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    ABSTRACT: Cough is a protective reflex and defence mechanism in healthy individuals, which helps clear excessive secretions and foreign material from the lungs. Cough often presents as the first and most persistent symptom of many respiratory diseases and some non-respiratory disorders, but can also be idiopathic, and is a common respiratory complaint for which medical attention is sought. Chronic cough of various aetiologies is a regular presentation to specialist respiratory clinics, and is reported as a troublesome symptom by a significant proportion of the population. Despite this, the treatment options for cough are limited. The lack of effective anti-tussives likely stems from our incomplete understanding of how the tussive reflex is mediated. However, research over the last decade has begun to shed some light on the mechanisms which provoke cough, and may ultimately provide us with better anti-tussive therapies. This review will focus on the in vitro and in vivo models that are currently used to further our understanding of the sensory innervation of the respiratory tract, and how these nerves are involved in controlling the cough response. Central to this are the Transient Receptor Potential (TRP) ion channels, a family of polymodal receptors that can be activated by such diverse stimuli as chemicals, temperature, osmotic stress, and mechanical perturbation. These ion channels are thought to be molecular pain integrators and targets for novel analgesic agents for the treatment of various pain disorders but some are also being developed as anti-tussives.
    Pulmonary Pharmacology &amp Therapeutics 03/2013; 26(5). DOI:10.1016/j.pupt.2013.02.007
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    ABSTRACT: Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality, which is most commonly associated with smoking or exposure to environmental pollutants. Unfortunately, there is an inadequate understanding of the molecular and physiological determinants governing one's susceptibility for developing COPD. Here, we describe a novel hypothesis: Individuals with intrinsically low aerobic exercise capacity are more likely to develop COPD after exposure to key risk factors. The hypothesis is based on observations that aerobic exercise capacity is tightly associated with mortality across many complex diseases. The premise is supported by recent studies demonstrating that smokers who exercise regularly are less likely to develop or be hospitalized for COPD. Herein, we describe the evolutionary and molecular basis for this hypothesis and how it is a natural extension of previous theories explaining COPD susceptibility.
    Pulmonary Pharmacology &amp Therapeutics 01/2013; DOI:10.1016/j.pupt.2013.01.004
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    ABSTRACT: Background and purpose:  Understanding the role of the EP(2) receptor has been hampered by the lack of a selective antagonist. Recently, a selective EP(2) receptor antagonist, PF-04418948, has been discovered. The aim of this study was to demonstrate the selectivity profile of PF-04418948 for the EP(2) receptor over other EP receptors, using a range of isolated tissue systems. Experimental approach:  PF-04418948 was profiled on a range of isolated tissues to assess its EP receptor potency and selectivity: ONO-DI-004-induced contraction of guinea pig trachea (EP(1) ); ONO-AE1-259 and PGE(2) - induced relaxation of mouse and guinea-pig trachea (EP(2) ); PGE(2) -induced depolarisation of guinea pig isolated vagus (EP(3) ); PGE(2) -induced relaxation of human and rat trachea (EP(4) ). PF-04418948 was also profiled in functional murine TP, IP, DP and FP receptors assays. Key results:  In bioassay systems, where assessment of potency/selectivity is made against the "native" receptor, PF-04418948 only acted as an antagonist of EP(2) -receptor-mediated events. PF-04418948 competitively inhibited relaxations of murine and guinea-pig trachea induced by ONO-AE1-259 and PGE(2) respectively. However, the affinity of PF 04418948 was not equal in the two preparations (murine trachea: pK(B) = 8.32; guinea-pig trachea pK(B) = 6.95. Conclusions and Implications:  Using a range of bioassay systems, we have demonstrated that PF-04418948 is a selective EP(2) -receptor antagonist. Interestingly, an atypically low affinity was found on the guinea-pig trachea questioning its utility as an EP(2) -receptor assay system. Nevertheless, this compound should be an invaluable tool for investigating the biological activity of PGE(2) and the role of EP(2) -receptors in health and disease. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
    British Journal of Pharmacology 07/2012; 168(1). DOI:10.1111/j.1476-5381.2012.02088.x
