Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0010200 (cough)
 23,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article expands the author's presentation at the First American Cough Conference in New York City, June 8-9, 2007. The results of a scientific literature search and application of personal research findings are included. A new hypothesis to explain irritant-induced cough as a being a dysfunction of the transient receptor potential vanilloid 1 (TRPV1) cation channels located in pulmonary excitable cells is presented. The TRPV1 cation channels regulate cellular transmembrane voltage by raising intracellular Ca(2+) and Na(+) concentrations and depolarizing sensory nerve cells containing C-fibers. The discussion centers on the "capsaicin receptor" (TRPV1) and another important ion channel, TRPA1. The author reviews results of published scientific investigations to support his contention that neural events, initiated by TRPV1 ion channels, lead to a cascade of alterations that progress to a cough endpoint. A potential mechanism to explain chronic cough in conditions where there is repeated or severe irritant-induced airway epithelial injury (e.g., RADS) is through persistent TRPV1 channel activation (e.g., TRPV1pathy) with accumulation of inflammatory mediators, tachykinins, and the release of neurotrophins leading to persistent cough and airway inflammation. The significance of the hypothesis is that, if proven, it may provide new therapeutic approaches for the treatment of chronic cough.
 ...
PMID:Irritant-induced chronic cough: irritant-induced TRPpathy. 1823 61

Sensory neurons in the airways are finely tuned to respond to reactive chemicals threatening airway function and integrity. Nasal trigeminal nerve endings are particularly sensitive to oxidants formed in polluted air and during oxidative stress as well as to chlorine, which is frequently released in industrial and domestic accidents. Oxidant activation of airway neurons induces respiratory depression, nasal obstruction, sneezing, cough, and pain. While normally protective, chemosensory airway reflexes can provoke severe complications in patients affected by inflammatory airway conditions like rhinitis and asthma. Here, we showed that both hypochlorite, the oxidizing mediator of chlorine, and hydrogen peroxide, a reactive oxygen species, activated Ca(2+) influx and membrane currents in an oxidant-sensitive subpopulation of chemosensory neurons. These responses were absent in neurons from mice lacking TRPA1, an ion channel of the transient receptor potential (TRP) gene family. TRPA1 channels were strongly activated by hypochlorite and hydrogen peroxide in primary sensory neurons and heterologous cells. In tests of respiratory function, Trpa1(-/-) mice displayed profound deficiencies in hypochlorite- and hydrogen peroxide-induced respiratory depression as well as decreased oxidant-induced pain behavior. Our results indicate that TRPA1 is an oxidant sensor in sensory neurons, initiating neuronal excitation and subsequent physiological responses in vitro and in vivo.
 ...
PMID:TRPA1 is a major oxidant sensor in murine airway sensory neurons. 1839 6

The transient receptor potential (TRP) family of channels is represented by at least six members in primary sensory neurons. These include the TRP vanilloid subtypes 1 (TRPV1), 2, 3, and 4, the cold and menthol receptor TRPM8, and TRPA1. Much interest has been directed to the study of the TRPV1, because capsaicin has been instrumental in discovering the unique role of a subset of primary sensory neurons in causing nociceptive responses, in activating reflex pathways including cough, and in producing neurogenic inflammation. TRPV1 is now regarded as an integrator of diverse sensory modalities because it undergoes marked plasticity and sensitization through a variety of mechanisms, including activation of G-protein-coupled or tyrosine kinase receptors. Evidence in experimental animals and in patients with airway diseases indicates a marked hypersensitivity to cough induced by TRPV1 agonists. Recent studies with newly developed high-affinity and selective TRPV1 antagonists have revealed that TRPV1 inhibition reduces cough induced by citric acid or antigen challenge.
 ...
PMID:Cough sensors. II. Transient receptor potential membrane receptors on cough sensors. 1882 35

