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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;
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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;
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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.
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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.
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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.
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    ABSTRACT: Asthma and chronic obstructive pulmonary disease are airway inflammatory diseases characterised by airflow obstruction. Currently approved bronchodilators such as long-acting β(2) adrenoceptor agonists are the mainstay treatments but often fail to relieve symptoms of chronic obstructive pulmonary disease and severe asthma and safety concerns have been raised over long-term use. The aim of the study was to identify the receptor involved in prostaglandin E(2) (PGE(2))-induced relaxation in guinea pig, murine, monkey, rat and human airways in vitro. Using an extensive range of pharmacological tools, the relaxant potential of PGE(2) and selective agonists for the EP(1-4) receptors in the presence and absence of selective antagonists in guinea pig, murine, monkey, rat and human isolated airways was investigated. In agreement with previous studies, it was found that the EP(2) receptor mediates PGE(2)-induced relaxation of guinea pig, murine and monkey trachea and that the EP(4) receptor mediates PGE(2)-induced relaxation of the rat trachea. These data have been confirmed in murine airways from EP(2) receptor-deficient mice (Ptger2). In contrast to previous publications, a role for the EP(4) receptor in relaxant responses in human airways in vitro was found. Relaxant activity of AH13205 (EP(2) agonist) was also demonstrated in guinea pig but not human airway tissue, which may explain its failure in clinical studies. Identification of the receptor mediating PGE(2)-induced relaxation represents a key step in developing a novel bronchodilator therapy. These data explain the lack of bronchodilator activity observed with selective EP(2) receptor agonists in clinical studies.
    Thorax 05/2011; 66(12):1029-35.
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    ABSTRACT: Ever since the discovery of prostaglandin E(2)(PGE(2)), this lipid mediator has been the focus of intense research. The diverse biological effects of PGE(2) are due, at least in part, to the existence of four distinct receptors (EP(1-4)). This can complicate the analysis of the biological effects produced by PGE2. While there are currently selective pharmacological tools to explore the roles of the EP(1,3,4) receptors in cellular and tissue responses, analysis of EP(2) receptor-induced responses has been hampered by the lack of a selective EP(2) receptor antagonist. The recent publication in this journal by af Forselles et al. suggests that such a tool compound is now available. In their manuscript, the authors describe a series of experiments that show PF-04418948 to be a potent and selective EP(2) receptor antagonist. The discovery of this tool compound will interest many scientists and through collaborations with Pfizer they may have access to PF-04418948 to facilitate further investigation of the biology of this fascinating lipid mediator.
    British Journal of Pharmacology 05/2011; 164(7):1845-6.
  • Nature medicine 01/2011; 17(7):776; author reply 776-8.
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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 01/2011; 6(7):e21827.
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    ABSTRACT: In the early 1990's ion channels of the Transient Receptor Potential (TRP) class were implicated in the afferent sensory loop of the cough reflex and in the heightened cough sensitivity seen in disease. Agonists of the TRPV1 capsaicin receptor such as vanilloids and protons were demonstrated to be amongst the most potent chemical stimuli which cause cough. However, more recently, the TRPA1 receptor (not activated by capsaicin) has become of interest in the cough field because it is known to be activated by ligands such as acrolein which is present in air pollution and the acrid smoke from organic material. TRPA1 is a Ca(2+)-permeant non-selective cation channel with 14 ankyrin repeats in its amino terminus which belongs to the larger TRP family. TRPA1 has been characterised as a thermoreceptor which is activated by cold temperature, environmental irritants and reactive electrophilic molecules which can be generated by oxidant stress and inflammation. TRPA1 is primarily expressed in small diameter, nociceptive neurons where its activation probably contributes to the perception of noxious stimuli and the phenomena known as inflammatory hyperalgesia and neurogenic inflammation. The respiratory tract is innervated by primary sensory afferent nerves which are activated by mechanical and chemical stimuli. Activation of these vagal sensory afferents leads to central reflexes including dyspnoea, changes in breathing pattern and cough. Recently, it has been demonstrated that stimulating TRPA1 channels activates vagal bronchopulmonary C-fibres in the guinea pig and rodent lung, and recent data have shown that TRPA1 ligands cause cough in both animal models and normal volunteers. In summary, due to their activation by a wide range of irritant and chemical substances, either by exogenous agents, endogenously produced mediators during inflammation or by oxidant stress, we suggest TRPA1 channels should be considered as one of the most promising targets currently identified for the development of novel anti-tussive drugs.
    Pulmonary Pharmacology &amp Therapeutics 11/2010; 24(3):286-8.
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