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    ABSTRACT: Cough is the most frequent reason for consultation with a family doctor, or with a general or respiratory physician. Treatment options are limited and a recent meta-analysis concluded that over-the-counter remedies are ineffective and there is increasing concern about their use in children. Endogenous inflammatory mediators such as prostaglandin E(2) (PGE(2)) and bradykinin (BK), which are often elevated in respiratory disease states, are also known to cause cough by stimulating airway sensory nerves. However, how this occurs is not understood. We hypothesised that the transient receptor potential (TRP) channels, TRPA1 and TRPV1, may have a role as 'common effectors' of tussive responses to these agents. We have employed a range of in vitro imaging and isolated tissue assays in human, murine and guinea pig tissue and an in vivo cough model to support this hypothesis. Using calcium imaging we demonstrated that PGE(2) and BK activated isolated guinea pig sensory ganglia and evoked depolarisation (activation) of vagal sensory nerves, which was inhibited by TRPA1 and TRPV1 blockers (JNJ17203212 and HC-030031). These data were confirmed in vagal sensory nerves from TRPA1 and TRPV1 gene deleted mice. TRPV1 and TRPA1 blockers partially inhibited the tussive response to PGE(2) and BK with a complete inhibition obtained in the presence of both antagonists together in a guinea pig conscious cough model. This study identifies TRPA1 and TRPV1 channels as key regulators of tussive responses elicited by endogenous and exogenous agents, making them the most promising targets currently identified in the development of anti-tussive drugs.
    Thorax 06/2012; 67(10):891-900. DOI:10.1136/thoraxjnl-2011-201443
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    ABSTRACT: Pharmacologists have used pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) for decades as a stimulus for studying mediators involved in inflammation and for the screening of anti-inflammatory compounds. However, in the view of immunologists, LPS was too non-specific for studying the mechanisms of immune signalling in infection and inflammation, as no receptors had been identified. This changed in the late 1990s with the discovery of the Toll-like receptors. These 'pattern recognition receptors' (PRRs) were able to recognise highly conserved sequences, the so called pathogen associated molecular patterns (PAMPs) present in or on pathogens. This specificity of particular PAMPs and their newly defined receptors provided a common ground between pharmacologists and immunologists for the study of inflammation. PRRs also recognise endogenous agonists, the so called danger-associated molecular patterns (DAMPs), which can result in sterile inflammation. The signalling pathways and ligands of many PRRs have now been characterised and there is no doubt that this rich vein of research will aid the discovery of new therapeutics for infectious conditions and chronic inflammatory disease.
    Pharmacology [?] Therapeutics 05/2012; 135(2):200-15. DOI:10.1016/j.pharmthera.2012.05.007
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    ABSTRACT: Cigarette smoking is responsible for 5 million deaths worldwide each year, and is a major risk factor for cardiovascular and lung diseases. Cigarette smoke contains a complex mixture of over 4000 chemicals containing 10(15) free radicals. Studies show smoke is perceived by cells as an inflammatory and xenobiotic stimulus, which activates an immune response. The specific cellular mechanisms driving cigarette smoke-induced inflammation and disease are not fully understood, although the innate immune system is involved in the pathology of smoking related diseases. To address the impact of smoke as an inflammagen on the innate immune system, THP-1 cells and Human PBMCs were stimulated with 3 and 10% (v/v) cigarette smoke extract (CSE) for 8 and 24 hours. Total RNA was extracted and the transcriptome analysed using Illumina BeadChip arrays. In THP-1 cells, 10% CSE resulted in 80 genes being upregulated and 37 downregulated by ≥1.5 fold after 8 hours. In PBMCs stimulated with 10% CSE for 8 hours, 199 genes were upregulated and 206 genes downregulated by ≥1.5 fold. After 24 hours, the number of genes activated and repressed by ≥1.5 fold had risen to 311 and 306 respectively. The major pathways that were altered are associated with cell survival, such as inducible antioxidants, protein chaperone and folding proteins, and the ubiquitin/proteosome pathway. Our results suggest that cigarette smoke causes inflammation and has detrimental effects on the metabolism and function of innate immune cells. In addition, THP-1 cells provide a genetically stable alternative to primary cells for the study of the effects of cigarette smoke on human monocytes.
