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Sensory Nerves in Lung and Airways

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ABSTRACT

Sensory nerves innervating the lung and airways play an important role in regulating various cardiopulmonary functions and maintaining homeostasis under both healthy and disease conditions. Their activities conducted by both vagal and sympathetic afferents are also responsible for eliciting important defense reflexes that protect the lung and body from potential health‐hazardous effects of airborne particulates and chemical irritants. This article reviews the morphology, transduction properties, reflex functions, and respiratory sensations of these receptors, focusing primarily on recent findings derived from using new technologies such as neural immunochemistry, isolated airway‐nerve preparation, cultured airway neurons, patch‐clamp electrophysiology, transgenic mice, and other cellular and molecular approaches. Studies of the signal transduction of mechanosensitive afferents have revealed a new concept of sensory unit and cellular mechanism of activation, and identified additional types of sensory receptors in the lung. Chemosensitive properties of these lung afferents are further characterized by the expression of specific ligand‐gated ion channels on nerve terminals, ganglion origin, and responses to the action of various inflammatory cells, mediators, and cytokines during acute and chronic airway inflammation and injuries. Increasing interest and extensive investigations have been focused on uncovering the mechanisms underlying hypersensitivity of these airway afferents, and their role in the manifestation of various symptoms under pathophysiological conditions. Several important and challenging questions regarding these sensory nerves are discussed. Searching for these answers will be a critical step in developing the translational research and effective treatments of airway diseases. Published 2014. Compr Physiol 4:287‐324, 2014.

