca2+ release. We generated novel human airway smooth muscle cell lines expressing shRNA to stably silence beta-dystroglycan expression. In these myocytes, caveolae arrays were disorganized, caveolae structural proteins caveolin-1 and PTRF/cavin were displaced, the signaling proteins PLCbeta1 and G(alphaq), which are required for receptor-mediated Ca2+ release, were absent from caveolae, and the sensitivity and responsiveness of methacholine-induced intracellular Ca2+ release, was diminished. These data reveal an interaction between caveolin-1 and beta-dystroglycan and demonstrate that this association, in concert with anchorage to the actin cytoskeleton, underpins the spatial organization and functional role of caveolae in receptor-mediated Ca2+ release, which is an essential initiator step in smooth muscle contraction.
Ghavami, S., Mutawe, M.M., Hauff, K., Stelmack, G.L., Schaafsma, D., Sharma, P., McNeill, K.D., Hynes, T.S., Kung, S.K., Unruh, H., Klonisch, T., Hatch, G.M., Los, M. & Halayko, A.J. 2010, 'Statin-triggered cell death in primary human lung mesenchymal cells involves p53-PUMA and release of Smac and Omi but not cytochrome c.', Biochimica et biophysica acta, vol. 1803, no. 4, pp. 452-467.
Statins inhibit 3-hydroxy-3-methyl-glutarylcoenzyme CoA (HMG-CoA) reductase, the proximal enzyme for cholesterol biosynthesis. They exhibit pleiotropic effects and are linked to health benefits for diseases including cancer and lung disease. Understanding their mechanism of action could point to new therapies, thus we investigated the response of primary cultured human airway mesenchymal cells, which play an effector role in asthma and chronic obstructive lung disease (COPD), to simvastatin exposure. Simvastatin induced apoptosis involving caspase-9, -3 and -7, but not caspase-8 in airway smooth muscle cells and fibroblasts. HMG-CoA inhibition did not alter cellular cholesterol content but did abrogate de novo cholesterol synthesis. Pro-apoptotic effects were prevented by exogenous mevalonate, geranylgeranyl pyrophosphate and farnesyl pyrophosphate, downstream products of HMG-CoA. Simvastatin increased expression of Bax, oligomerization of Bax and Bak, and expression of BH3-only p53-dependent genes, PUMA and NOXA. Inhibition of p53 and silencing of p53 unregulated modulator of apoptosis (PUMA) expression partly counteracted simvastatin-induced cell death, suggesting a role for p53-independent mechanisms. Simvastatin did not induce mitochondrial release of cytochrome c, but did promote release of inhibitor of apoptosis (IAP) proteins, Smac and Omi. Simvastatin also inhibited mitochondrial fission with the loss of mitochondrial Drp1, an essential component of mitochondrial fission machinery. Thus, simvastatin activates novel apoptosis pathways in lung mesenchymal cells involving p53, IAP inhibitor release, and disruption of mitochondrial fission.
Hashemi, M., Sharma, P., Eshraghi, M., Naderi, M., Moazeni-Roodi, A., Mehrabifar, H. & Taheri, M. 2010, 'Alpha-1 Antitrypsin: It's Role in Health and Disease.', Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry., vol. 9, no. 4, pp. 279-288.
Sharma, P. & Halayko, A.J. 2009, 'Emerging molecular targets for the treatment of asthma.', Indian journal of biochemistry & biophysics, vol. 46, no. 6, pp. 447-460.
Current therapeutic approaches for the treatment of asthma have limitations in their ability to target all the features of the disease. Indeed, existing pharmacological asthma therapies are based on decades old strategies that were developed prior to the rapid growth in knowledge stemming from cell and molecular biology in the past decade. Thus, there is an unmet need for developing new drugs to target these features along with improved efficacy and safety. In the present review, the limitations of prevalent pharmacological asthma therapy are discussed briefly, and some explanations are suggested as to why new therapeutic targets are required to treat asthma, and finally directions for novel asthma therapies are proposed.
Halayko, A.J. & Sharma, P. 2009, 'S100A8/A9 as a pro-inflammatory cytokine in obstructive airway disease via the multi-ligand receptor, RAGE', Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry, vol. 8, no. 4, pp. 306-317.
