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Pharmacology of Cough
24
Abstracts / Autonomic Neuroscience: Basic and Clinical 177 (2013) 1–65
We elaborated an original model of chronic stress based on anticipatory social defeat, that induced an anxiety- like state in defeated rats. Using our paradigm, we were able to modelize all cardiovascular modifications found in mood disorders, including the baroreflex reduction, that was not evidenced in any other rat model of chronic stress. The central pathway involved in these modifications involves DMH activation, leading to a decrease in baroreflex gain and parasympathetic activity via NTS 5-HT3 receptor excitation, and an increase in sympathetic tone independently of the NTS. Specific treatment for mood disorders restores vagal cardiac function only partially or increases cardiac alteration. Our data bring the possibility that systemic treatment with granisetron —a potent anti-emetic used to treat patients undergoing treatment for cancer therapy, with a highly safe profile due to its high selectivity for 5-HT3 receptors— could be used to improve parasympathetic activity and, thus, to reduce the likelihood of adverse cardiac events in patients with high anxiety scores and in patients with induced dysautonomia, as observed after ischemic stroke, for example. doi:10.1016/j.autneu.2013.05.025
Abstract 4.1
symptom of many respiratory diseases. Treatment options are limited. Despite its importance our understanding of the mechanisms which provoke cough is poor. The respiratory tract is innervated by sensory afferent nerves which are activated by mechanical and chemical stimuli. Activation of capsaicin-sensitive C-fibres and acid-sensitive, capsaicininsensitive mechanoreceptors innervating the larynx, trachea, and large bronchi regulate the cough reflex. Recently, ion channels of the Transient Receptor Potential (TRP) class such as TRPV1 have been implicated in the afferent sensory loop of the cough reflex and in the heightened cough sensitivity seen in disease. TRPA1 is a Ca2 +-permeant non-selective channel with 14 ankyrin repeats in its amino terminus which also belongs to the larger TRP family. TRPA1 channels are activated by a range of natural products found in mustard oil, garlic and cannabis and by environmental irritants and is expressed in small diameter, nociceptive neurons. It has been demonstrated that stimulating TRPA1 channels activates vagal broncho-pulmonary C-fibers causing cough both in guinea-pig models and in normal human volunteers. The TRPV4 channel is also widely expressed in mammalian tissues including lung, heart, kidney, sensory neurons. We have preliminary data to suggest that TRPV4 may be present on vagal sensory nerve endings and involved in the activation of lung specific afferents in response to endogenous stimuli such as hypotonicity. Although many exogenous stimuli are known to activate particularly TRPA1 and TRPV1, it is still unknown how cough and other reflexes are elicited in health and disease by endogenous agents, and whether these ion channels are involved.
Activation Mechanisms Of Airway Afferent Nerve doi:10.1016/j.autneu.2013.05.027 Bradley J. Undem (Johns Hopkins University School of Medicine, Baltimore Maryland USA) Activation of primary afferent nerves is initiated by a stimulusinduced membrane depolarization referred to as a generator potential (GP). Bronchopulmonary C-fibers are “polymodal” meaning several disparate stimuli can evoke GPs in these nerves. The stimulus profile of the bronchopulmonary C-fibers is strictly dependent on whether the cell body is situated in the nodose or jugular ganglion. Among the ligand-gated ion channels involved in GPS, TRPA1 and TRPV1 serve to integrate many stimuli relevant to respiratory biology. TRPA1 can be gated by environmental irritants including ozone and TDI, and products of oxidative stress including oxidized prostanoids and hydroy- and oxynanenols. TRPV1 can be gated by inflammatory mediators that act via Gq GPCRs, certain eicosanoids, and decreases in pH. The GP leads to action potential (AP) discharge only if the depolarization reaches the voltage threshold for voltage gated sodium channels (NaVs). We have obtained both transcriptional evidence and electrophysiological evidence, that nociceptive C-fibers and non-nociceptive A-fibers innervating the airways express categorically and nearly exclusively NaV1.7, NaV 1.8 and NaV 1.9. NaV1.7 appears to be critically involved in setting voltage threshold, regulation of AP frequency, and AP conduction in these nerves. NaV 1.8 and 1.9 are suspected to play a key role in the increased excitability associated with airway inflammation.