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Figure 1. Figure 1. Laryngeal sensory receptors exhibiting respiratory‐related activities. (A) A schematic drawing of the experimental setup for studying laryngeal afferents in anesthetized dog. Mouth and nares are sealed around tube (u). When the side arm of the tracheal cannula (v) is occluded, the dog breathes through the upper airway: when v is open and u occluded the dog breathes through the tracheostomy, upper airway occlusion is performed by closing both u and v, and tracheal occlusion by obstructing the tracheal cannula at (t) by inflating the cuff of a Foley catheter. Electrodes record the action potentials from “single” fibers isolated from the peripheral cut end of the internal branch of the superior laryngeal nerve (S.L.N.). In all records (B, C, and D), upper panel: upper airway breathing changed to tracheostomy breathing at the arrow; middle panel: upper airway breathing and upper airway occlusion; lower panels: tracheostomy breathing and tracheal occlusion. (B) A laryngeal “pressure” receptor responding to negative transmural pressure. Note that maximal activity is seen during upper airway occlusion, in which the larynx is subjected to increased negative pressure. (C) A cold (“flow”) receptor (see explanations in the text). Note that a phasic inspiratory activity is present only when air flows through the larynx. (D) A “drive” receptor responding to distortion due to the action of upper airway muscles. Note that an inspiratory activity is present and is not influenced by flow. The inspiratory activity and duration increase when the inspiratory “drive” increases in response to airway occlusion. (E) Distribution (percentage) of the three types of laryngeal receptors recorded in this study (n = 110). Note that pressure receptors are the most frequently occurring type. A.P., action potentials; Pes, esophageal pressure; Ptr, tracheal pressure; kPa, kilopascal. [Modified, with permission, from reference ().]
Figure 2. Figure 2. Sensitivity of tracheal cough receptors to acid and mechanical probing. (A) A schematic diagram of the preparation used to study cough in anesthetized guinea pigs. Pressure changes at the tracheal cannula (PT) are used to monitor respiration and cough. The extrathoracic trachea was continuously perfused with Krebs bicarbonate buffer throughout the experiments. (B) A representative trace of coughing initiated by mechanically probing the tracheal mucosa. Cough is defined visually by the experimenter, and based on the magnitude of the inspiratory (appearing as a downward deflection in PT) and expiratory (>500% of expiratory pressure during tidal breathing) efforts. (C) A representative trace of citric acid‐evoked coughing. Citric acid (0.001‐2 mol/L) was applied topically in 100 μL aliquots directly to the tracheal mucosa. Concentrations of citric acid ≥0.03 mol/L consistently evoked 1 to 2 coughs within seconds of application. (D) Cumulative coughs evoked by citric acid (n = 83), sodium citrate (n = 3), and HCl (n = 3). Note that the tussive effect of citric acid on coughing is mimicked by HCl but not by sodium citrate. [Modified, with permission, from references ().]
Figure 3. Figure 3. A macro‐view of interrelationships of mechanoreceptors in one third of a rabbit tracheal smooth muscle (15×3.3 = 49.5 mm2). The tissue is immunohistochemically stained by antibodies for Na+/K+‐ATPase to visualize the immunoreactive structures under a fluorescent microscope. Thirty one receptor structures are identified (some pointed by arrows). These structures are regularly spaced and have varied shapes and orientations. Most receptor structures have their long axis roughly running transversely. This figure not only shows detailed information of the “tree” (please see the online figure for enlarged views) but also global information for the “forest.”
Figure 4. Figure 4. Confocal microscopic views of a network structure of SP‐IR nerve fibers in bronchial mucosa of a pig (bar = 50 μm). Large panel, a lumenal projection, shows nerve terminals in the mucosa have swollen varicosities. Right and bottom panels are cross‐sectional projections, where nerves in the epithelium converge into bundles as they enter the lamina propria. Some bundles run longitudinally along the airway below the epithelium (arrow) and the others penetrate deeper (arrowhead). [Modified, with permission, from reference ().]
Figure 5. Figure 5. NEBs are richly innervated by different types of nerve fibers. They are taking different shapes and immune reactive to a variety of antibodies. They can be cylindrical (top), ball shaped (bottom left), or irregular (bottom right). Top figure, immunocytochemical triple staining for VGLUT2 (vesicular glutamate transporter 2; red), CB (calbindin D28 k; green) and MBP (myelin basic protein; blue), shows that a NEB is contacted by a CB‐IR vagal nodose sensory fiber that is surrounded by myelin sheath (MBP‐IR; open arrowheads). VGLUT2 IR is seen in nerve terminals between the NEB cells. Bottom left, triple stained for VGLUT2 (red), CGRP (blue), and nNOS (neuronal nitric oxide synthase; green), shows a NEB receiving nNOS‐IR nerve fibers. Bottom right, triple stained for VGLUT2 (red), CGRP (blue), and CB (green), shows that a NEB is contacted by a CGRP+/CB+/VGLUT2+ spinal sensory fiber (open arrow) and red nerve fibers (arrowheads) surround a NEB cell (asterisk). [Modified, with performance, from reference ().]
Figure 6. Figure 6. A schematic model of a sensory unit with two encoders (left) and a double staining approach to illustrate a sensory unit identified in a rabbit medium sized airway (700 μm; right). The sensory unit's functional structures can be divided into four regions: transduction, summation, encoding, and interaction/transmission. Mechanoelectrical transduction occurs in the transduction region. Mechanical force opens stretch‐activated cation channels, causing cations influx and membrane depolarization in the terminal (inset A). These local depolarizations summate temporally and spatially in the summation region. Summation determines the size of generator potential (GP) at the potential generating site (PGS) in the encoding region (inset B). When the GP reaches threshold, action potentials (AP) are produced by opening and closing of Na+ and K+ channels; the ion disturbance is restored by a Na+ pump (inset B). AP discharge at the PGS is proportional to the GP, which, in turn, is directly related to the force acting on the receptor terminals (inset C). At the interaction and transmission region, AP reaching the bifurcation will propagate antidromically toward the other encoder for interaction, and centrally for further information processing (see arrows). The sensory unit integrates information by an amplitude modulating mechanism before encoding, and by a frequency modulating mechanism after encoding. At the right the sensory structures are labeled by Na+/K+‐ATPase (red), and myelin basic protein (MBP; green) antibodies; yellow parts show costaining (red+green). The parent axon of the sensory unit is running from the bottom up at the right side. It gives off two branches (left and right) indicated by an arrow head, respectively. The left branch further divides into two. Clearly, the axon demyelinated at the junction (pointed by the arrow) to the sensory device (encoder, pure red portions without costain with MBP), where action potentials are generated. The white bar is 50 μm in length. Please note that two encoders in the unit can be homogenous (both encoders being SAR or RAR) or heterogeneous (that is one encoder is SAR and the other is RAR or DAR; or one encoder is RAR and the other is DAR). [Left figure is adapted, with permission, from reference ().]
Figure 7. Figure 7. Activity of an SAR unit with two encoders: one gives high discharge frequency with a high threshold (encoder H), whereas the other produces low discharge frequency with a low threshold (encoder L). A is control, where the unit activity is from both encoders; B is after blocking encoder L with lidocaine. Thus, the unit activity is from encoder H only. The bar in A indicates where unit activity switches from encoder H to encoder L. The maximal frequency of encoder L is somewhere between the frequency at the bar and at the peak (the maximal frequency of encoder H). The arrow in B indicates where discharge of encoder H is about to exceed that of encoder L. Drawing two vertical lines crossing figure A at the arrow in B and at the beginning of the bar in A divides the time into three sections. The activity during deflation (first and third sections) is determined by encoder L, whereas the activity during inflation (second section) is determined by encoder H. Thus, the pacemaker switches back‐and‐forth between the two encoders within a ventilator cycle. Please see Fig. for a schematic illustration for interaction of two encoders in a unit. IMP, impulses; Paw, airway pressure. [Adapted, with permission, from reference ().]
Figure 8. Figure 8. Coexpression of transient receptor potential vanilloid type 1 channel (TRPV1) and calcitonin gene‐related peptide (CGRP) in airway sensory nerves. Confocal images showing TRPV1 (A, D) and CGRP (B, E)‐immunoreactive axons in the guinea‐pig trachea (A‐C) and alveoli (D‐F). Merged images illustrating co‐localization of TRPV1 and CGRP are also shown (C, F). In the epithelium of the trachea (A‐C), a fine network of coexisting TRPV1‐ and CGRP‐immunoreactive axons is visible, derived from the subepithelial plexus. Arrows indicate double‐labeled axons. In the lung, TRPV1‐immunoreactive axons (arrows) are also visible within parenchymal lung tissue (D), and extensively colocalize with CGRP (E, F). Scale bars are 20 μm (A‐C) and 100 μm (D‐F). [Modified, with permission, from reference ().]