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Asthma and chronic obstructive pulmonary disease (COPD) are persistent inflammatory conditions that have exhibited significantly increased prevalence in the past two decades. Though many current medications relieve the symptoms of obstructive airway disease, morbidity can still increase over time in individual patients. With particular respect to asthma, despite satisfactory control of symptoms in most patients with inhaled steroids, a sub-phenotype of subjects, representing 15% of all asthmatics, do not respond to steroids - these patients can exhibit severe asthma, which accounts for 50% of asthma health care costs. Moreover, inhaled steroids are not recommended as a sole therapy for COPD, and there is limited evidence for their effectiveness in preventing disease pathogenesis. Thus, it is important to better understand mechanisms for severe asthma and COPD and identify mediators released by cells, such as neutrophils, that are unresponsive to steroid therapy. This review focuses on the probable role of one the most abundant neutrophil proteins, called S100A8/A9, in asthma. S100A8/A9 is released in abundance in rheumatoid arthritis, inflammatory bowel disease and cancer, but there are no definitive studies on its role in obstructive airways disease. A primary receptor for S100A8/A9, which is uniquely expressed in high abundance in the lung, is the multi-ligand receptor for advanced glycated endproducts (RAGE) of the immunoglobin-like receptor family. RAGE participates in mediating fibroproliferative lung remodeling in idiopathic pulmonary fibrosis, and in bleomycin-exposed animal models. This review provides an overview of the S100A8/A9-RAGE axis, and discusses its potential in mediating chronic airway inflammation and tissue remodeling in asthma and COPD. © 2009 Bentham Science Publishers Ltd.
Hirota, J.A., Nguyen, T.T.B., Schaafsma, D., Sharma, P. & Tran, T. 2009, 'Airway smooth muscle in asthma: phenotype plasticity and function.', Pulmonary pharmacology & therapeutics, vol. 22, no. 5, pp. 370-378.
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Clinical asthma is characterized by reversible airway obstruction which is commonly due to an exaggerated airway narrowing referred to as airway hyperresponsiveness (AHR). Although debate exists on the complex etiology of AHR, it is clear that airway smooth muscle (ASM) mediated airway narrowing is a major contributor to airway dysfunction. More importantly, it is now appreciated that smooth muscle is far from being a simple cell with only contractile ability properties. Rather, it is more versatile with the capacity to exhibit numerous cellular functions as it adapts to the microenvironment to which it is exposed. The emerging ability of individual smooth muscle cells to undergo changes in their phenotype (phenotype plasticity) and function (functional plasticity) in response to physiological and pathological cues is an important and active area of research. This article provides a brief review of the current knowledge and emerging concepts in the field of ASM phenotype and function both under healthy and asthmatic conditions.
Dastidar, S.G., Ray, A., Shirumalla, R., Rajgopal, D., Chaudhary, S., Nanda, K., Sharma, P., Seth, M.K., Balachandran, S., Gupta, N. & Palle, V. 2009, 'Pharmacology of a Novel, Orally Active PDE4 Inhibitor.', Pharmacology, vol. Pharmacology, no. 83 (5), pp. 275-286.
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Sharma, P. & Halayko, A.J. 2009, 'Emerging molecular targets for the treatment of asthma', Indian Journal of Biochemistry and Biophysics, vol. 46, no. 6, pp. 447-460.
Current therapeutic approaches for the treatment of asthma have limitations in their ability to target all the features of the disease. Indeed, existing pharmacological asthma therapies are based on decades old strategies that were developed prior to the rapid growth in knowledge stemming from cell and molecular biology in the past decade. Thus, there is an unmet need for developing new drugs to target these features along with improved efficacy and safety. In the present review, the limitations of prevalent pharmacological asthma therapy are discussed briefly, and some explanations are suggested as to why new therapeutic targets are required to treat asthma, and finally directions for novel asthma therapies are proposed.