American guidelines, unlike European guidelines, support the use of antihistamines as a first line of treatment for some causes of chronic cough. Transient receptor potential vanilloid-1 (TRPV1) is an ion channel activated by the tussive agents capsaicin, resiniferatoxin, and protons. It is predominantly expressed by C-fiber and some Adelta -fiber sensory neurons and is thought to be a cough receptor. By measuring increases in intracellular calcium as an indicator of TRPV1 activation, the authors sought to determine whether antihistamines could antagonise TRPV1 permanently expressed in HEK and Pro5 cells and TRPV1 endogenously expressed in rat dorsal root ganglia neurons. In human TRPV1-expressing HEK cells (hTRPV1-HEK), diphenhydramine and fexofenadine failed to inhibit capsaicin-triggered calcium responses. However, both dexbrompheniramine and chlorpheniramine significantly inhibited capsaicin-evoked responses in hTRPV1-HEK. Dexbrompheniramine also inhibited activation of rat TRPV1 expressed in HEK and Pro5 cells, without interfering with TRPA1 and proteinase-activated receptor-2 (PAR(2)) activation. Finally, in rat dorsal root ganglia neuron preparations, dexbrompheniramine dose-dependently inhibited capsaicin-evoked calcium responses. Thus, the inhibition of TRPV1 activation by dexbrompheniramine may provide one potential mechanism whereby this antihistamine exerts its therapeutic effect in chronic cough.
 ...
PMID:Transient receptor potential vanilloid-1-mediated calcium responses are inhibited by the alkylamine antihistamines dexbrompheniramine and chlorpheniramine. 1908 65

Chronic cough in gastroesophageal reflux disease (GERD) has been attributed to irritation of the esophagus and/or upper airways by reflux of gastric content. Animal models have provided insight into both of these putative mechanisms. In patients with chronic cough and GERD, stimuli associated with reflex in the esophagus sensitize the cough reflex. This sensitization can be reproduced in the guinea pig and is most likely mediated by the esophageal afferent nerve fibers carried by the vagus nerves. Studies in animals have identified several subtypes of vagal esophageal C-fibers that may subserve this function. The putative nociceptive vagal C-fibers in the guinea pig esophagus are stimulated by acid and express the TRPV1 and TRPA1 receptors that confer responsiveness to disparate noxious stimuli. Acute and/or chronic irritation of the upper airways by reflux may contribute to cough by stimulation and/or sensitization of the airway afferent nerves. Studies in animals have identified airway nerves that likely initiate cough due to aspirated reflux; have characterized their pharmacology; and have provided insight into changes of their sensitivity. Studies in animal models have also described the neurophysiology of reflexes that protect the airways from reflux. In conclusion, animal models provide mechanistic insight into the modulation of cough from the esophagus and the pharmacology of neural pathways mediating cough in GERD.
 ...
PMID:Cough and gastroesophageal reflux: insights from animal models. 1913 51

Cough occurs as a result of the activation of specific airway sensory nerves. The mechanisms by which tussive stimuli activate these sensory nerves are starting to be understood and suggest that TRPA1 channels are heavily involved. TRPA1 channels are nociceptor-specific ion channels that are gated by a wide range of exogenous irritants and endogenously-produced inflammatory mediators, suggesting that the blockade of TRPA1 represents a novel therapy for the treatment of cough in humans.
 ...
PMID:TRPA1: a potential target for anti-tussive therapy. 1915 Apr 9

Sneezing, cough, mucus secretion, and bronchoconstriction represent the main components of a coordinated and efficient reaction direct to expel or neutralize irritant agents from the respiratory system. A dense network of sensory nerves localized from the nose to the lower airways beneath the epithelium subserves this function. A variety of receptors and channels present in sensory nerve terminals by sensing irritant stimuli activate the system in emergence and initiate protective reflex responses, including cough. Previous and recent literature highlights the prominent role of some transient receptor potential (TRP) ion channels, and specifically the vanilloid 1 (TRPV1) and the ankyrin 1 (TRPA1) as sensors of airway irritation and initiators of the cough reflex.
 ...
PMID:Cough: The Emerging Role of the TRPA1 Channel. 2009 Oct 46