Figure 9. Figure 9. Schematic illustration of the function of TRPV1‐expressing sensory nerves and their interaction with other cell types in airway mucosa. SO2, sulfur dioxide; EO, eosinophil; LO, lipoxygenase; PGE2, prostaglandin E2; BK, bradykinin; NGF, nerve growth factor; TKs, tachykinins; CGRP, calcitonin gene‐related peptide. See text for details. [Modified, with permission, from reference ().]
Figure 10. Figure 10. Acid‐evoked whole cell inward currents and inhibition by amiloride and capsazepine in rat vagal pulmonary sensory neurons. (A) Low pH with increasing proton concentrations are applied for 6 s (as indicated by the horizontal bars) to four different neurons. Note distinct pH sensitivities and different phenotypes of inward currents in response to acidic challenges. (B) Effect of 2‐min pretreatments with amiloride (100 μmol/L) and capsazepine (CPZ; 10 μmol/L) on acid (pH 5.5)‐evoked inward currents. (C) Acid (pH 6.5‐5.5)‐evoked both transient and sustaining components are inhibited by amiloride and CPZ. * P < 0.05 as compared with the corresponding control. [Modified, with permission, from reference ().]
Figure 11. Figure 11. Specificity of blocking effect of hexamethonium on pulmonary C‐fiber response to cigarette smoke. The location of the sensory terminal was identified in the right cardiac lobe of an anesthetized and open‐chest dog. Left: control responses; right: responses 5 min after hexamethonium (0.8 mg/kg, i.v.). Above: capsaicin (2 μg/kg) injected into catheter at first arrow and flushed into right atrium at second. Below: 120 mL high‐nicotine cigarette smoke delivered to lungs in a single ventilatory cycle; note sudden increase in inspiratory CO2 concentration. Arrow, whose position has been adjusted to correct for time lag of CO2 analyzer, indicates arrival of smoke in airways. Note that hexamethonium decreased mean arterial blood pressure by about 45 mmHg. Interval of 20 min elapsed between injection of capsaicin and inhalation of smoke. AP, action potentials; CO2, CO2 concentration in trachea; ABP, arterial blood pressure. [Modified, with permission, from reference ().]
Figure 12. Figure 12. Effect of increasing temperature on the response of vagal pulmonary sensory neurons to capsaicin (Cap). (A) Experimental records illustrating that both membrane depolarization and number of action potentials evoked by Cap (1 μmol/L, 4 s) were increased in current‐clamp mode when the temperature was increased from 36.0 to 40.6°C in a jugular neuron; the response recovered when the temperature was returned. V m, membrane potential; T, temperature. (B) Group data for the baseline membrane potential at the two different temperatures: BT, body temperature (35.7 ± 0.09°C); HT, hyperthermic temperature (40.5 ± 0.11°C). (C) Group data for Cap (0.3‐1 μmol/L, 1‐8 s)‐evoked membrane depolarization, ΔV m (Cap), at the two temperatures. (D) Experimental records illustrating that the Cap (0.3 μmol/L, 2 s)‐evoked current was increased when the temperature was increased from 35.8 to 40.6°C in a nodose neuron in voltage‐clamp mode. (E) Group data for the Cap (0.3 μmol/L, 2‐4 s)‐evoked current response (ΔI) at the two different temperatures. (F) Experimental records illustrating that Cap (0.1 μmol/L, 1 s)‐evoked current was increased progressively in a jugular neuron when temperature was elevated from 35.9 to 40.4°C by successive steps of ∼1.5°C. (G) Group data for the Cap (0.1 or 0.3 μmol/L, 1‐3 s)‐evoked current response at the five different temperatures as indicated. * P < 0.05 and ** P < 0.01 compared with the corresponding response at BT (36°C). [Modified, with permission, from reference ().]
Figure 13. Figure 13. Voltage shifts of TRPV1 activation curves by temperature and capsaicin. (A) Voltage dependence of the open probability of TRPV1 channels at 17°C (triangles) and 42°C (circles). The inset shows the respective current families obtained from a voltage‐step protocol (holding potential 0 mV, voltage steps of 100‐ms duration from –120 to +160 mV in 40‐mV increments). Note the leftward shift of the activation curve toward negative potentials by increasing the temperature. (B) The same voltage protocol as in A, and the temperature was held at 24°C. Activation of TRPV1 by capsaicin (100 nmol/L; circles) also caused a pronounced leftward shift of the activation curve. [Modified, with permission, from reference ().]
Figure 14. Figure 14. Expression of P2X2 and P2X3 receptors in capsaicin‐sensitive pulmonary neurons isolated from nodose ganglion but not from jugular or dorsal root ganglia. (A) Inward currents were elicited by α,β‐methylene ATP (30 μmol/L; bars) in pulmonary (DiI‐labeled) nodose ganglion (left), jugular ganglion (middle), and dorsal root ganglion (DRG; right) neurons. Neurons were capsaicin sensitive. Standard ruptured patch whole cell recordings were made at room temperature. Holding potential was –60 mV. (B) Comparison of peak α,β‐methylene ATP‐elicited current density revealed a significant overall difference among the three populations of neurons (1‐way ANOVA, P < 0.001); and significant differences between nodose (n = 10) and jugular (n = 14) populations (P < 0.05; Tukey test) and between nodose and DRG (n = 7) populations (P < 0.05). Single‐cell RT‐PCR analysis of 24 lung‐specific nodose neurons (C), 22 lung‐specific jugular neurons (D), and 13 lung‐specific DRG neurons (E). Message for P2X2 and P2X3 was analyzed in TRPV1‐positive neurons. β‐actin was used as a positive control. Top, middle, and bottom bands of the ladder represent 300, 200, and 100 bp, respectively. Lanes +, –, and B indicate positive control from whole trigeminal ganglion, no‐RT control, and a representative bath control, respectively. [Modified, with permission, from reference ().]
Figure 15. Figure 15. Involvement of cholinergic reflex in the bronchoconstriction evoked by increasing airway temperature in patients with asthma. (A) Representative responses of specific airway resistance (SRaw) to hyperventilation of humidified room air (open circles; 20‐22°C, 65‐75% relative humidity) and hot air (closed circles; 49°C, 75‐80% relative humidity) in an asthmatic patient (left) and a healthy subject (right). Each point represents the data averaged over four consecutive breaths. During hyperventilation (shaded bars), the subjects breathed at 40% of maximal voluntary ventilation for 4 min of a gas mixture of 4.5% CO2 balance air. Only one experiment was performed in each subject on the same day. (B) Effect of pretreatment with ipratropium aerosol (500 mg; 2.5 ml of 0.02% solution) on hot humid air‐induced bronchoconstriction in asthmatic patients. Left: representative SRaw responses obtained in an asthmatic patient. Ipratropium and placebo aerosols were administered in a double‐blind fashion, and the response to hot air challenge was tested 90 min after the aerosol inhalation; the two tests were performed about a week apart. Right: average data collected from all six asthmatic patients comparing the peak SRaw responses to hot humid air challenge after ipratropium and placebo pretreatments. Baseline and peak SRaw were averaged over eight and four consecutive breaths before and after hyperventilation of hot air, respectively, in each subject. * denotes significantly different (P < 0.05) from the baseline. # denotes significant difference (P < 0.05) comparing the corresponding data between ipratropium and placebo pretreatments. Data are means ± SEM. [Modified, with permission, from reference ().]
Figure 16. Figure 16. Effect of ovalbumin sensitization on TRPV1 expression in neurofilament (NF)‐positive and NF‐negative neurons with DiI labeling in nodose ganglion. (A) Percentages of NF‐positive and NF‐negative neurons in DiI‐labeled pulmonary neurons. (B) Percentages of TRPV1‐positive neurons in NF‐positive and NF‐negative neurons labeled with DiI. Open bars, average data obtained from control rats (n = 4); filled bars, sensitized rats (n = 4). Values are means ± SEM. * denotes P < 0.05, significant difference in responses between control and sensitized rats. (C) Representative 20× photographs of triple‐labeling immunohistochemistry of NF, DiI, and TRPV1 in nodose ganglia of both control and sensitized rats. The first column from left, NF staining in blue; second, DiI labeling in red; third, TRPV1 staining in green; fourth, the merged image. Arrows are added to depict colocalization of NF staining, DiI labeling and TRPV1 staining in the same neurons. Asterisk depicts the neuron with colocalization of NF staining and DiI labeling, but without TRPV1 staining. Scale bar, 100 μm. [Modified, with permission, from reference ().]
Figure 17. Figure 17. Sympathetic afferent activity recorded from a multifiber preparation in the right second thoracic white ramus. The afferents respond to increases in tracheal pressure during positive‐pressure ventilation. Signal‐to‐noise ratio was electronically enhanced. TP, tracheal pressure; NA, nerve activity. [Modified, with permission, from reference ().]