Dastidar, S.G., Ray, A., Shirumalla, R., Rajagopal, D., Chaudhary, S., Nanda, K., Sharma, P., Seth, M.K., Balachandran, S., Gupta, N. & Palle, V. 2009, 'Pharmacology of a novel, orally active PDE4 inhibitor.', Pharmacology, vol. 83, no. 5, pp. 275-286.
BACKGROUND: Intracellular cyclic adenosine monophosphate (cAMP) in inflammatory cells and airway smooth muscle is critical to the modulation of inflammatory response generation. Phosphodiesterase 4 (PDE4), an enzyme that catalyzes cAMP degradation, is therefore being actively explored as a molecular target for the treatment of airway inflammation, particularly asthma and chronic obstructive pulmonary disease. The field has undergone major advances in optimizing generation of compounds with a safe therapeutic margin; however, most PDE4 inhibitors tested so far have unacceptable side effects, particularly nausea and vomiting. METHODS: We evaluated NIS-62949 in a wide range of in vitro and ex vivo cell-based assays to ascertain its anti-inflammatory potential. The compound was evaluated in murine models of lipopolysaccharide-induced endotoxemia and pulmonary neutrophilia. Parameters of airway inflammation, airway hyperreactivity and bronchoconstriction were evaluated in a guinea pig model of antigen-induced allergy. In order to assess the emetic potential, the compound was evaluated biochemically for binding to high-affinity rolipram-binding site. Subsequently, the compound was tested in a surrogate model for emesis, and the results obtained were correlated directly to tests conducted in a Beagle dog model. RESULTS: NIS-62949 is a potent, highly selective PDE4 inhibitor. The compound demonstrated potent ability to inhibit tumor necrosis factor-alpha release from human peripheral blood mononuclear cells, lymphocyte proliferation and cytokine production. The in vitro profile of NIS-62949 prompted further evaluation of the compound in vivo and the compound was found to be comparable to roflumilast in several experimental models of pulmonary inflammation. Importantly, NIS-62949 displayed a safer profile compared to roflumilast. CONCLUSIONS: Our results report the development of a promising, novel PDE4 inhibitor, NIS-62949, with a wider therapeutic window as compared to...
Sharma, P., Tran, T., Stelmack, G.L., McNeill, K., Gosens, R., Mutawe, M.M., Unruh, H., Gerthoffer, W.T. & Halayko, A.J. 2008, 'Expression of the dystrophin-glycoprotein complex is a marker for human airway smooth muscle phenotype maturation.', American journal of physiology. Lung cellular and molecular physiology, vol. 294, no. 1, pp. L57-L68.
Airway smooth muscle (ASM) cells may contribute to asthma pathogenesis through their capacity to switch between a synthetic/proliferative and a contractile phenotype. The multimeric dystrophin-glycoprotein complex (DGC) spans the sarcolemma, linking the actin cytoskeleton and extracellular matrix. The DGC is expressed in smooth muscle tissue, but its functional role is not fully established. We tested whether contractile phenotype maturation of human ASM is associated with accumulation of DGC proteins. We compared subconfluent, serum-fed cultures and confluent cultures subjected to serum deprivation, which express a contractile phenotype. Western blotting confirmed that beta-dystroglycan, beta-, delta-, and epsilon-sarcoglycan, and dystrophin abundance increased six- to eightfold in association with smooth muscle myosin heavy chain (smMHC) and calponin accumulation during 4-day serum deprivation. Immunocytochemistry showed that the accumulation of DGC subunits was specifically localized to a subset of cells that exhibit robust staining for smMHC. Laminin competing peptide (YIGSR, 1 microM) and phosphatidylinositol 3-kinase (PI3K) inhibitors (20 microM LY-294002 or 100 nM wortmannin) abrogated the accumulation of smMHC, calponin, and DGC proteins. These studies demonstrate that the accumulation of DGC is an integral feature for phenotype maturation of human ASM cells. This provides a strong rationale for future studies investigating the role of the DGC in ASM smooth muscle physiology in health and disease.
Shirumalla, R., Sharma, P., Dastidar, S., Paliwal, J., Kakar, S., Varshney, B., Saini, G.S., Sattigeri, V., Salman, M. & Ray, A. 2008, 'Pharmacodynamic and pharmacokinetic characterization of RBx 7796: a novel 5-lipoxygenase inhibitor.', Inflammation Research., vol. 57, no. 3, pp. 135-143.