doi:10.1016/j.autneu.2013.05.026
Abstract 4.2
Abstract 4.3 Novel insights in the postnatal role of pulmonary neuroepithelial bodies Kathy Schnorbusch, Robrecht Lembrechts, Inge Brouns, Dirk Adriaensen, Jean-Pierre Timmermans (Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium) Pulmonary neuroepithelial bodies (NEBs) are small, densely innervated clusters of neuroendocrine cells located in the airway epithelium of all air-breathing vertebrates, including humans. A variety of proposed possible functions of these NEBs in the regulation of physiological events in the lungs have led to many controversies in the past decades. Until recently, these structures were believed to detect local intrapulmonary oxygen levels. Using an ex vivo lung slice model and a combined laser microdissection and RT-PCR approach, we were able to provide proof of the capability of these cells to sense both mechanical and chemical changes in the airways. Apart from being airway sensors, we have evidence to believe that these neuroendocrine cellular aggregates harbor an epithelial stem cell niche, which might disclose the possible link of these cells with the development of small cell lung carcinoma. In addition, the availability of the GAD67-GFP transgenic mouse model further opens new perspectives for unraveling the distinct roles of these cells under normal and inflammatory conditions. doi:10.1016/j.autneu.2013.05.028
Pharmacology of Cough Maria G. Belvisi, Megan Grace, Sarah Maher, Michael Wortley, Eric Dubuis, John Adcock, Sara Bonvini, Mark A. Birrell (NHLI, Imperial College London, UK)
Abstract 4.4
Cough is the most common respiratory complaint for which medical attention is sought and often presents as the first and most persistent
G. Krasteva-Christ (Institute of Anatomy and Cell Biology, JustusLiebig-University, Giessen, Germany), A. Rafiq (Institute of Anatomy
“Tasting” the airway lining fluid
Abstracts / Autonomic Neuroscience: Basic and Clinical 177 (2013) 1–65
We elaborated an original model of chronic stress based on anticipatory social defeat, that induced an anxiety- like state in defeated rats. Using our paradigm, we were able to modelize all cardiovascular modifications found in mood disorders, including the baroreflex reduction, that was not evidenced in any other rat model of chronic stress. The central pathway involved in these modifications involves DMH activation, leading to a decrease in baroreflex gain and parasympathetic activity via NTS 5-HT3 receptor excitation, and an increase in sympathetic tone independently of the NTS. Specific treatment for mood disorders restores vagal cardiac function only partially or increases cardiac alteration. Our data bring the possibility that systemic treatment with granisetron —a potent anti-emetic used to treat patients undergoing treatment for cancer therapy, with a highly safe profile due to its high selectivity for 5-HT3 receptors— could be used to improve parasympathetic activity and, thus, to reduce the likelihood of adverse cardiac events in patients with high anxiety scores and in patients with induced dysautonomia, as observed after ischemic stroke, for example. doi:10.1016/j.autneu.2013.05.025
Abstract 4.1
symptom of many respiratory diseases. Treatment options are limited. Despite its importance our understanding of the mechanisms which provoke cough is poor. The respiratory tract is innervated by sensory afferent nerves which are activated by mechanical and chemical stimuli. Activation of capsaicin-sensitive C-fibres and acid-sensitive, capsaicininsensitive mechanoreceptors innervating the larynx, trachea, and large bronchi regulate the cough reflex. Recently, ion channels of the Transient Receptor Potential (TRP) class such as TRPV1 have been implicated in the afferent sensory loop of the cough reflex and in the heightened cough sensitivity seen in disease. TRPA1 is a Ca2 +-permeant non-selective channel with 14 ankyrin repeats in its amino terminus which also belongs to the larger TRP family. TRPA1 channels are activated by a range of natural products found in mustard oil, garlic and cannabis and by environmental irritants and is expressed in small diameter, nociceptive neurons. It has been demonstrated that stimulating TRPA1 channels activates vagal broncho-pulmonary C-fibers causing cough both in guinea-pig models and in normal human volunteers. The TRPV4 channel is also widely expressed in mammalian tissues including lung, heart, kidney, sensory neurons. We have preliminary data to suggest that TRPV4 may be present on vagal sensory nerve endings and involved in the activation of lung specific afferents in response to endogenous stimuli such as hypotonicity. Although many exogenous stimuli are known to activate particularly TRPA1 and TRPV1, it is still unknown how cough and other reflexes are elicited in health and disease by endogenous agents, and whether these ion channels are involved.