Figure 1. Laryngeal sensory receptors exhibiting respiratory‐related activities. (A) A schematic drawing of the experimental setup for studying laryngeal afferents in anesthetized dog. Mouth and nares are sealed around tube (u). When the side arm of the tracheal cannula (v) is occluded, the dog breathes through the upper airway: when v is open and u occluded the dog breathes through the tracheostomy, upper airway occlusion is performed by closing both u and v, and tracheal occlusion by obstructing the tracheal cannula at (t) by inflating the cuff of a Foley catheter. Electrodes record the action potentials from “single” fibers isolated from the peripheral cut end of the internal branch of the superior laryngeal nerve (S.L.N.). In all records (B, C, and D), upper panel: upper airway breathing changed to tracheostomy breathing at the arrow; middle panel: upper airway breathing and upper airway occlusion; lower panels: tracheostomy breathing and tracheal occlusion. (B) A laryngeal “pressure” receptor responding to negative transmural pressure. Note that maximal activity is seen during upper airway occlusion, in which the larynx is subjected to increased negative pressure. (C) A cold (“flow”) receptor (see explanations in the text). Note that a phasic inspiratory activity is present only when air flows through the larynx. (D) A “drive” receptor responding to distortion due to the action of upper airway muscles. Note that an inspiratory activity is present and is not influenced by flow. The inspiratory activity and duration increase when the inspiratory “drive” increases in response to airway occlusion. (E) Distribution (percentage) of the three types of laryngeal receptors recorded in this study (n = 110). Note that pressure receptors are the most frequently occurring type. A.P., action potentials; Pes, esophageal pressure; Ptr, tracheal pressure; kPa, kilopascal. [Modified, with permission, from reference ().]