    PLoS ONE 02/2012; 7(2):e30120. DOI:10.1371/journal.pone.0030120
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    ABSTRACT: Cough is a troublesome symptom associated with many respiratory diseases. In some instances cough can become prolonged and excessive, and chronic cough of various aetiologies is a common presentation to specialist respiratory clinics. However, current treatment options are limited. Despite its importance, our understanding of the mechanisms that provoke cough is poor. Recent investigation has focused on the interaction between G-protein-coupled receptors and ion channels expressed on airway sensory nerves that are responsible for driving the cough reflex. In particular, the Transient Receptor Potential class of ion channels appears to play a major role as a regulator of the afferent arm of the cough reflex and could be involved in the heightened cough response observed in disease states. Current research investigating the pathogenesis of cough supports the development of TRP channel inhibitors as novel and selective treatment modalities.
    Beiträge zur Klinik der Tuberkulose 10/2011; 190(1):11-5. DOI:10.1007/s00408-011-9322-3
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    ABSTRACT: It is widely believed that the alveolar epithelium is unresponsive to LPS, in the absence of serum, due to low expression of TLR4 and CD14. Furthermore, the responsiveness of the epithelium to TLR-2 ligands is also poorly understood. We hypothesised that human alveolar type I (ATI) and type II (ATII) epithelial cells were responsive to TLR2 and TLR4 ligands (MALP-2 and LPS respectively), expressed the necessary TLRs and co-receptors (CD14 and MD2) and released distinct profiles of cytokines via differential activation of MAP kinases. Primary ATII cells and alveolar macrophages and an immortalised ATI cell line (TT1) elicited CD14 and MD2-dependent responses to LPS which did not require the addition of exogenous soluble CD14. TT1 and primary ATII cells expressed CD14 whereas A549 cells did not, as confirmed by flow cytometry. Following LPS and MALP-2 exposure, macrophages and ATII cells released significant amounts of TNFα, IL-8 and MCP-1 whereas TT1 cells only released IL-8 and MCP-1. P38, ERK and JNK were involved in MALP-2 and LPS-induced cytokine release from all three cell types. However, ERK and JNK were significantly more important than p38 in cytokine release from macrophages whereas all three were similarly involved in LPS-induced mediator release from TT1 cells. In ATII cells, JNK was significantly more important than p38 and ERK in LPS-induced MCP-1 release. MALP-2 and LPS exposure stimulated TLR4 protein expression in all three cell types; significantly more so in ATII cells than macrophages and TT1 cells. In conclusion, this is the first study describing the expression of CD14 on, and TLR2 and 4 signalling in, primary human ATII cells and ATI cells; suggesting that differential activation of MAP kinases, cytokine secretion and TLR4 expression by the alveolar epithelium and macrophages is important in orchestrating a co-ordinated response to inhaled pathogens.
    PLoS ONE 07/2011; 6(7):e21827. DOI:10.1371/journal.pone.0021827
  • Nature medicine 07/2011; 17(7):776; author reply 776-8. DOI:10.1038/nm0711-776a
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    ABSTRACT: Cough is a protective mechanism but can occur excessively in disease. Cough can be modulated by a range of GPCRs which can be either inhibitory or excitatory. Prostaglandin E2 and bradykinin can activate airway sensory nerves via EP3 and B2 receptors receptively and have both been shown to mediate their effects though TRPV1 and TRPA1 receptors. Activation of the β2-adrenoceptor and cannabinoid CB2 receptors can inhibit sensory nerves and prevent cough. It is currently thought that activation of the β2-adrenoceptor causes c-AMP dependent activation of PKA; however, recent research has suggested that the pathway involves PKG-mediated opening of the BKCa channel leading to hyperpolarization.
    Current Opinion in Pharmacology 06/2011; 11(3):248-53. DOI:10.1016/j.coph.2011.06.005
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