Subtypes of vagal afferent C‐fibres in guinea‐pig lungs

Undem, Bradley J.; Chuaychoo, Benjamas; Lee, M. G.; Weinreich, Daniel; Myers, Allen C.; Kollárik, Marián

doi:10.1113/jphysiol.2003.060079

Cited by 233 publications

(277 citation statements)

References 36 publications

(55 reference statements)

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“…The matrix appears uncoupled from the underlying smooth muscle, as muscle contraction does not activate the cough receptors or alter their excitability. Epithelial cells (including neuroendocrine cells) and epithelial-derived signaling molecules also appear to play no role in transducing cough receptor reflexes [based on the physical dissociation of the cough receptors from the epithelium, the lack of effect of epithelium removal on cough receptor activation and evoked cough, and cough receptor insensitivity to 5-HT, ATP, 15-HETE, and adenosine (Canning et al, 2006a;Carr et al, 2001;Chou et al;2008;Hwang et al, 2000;Kwong et al, 2008;Mazzone and Canning, 2002;Undem et al, 2004)]. …”

Section: Discussionmentioning

confidence: 99%

Selective Expression of a Sodium Pump Isozyme by Cough Receptors and Evidence for Its Essential Role in Regulating Cough

Mazzone¹,

Reynolds²,

Mori³

et al. 2009

J. Neurosci.

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107

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We have identified a distinct subtype of airway vagal afferent nerve that plays an essential role in regulating the cough reflex. These afferents are exquisitely sensitive to punctate mechanical stimuli, acid, and decreases in extracellular chloride concentrations, but are insensitive to capsaicin, bradykinin, histamine, adenosine, serotonin, or changes in airway intraluminal pressures. In this study we used intravital imaging, retrograde neuronal tracing, and electrophysiological analyses to characterize the structural basis for their peculiar mechanical sensitivity and to further characterize the regulation of their excitability. In completing these experiments, we uncovered evidence for an essential role of an isozyme of Na ϩ -K ϩ ATPase in regulating cough. These vagal sensory neurons arise bilaterally from the nodose ganglia and are selectively and brilliantly stained intravitally with the styryl dye FM2-10. Cough receptor terminations are confined and adherent to the extracellular matrix separating the airway epithelium and smooth muscle layers, a site of extensive remodeling in asthma and chronic obstructive pulmonary disease. The cough receptor terminals uniquely express the ␣ 3 subunit of Na ϩ -K ϩ ATPase. Intravital staining of cough receptors by FM2-10, cough receptor excitability in vitro, and coughing in vivo are potently and selectively inhibited by the sodium pump inhibitor ouabain. These data provide the first detailed morphological description of the peripheral terminals of the sensory nerves regulating cough and identify a selective molecular target for their modulation.

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Section: Discussionmentioning

confidence: 99%

Selective Expression of a Sodium Pump Isozyme by Cough Receptors and Evidence for Its Essential Role in Regulating Cough

Mazzone¹,

Reynolds²,

Mori³

et al. 2009

J. Neurosci.

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107

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“…Nodose C-fibers primarily innervate structures within the lungs and are less likely to express neurokinins, but 100 % of them express P2X receptors in both their terminals and cell bodies as indicated by their responsiveness to α,β-methylene-ATP (Undem, Chuaychoo et al 2004). Nodose sensory neuron terminals are not in the epithelium, but are labeled by dye in the submucosa (Hunter and Undem 1999).…”

Section: Airway Receptors: Better Methods Reveal More Diversitymentioning

confidence: 99%

“…Virtually all of the tracheal epithelial terminals tested arose from jugular C-fibers that innervate the larynx, trachea and bronchus. About 60% of the jugular C-fibers with epithelia terminals expressed SP (Hunter and Undem 1999), and none of them expressed P2X receptors (Undem, Chuaychoo et al 2004). The jugular afferents include C and Aδ axons, and these respond differentially to capsaicin (mainly C fibers) and hypertonic saline (mainly Aδ axons (Fig.…”

Section: Airway Receptors: Better Methods Reveal More Diversitymentioning

confidence: 99%

Parasympathetic control of airway submucosal glands: Central reflexes and the airway intrinsic nervous system