Figure 2. Sensitivity of tracheal cough receptors to acid and mechanical probing. (A) A schematic diagram of the preparation used to study cough in anesthetized guinea pigs. Pressure changes at the tracheal cannula (PT) are used to monitor respiration and cough. The extrathoracic trachea was continuously perfused with Krebs bicarbonate buffer throughout the experiments. (B) A representative trace of coughing initiated by mechanically probing the tracheal mucosa. Cough is defined visually by the experimenter, and based on the magnitude of the inspiratory (appearing as a downward deflection in PT) and expiratory (>500% of expiratory pressure during tidal breathing) efforts. (C) A representative trace of citric acid‐evoked coughing. Citric acid (0.001‐2 mol/L) was applied topically in 100 μL aliquots directly to the tracheal mucosa. Concentrations of citric acid ≥0.03 mol/L consistently evoked 1 to 2 coughs within seconds of application. (D) Cumulative coughs evoked by citric acid (n = 83), sodium citrate (n = 3), and HCl (n = 3). Note that the tussive effect of citric acid on coughing is mimicked by HCl but not by sodium citrate. [Modified, with permission, from references ().]


Figure 3. A macro‐view of interrelationships of mechanoreceptors in one third of a rabbit tracheal smooth muscle (15×3.3 = 49.5 mm2). The tissue is immunohistochemically stained by antibodies for Na+/K+‐ATPase to visualize the immunoreactive structures under a fluorescent microscope. Thirty one receptor structures are identified (some pointed by arrows). These structures are regularly spaced and have varied shapes and orientations. Most receptor structures have their long axis roughly running transversely. This figure not only shows detailed information of the “tree” (please see the online figure for enlarged views) but also global information for the “forest.”