Activation Mechanisms Of Airway Afferent Nerve doi:10.1016/j.autneu.2013.05.027 Bradley J. Undem (Johns Hopkins University School of Medicine, Baltimore Maryland USA) Activation of primary afferent nerves is initiated by a stimulusinduced membrane depolarization referred to as a generator potential (GP). Bronchopulmonary C-fibers are “polymodal” meaning several disparate stimuli can evoke GPs in these nerves. The stimulus profile of the bronchopulmonary C-fibers is strictly dependent on whether the cell body is situated in the nodose or jugular ganglion. Among the ligand-gated ion channels involved in GPS, TRPA1 and TRPV1 serve to integrate many stimuli relevant to respiratory biology. TRPA1 can be gated by environmental irritants including ozone and TDI, and products of oxidative stress including oxidized prostanoids and hydroy- and oxynanenols. TRPV1 can be gated by inflammatory mediators that act via Gq GPCRs, certain eicosanoids, and decreases in pH. The GP leads to action potential (AP) discharge only if the depolarization reaches the voltage threshold for voltage gated sodium channels (NaVs). We have obtained both transcriptional evidence and electrophysiological evidence, that nociceptive C-fibers and non-nociceptive A-fibers innervating the airways express categorically and nearly exclusively NaV1.7, NaV 1.8 and NaV 1.9. NaV1.7 appears to be critically involved in setting voltage threshold, regulation of AP frequency, and AP conduction in these nerves. NaV 1.8 and 1.9 are suspected to play a key role in the increased excitability associated with airway inflammation.
doi:10.1016/j.autneu.2013.05.026
Abstract 4.2
Abstract 4.3 Novel insights in the postnatal role of pulmonary neuroepithelial bodies Kathy Schnorbusch, Robrecht Lembrechts, Inge Brouns, Dirk Adriaensen, Jean-Pierre Timmermans (Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium) Pulmonary neuroepithelial bodies (NEBs) are small, densely innervated clusters of neuroendocrine cells located in the airway epithelium of all air-breathing vertebrates, including humans. A variety of proposed possible functions of these NEBs in the regulation of physiological events in the lungs have led to many controversies in the past decades. Until recently, these structures were believed to detect local intrapulmonary oxygen levels. Using an ex vivo lung slice model and a combined laser microdissection and RT-PCR approach, we were able to provide proof of the capability of these cells to sense both mechanical and chemical changes in the airways. Apart from being airway sensors, we have evidence to believe that these neuroendocrine cellular aggregates harbor an epithelial stem cell niche, which might disclose the possible link of these cells with the development of small cell lung carcinoma. In addition, the availability of the GAD67-GFP transgenic mouse model further opens new perspectives for unraveling the distinct roles of these cells under normal and inflammatory conditions. doi:10.1016/j.autneu.2013.05.028
Pharmacology of Cough Maria G. Belvisi, Megan Grace, Sarah Maher, Michael Wortley, Eric Dubuis, John Adcock, Sara Bonvini, Mark A. Birrell (NHLI, Imperial College London, UK)
Abstract 4.4
Cough is the most common respiratory complaint for which medical attention is sought and often presents as the first and most persistent
G. Krasteva-Christ (Institute of Anatomy and Cell Biology, JustusLiebig-University, Giessen, Germany), A. Rafiq (Institute of Anatomy
“Tasting” the airway lining fluid