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Objective: RBx 7796, a 5-lipoxygenase inhibitor, was evaluated in in vivo efficacy models, in vitro ADME and in vivo pharmacokinetic models. Method: RBx 7796 was evaluated for inhibition of 5-lipoxygenase enzyme and release of LTB4 from isolated rat and human neutrophils. RBx 7796 was tested in allergic bronchoconstriction model in Balb/c mice and LPS induced airway hyperreactivity model in rats. RBx 7796 was evaluated for metabolic stability in liver microsomes and cytochrome P450 inhibition potential. Pharmacokinetic profile of RBx 7796 was also determined in rat and dog. Results: RBx 7796 inhibited 5-lipoxygenase enzyme and inhibited release of LTB4 from neutrophils. RBx 7796 also inhibited early and late airway reactivity following allergen challenge in mouse model. LPS induced increase in airway reactivity was blocked by RBx 7796. Compound was found to be stable in liver microsomes and devoid of major cytochrome P450 inhibition potential. The oral bioavailability of RBx 7796 in rat and dog was 83 % and 47 %, respectively. Following repeated daily administration, compound did not exhibit any sign of accumulation and/or tendency to induce its own metabolism. Conclusion: The results suggest that RBx 7796 is an inhibitor of 5-lipoxygenase enzyme that is orally efficacious in two different models of airway reactivity. The molecule also demonstrated acceptable pharmacokinetic profile warranting further development.
Sharma, P., Schaafsma, D., halayko, A.J. & meurs, H. 2007, 'Insulin increases expression of contractile phenotypic markers in airway smooth muscle', Am J Physiol Cell Physiol., vol. 293, no. 1, pp. 429-439.
We have previously demonstrated that long-term exposure of bovine tracheal smooth muscle (BTSM) strips to insulin induces a functional hypercontractile phenotype. To elucidate molecular mechanisms by which insulin might induce maturation of contractile phenotype airway smooth muscle (ASM) cells, we investigated effects of insulin stimulation in serum-free primary BTSM cell cultures on protein accumulation of specific contractile phenotypic markers and on the abundance and stability of mRNA encoding these markers. In addition, we used microscopy to assess insulin effects on ASM cell morphology, phenotype, and induction of phosphatidylinositol (PI) 3-kinase signaling. It was demonstrated that protein and mRNA levels of smooth muscle-specific contractile phenotypic markers, including sm-myosin, are significantly increased after stimulation of cultured BTSM cells with insulin (1 microM) for 8 days compared with cells treated with serum-free media, whereas mRNA stability was unaffected. In addition, insulin treatment promoted the formation of large, elongate ASM cells, characterized by dramatic accumulation of contractile phenotype marker proteins and phosphorylated p70(S6K) (downstream target of PI 3-kinase associated with ASM maturation). Insulin effects on protein accumulation and cell morphology were abrogated by combined pretreatment with the Rho kinase inhibitor Y-27632 (1 microM) or the PI 3-kinase inhibitor LY-294002 (10 microM), indicating that insulin increases the expression of contractile phenotypic markers in BTSM in a Rho kinase- and PI 3-kinase-dependent fashion. In conclusion, insulin increases transcription and protein expression of contractile phenotypic markers in ASM. This could have important implications for the use of recently approved aerosolized insulin formulations in diabetes mellitus.


Sharma, P. 2017, 'Lung experts warn against legalising nicotine in e-cigarettes'.
Sharma, P., Yi, R., Nayak, A., Wang, N., Tang, F., Knight, M., Pan, S., Oliver, B. & Deshpande, D. 2017, 'Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice'.
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Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.

Dr. Andrew Halayko, University of Manitoba, Winnipeg, MB, Canada

Dr. Raymond Penn, Thomas Jefferson University, Philadelphia, PA, USA

Dr. Deepak Deshoande, Thomas Jefferson University, Philadelphia, PA, USA

Dr. Saeid Ghavami, University of Manitoba, Winnipeg, MB, Canada