Figure 4. Confocal microscopic views of a network structure of SP‐IR nerve fibers in bronchial mucosa of a pig (bar = 50 μm). Large panel, a lumenal projection, shows nerve terminals in the mucosa have swollen varicosities. Right and bottom panels are cross‐sectional projections, where nerves in the epithelium converge into bundles as they enter the lamina propria. Some bundles run longitudinally along the airway below the epithelium (arrow) and the others penetrate deeper (arrowhead). [Modified, with permission, from reference ().]


Figure 5. NEBs are richly innervated by different types of nerve fibers. They are taking different shapes and immune reactive to a variety of antibodies. They can be cylindrical (top), ball shaped (bottom left), or irregular (bottom right). Top figure, immunocytochemical triple staining for VGLUT2 (vesicular glutamate transporter 2; red), CB (calbindin D28 k; green) and MBP (myelin basic protein; blue), shows that a NEB is contacted by a CB‐IR vagal nodose sensory fiber that is surrounded by myelin sheath (MBP‐IR; open arrowheads). VGLUT2 IR is seen in nerve terminals between the NEB cells. Bottom left, triple stained for VGLUT2 (red), CGRP (blue), and nNOS (neuronal nitric oxide synthase; green), shows a NEB receiving nNOS‐IR nerve fibers. Bottom right, triple stained for VGLUT2 (red), CGRP (blue), and CB (green), shows that a NEB is contacted by a CGRP+/CB+/VGLUT2+ spinal sensory fiber (open arrow) and red nerve fibers (arrowheads) surround a NEB cell (asterisk). [Modified, with performance, from reference ().]