Occupational and environmental irritants play a role in the pathogenesis of chronic cough. An irritant is a non-corrosive chemical, which causes a reversible inflammatory change on living tissue by chemical action at the site of contact. The clinical and pathologic spectrum of chemically induced respiratory tract irritation ranges from neurogenically mediated alterations in regional blood flow, mucus secretion, and airway caliber to the initiation of cough. In an evolutionary perspective, two types of cough reflexes were created for different protective purposes, but each type used the same anatomic and physiologic neural and muscular structures. The mechanosensory type evolved as human ancestors adapted phonation over olfaction and the larynx moved in close proximity to the esophageal opening. The chemosensory type evolved to protect against an injured lung from a respiratory tract infection or after inhaling high levels of irritant gases and particulates that accumulated in confined quarters of early times. For this latter type of cough reflex, normally quiescent transient receptor potential (TRP) cation channels TRPV1(vanilloid) and TRPA1 (ankyrin) become activated or hyperactivated after lung injury, with lung inflammation, or in response to chemicals. Although animal and laboratory investigations support the possibility of human TRPpathies, further investigations are essential for the further elucidation of the role of TRP cationic channels in instigating chronic cough in humans.
 ...
PMID:Occupational, environmental, and irritant-induced cough. 2017 59

A subpopulation of nociceptive primary sensory neurons expresses six different transient receptor potential (TRP) ion channels of the vanilloid (V1, V2, V3 and V4), melastatin (M8) and ankyrin (A1) subtypes. TRPV1 mediates the tussive action of capsaicin, which is widely used in cough provocation studies. The upregulation of TRPV1 expression and function has been reported in asthma and other inflammatory conditions. TRPA1 is targeted by a series of byproducts of oxidative and nitrative stress, including acrolein, 4-hydroxy-2-nonenal and hydrogen peroxide. Proinflammatory neuropeptides are released from nociceptive nerve terminals after TRPV1/TRPA1 stimulation, thereby causing airway neurogenic inflammation. In addition, the early inflammatory response to cigarette smoke is mediated entirely by neuronal TRPA1. TRPV1 and TRPA1 antagonists may therefore represent potential antitussive and anti-inflammatory therapeutics for respiratory airway diseases.
 ...
PMID:Transient receptor potential channels as novel drug targets in respiratory diseases. 2041 99

The inhalation of reactive gases and vapors can lead to severe damage of the airways and lung, compromising the function of the respiratory system. Exposures to oxidizing, electrophilic, acidic, or basic gases frequently occur in occupational and ambient environments. Corrosive gases and vapors such as chlorine, phosgene, and chloropicrin were used as warfare agents and in terrorist acts. Chemical airway exposures are detected by the olfactory, gustatory, and nociceptive sensory systems that initiate protective physiological and behavioral responses. This review focuses on the role of airway nociceptive sensory neurons in chemical sensing and discusses the recent discovery of neuronal receptors for reactive chemicals. Using physiological, imaging, and genetic approaches, Transient Receptor Potential (TRP) ion channels in sensory neurons were shown to respond to a wide range of noxious chemical stimuli, initiating pain, respiratory depression, cough, glandular secretions, and other protective responses. TRPA1, a TRP ion channel expressed in chemosensory C-fibers, is activated by almost all oxidizing and electrophilic chemicals, including chlorine, acrolein, tear gas agents, and methyl isocyanate, the highly noxious chemical released in the Bhopal disaster. Chemicals likely activate TRPA1 through covalent protein modification. Animal studies using TRPA1 antagonists or TRPA1-deficient mice confirmed the role of TRPA1 in chemically induced respiratory reflexes, pain, and inflammation in vivo. New research shows that sensory neurons are not merely passive sensors of chemical exposures. Sensory channels such as TRPA1 are essential for maintenance of airway inflammation in asthma and may contribute to the progression of airway injury following high-level chemical exposures.
 ...
PMID:Sensory detection and responses to toxic gases: mechanisms, health effects, and countermeasures. 2060 31


1 2 3 4 Next >>