Wine

2007

Autonomic Neuroscience

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Airway submucosal glands produce the mucus that lines the upper airways to protect them against insults. This review summarizes evidence for two forms of gland secretion, and hypothesizes that each is mediated by different but partially overlapping neural pathways. Airway innate defense comprises low level gland secretion, mucociliary clearance and surveillance by airway-resident phagocytes to keep the airways sterile in spite of nearly continuous inhalation of low levels of pathogens. Gland secretion serving innate defense is hypothesized to be under the control of intrinsic (peripheral) airway neurons and local reflexes, and these may depend disproportionately on noncholinergic mechanisms, with most secretion being produced by VIP and tachykinins. In the genetic disease cystic fibrosis, airway glands no longer secrete in response to VIP alone and fail to show the synergy between VIP, tachykinins and ACh that is observed in normal glands. The consequent crippling of the submucosal gland contribution to innate defense may be one reason that cystic fibrosis airways are infected by mucus-resident bacteria and fungi that are routinely cleared from normal airways. By contrast, the acute (emergency) airway defense reflex is centrally mediated by vagal pathways, is primarily cholinergic, and stimulates copious volumes of gland mucus in response to acute, intense challenges to the airways, such as those produced by very vigorous exercise or aspiration of foreign material. In cystic fibrosis, the acute airway defense reflex can still stimulate the glands to secrete large amounts of mucus, although its properties are altered. Importantly, treatments that recruit components of the acute reflex, such as inhalation of hypertonic saline, are beneficial in treating cystic fibrosis airway disease. The situation for recipients of lung transplants is the reverse; transplanted airways retain the airway intrinsic nervous system but lose centrally mediated reflexes. The consequences of this for gland secretion and airway defense are poorly understood, but it is possible that interventions to modify submucosal gland secretion in transplanted lungs might have therapeutic consequences.

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“…Recent studies identified Aδ afferent neurons as essential in cough in the anesthetized guinea-pig, and the term "cough receptors" (Widdicombe 1954a(Widdicombe , 1954b was re-introduced (Canning et al 2004;Mazzone et al 2005Mazzone et al , 2009) for the following reasons. (i) Conduction velocity of "cough receptors" is much slower than that of rapidly adapting stretch receptors (RARs) or slowly adapting stretch receptors (SARs) (Bergren and Sampson 1982;Ho et al 2001;Canning et al 2004;Undem et al 2004), but much faster than that of C-fibers (Riccio et al 1996;Ho et al 2001). These "cough receptors" can also be differentiated from intrapulmonary RARs and SARs (Sano et al 1992;Schelegle and Green 2003;Widdicombe 2003), by their insensitivity to smooth muscle contractions and/or lung distension (Fox et al 1993;Canning et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Potent cough suppression by physiologically active substance in human plasma

Akaike¹,

Ito²,

Ogawa³

et al. 2014

gpb

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Abstract. Human plasma contains wide variety of bioactive proteins that have proved essential in therapeutic discovery. However, many human plasma proteins remain orphans with unknown biological functions. Evidences suggest that some plasma components target the respiratory system. In the present study we adapted heparin affinity chromatography to fractionate human plasma for functional bioassay. Fractions from pooled human plasma yielded particular plasma fractions with strong cough suppressing effects. Purification yielded a fraction that was finally identified as an activated blood coagulation factor XIa (fXIa) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI/TOF-MS). The fraction almost completely suppressed coughs induced by either chemical or mechanical stimulation applied to larynx or bifurcation of guinea-pig trachea. Cough suppressing effect of the fraction and commercially available fXIa were one million times stronger than codeine and codeine only partially suppressed the mechanically triggered coughing in animal model. Recent reviews highlighted prominent shortcomings of current available antitussives, including narcotic opioids such as codeine and their unpleasant or intolerable side effects. Therefore, safer and more effective cough suppressants would be welcome, and present findings indicate that fXIa in human plasma as a very promising, new therapeutic candidate for effective antitussive action.

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Subtypes of vagal afferent C‐fibres in guinea‐pig lungs

Cited by 233 publications

References 36 publications

Selective Expression of a Sodium Pump Isozyme by Cough Receptors and Evidence for Its Essential Role in Regulating Cough

Selective Expression of a Sodium Pump Isozyme by Cough Receptors and Evidence for Its Essential Role in Regulating Cough

Parasympathetic control of airway submucosal glands: Central reflexes and the airway intrinsic nervous system

Potent cough suppression by physiologically active substance in human plasma

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