Figure 6. A schematic model of a sensory unit with two encoders (left) and a double staining approach to illustrate a sensory unit identified in a rabbit medium sized airway (700 μm; right). The sensory unit's functional structures can be divided into four regions: transduction, summation, encoding, and interaction/transmission. Mechanoelectrical transduction occurs in the transduction region. Mechanical force opens stretch‐activated cation channels, causing cations influx and membrane depolarization in the terminal (inset A). These local depolarizations summate temporally and spatially in the summation region. Summation determines the size of generator potential (GP) at the potential generating site (PGS) in the encoding region (inset B). When the GP reaches threshold, action potentials (AP) are produced by opening and closing of Na+ and K+ channels; the ion disturbance is restored by a Na+ pump (inset B). AP discharge at the PGS is proportional to the GP, which, in turn, is directly related to the force acting on the receptor terminals (inset C). At the interaction and transmission region, AP reaching the bifurcation will propagate antidromically toward the other encoder for interaction, and centrally for further information processing (see arrows). The sensory unit integrates information by an amplitude modulating mechanism before encoding, and by a frequency modulating mechanism after encoding. At the right the sensory structures are labeled by Na+/K+‐ATPase (red), and myelin basic protein (MBP; green) antibodies; yellow parts show costaining (red+green). The parent axon of the sensory unit is running from the bottom up at the right side. It gives off two branches (left and right) indicated by an arrow head, respectively. The left branch further divides into two. Clearly, the axon demyelinated at the junction (pointed by the arrow) to the sensory device (encoder, pure red portions without costain with MBP), where action potentials are generated. The white bar is 50 μm in length. Please note that two encoders in the unit can be homogenous (both encoders being SAR or RAR) or heterogeneous (that is one encoder is SAR and the other is RAR or DAR; or one encoder is RAR and the other is DAR). [Left figure is adapted, with permission, from reference ().]


Figure 7. Activity of an SAR unit with two encoders: one gives high discharge frequency with a high threshold (encoder H), whereas the other produces low discharge frequency with a low threshold (encoder L). A is control, where the unit activity is from both encoders; B is after blocking encoder L with lidocaine. Thus, the unit activity is from encoder H only. The bar in A indicates where unit activity switches from encoder H to encoder L. The maximal frequency of encoder L is somewhere between the frequency at the bar and at the peak (the maximal frequency of encoder H). The arrow in B indicates where discharge of encoder H is about to exceed that of encoder L. Drawing two vertical lines crossing figure A at the arrow in B and at the beginning of the bar in A divides the time into three sections. The activity during deflation (first and third sections) is determined by encoder L, whereas the activity during inflation (second section) is determined by encoder H. Thus, the pacemaker switches back‐and‐forth between the two encoders within a ventilator cycle. Please see Fig. for a schematic illustration for interaction of two encoders in a unit. IMP, impulses; Paw, airway pressure. [Adapted, with permission, from reference ().]


Figure 8. Coexpression of transient receptor potential vanilloid type 1 channel (TRPV1) and calcitonin gene‐related peptide (CGRP) in airway sensory nerves. Confocal images showing TRPV1 (A, D) and CGRP (B, E)‐immunoreactive axons in the guinea‐pig trachea (A‐C) and alveoli (D‐F). Merged images illustrating co‐localization of TRPV1 and CGRP are also shown (C, F). In the epithelium of the trachea (A‐C), a fine network of coexisting TRPV1‐ and CGRP‐immunoreactive axons is visible, derived from the subepithelial plexus. Arrows indicate double‐labeled axons. In the lung, TRPV1‐immunoreactive axons (arrows) are also visible within parenchymal lung tissue (D), and extensively colocalize with CGRP (E, F). Scale bars are 20 μm (A‐C) and 100 μm (D‐F). [Modified, with permission, from reference ().]


Figure 9. Schematic illustration of the function of TRPV1‐expressing sensory nerves and their interaction with other cell types in airway mucosa. SO2, sulfur dioxide; EO, eosinophil; LO, lipoxygenase; PGE2, prostaglandin E2; BK, bradykinin; NGF, nerve growth factor; TKs, tachykinins; CGRP, calcitonin gene‐related peptide. See text for details. [Modified, with permission, from reference ().]


Figure 10. Acid‐evoked whole cell inward currents and inhibition by amiloride and capsazepine in rat vagal pulmonary sensory neurons. (A) Low pH with increasing proton concentrations are applied for 6 s (as indicated by the horizontal bars) to four different neurons. Note distinct pH sensitivities and different phenotypes of inward currents in response to acidic challenges. (B) Effect of 2‐min pretreatments with amiloride (100 μmol/L) and capsazepine (CPZ; 10 μmol/L) on acid (pH 5.5)‐evoked inward currents. (C) Acid (pH 6.5‐5.5)‐evoked both transient and sustaining components are inhibited by amiloride and CPZ. * P < 0.05 as compared with the corresponding control. [Modified, with permission, from reference ().]


Figure 11. Specificity of blocking effect of hexamethonium on pulmonary C‐fiber response to cigarette smoke. The location of the sensory terminal was identified in the right cardiac lobe of an anesthetized and open‐chest dog. Left: control responses; right: responses 5 min after hexamethonium (0.8 mg/kg, i.v.). Above: capsaicin (2 μg/kg) injected into catheter at first arrow and flushed into right atrium at second. Below: 120 mL high‐nicotine cigarette smoke delivered to lungs in a single ventilatory cycle; note sudden increase in inspiratory CO2 concentration. Arrow, whose position has been adjusted to correct for time lag of CO2 analyzer, indicates arrival of smoke in airways. Note that hexamethonium decreased mean arterial blood pressure by about 45 mmHg. Interval of 20 min elapsed between injection of capsaicin and inhalation of smoke. AP, action potentials; CO2, CO2 concentration in trachea; ABP, arterial blood pressure. [Modified, with permission, from reference ().]


Figure 12. Effect of increasing temperature on the response of vagal pulmonary sensory neurons to capsaicin (Cap). (A) Experimental records illustrating that both membrane depolarization and number of action potentials evoked by Cap (1 μmol/L, 4 s) were increased in current‐clamp mode when the temperature was increased from 36.0 to 40.6°C in a jugular neuron; the response recovered when the temperature was returned. V m, membrane potential; T, temperature. (B) Group data for the baseline membrane potential at the two different temperatures: BT, body temperature (35.7 ± 0.09°C); HT, hyperthermic temperature (40.5 ± 0.11°C). (C) Group data for Cap (0.3‐1 μmol/L, 1‐8 s)‐evoked membrane depolarization, ΔV m (Cap), at the two temperatures. (D) Experimental records illustrating that the Cap (0.3 μmol/L, 2 s)‐evoked current was increased when the temperature was increased from 35.8 to 40.6°C in a nodose neuron in voltage‐clamp mode. (E) Group data for the Cap (0.3 μmol/L, 2‐4 s)‐evoked current response (ΔI) at the two different temperatures. (F) Experimental records illustrating that Cap (0.1 μmol/L, 1 s)‐evoked current was increased progressively in a jugular neuron when temperature was elevated from 35.9 to 40.4°C by successive steps of ∼1.5°C. (G) Group data for the Cap (0.1 or 0.3 μmol/L, 1‐3 s)‐evoked current response at the five different temperatures as indicated. * P < 0.05 and ** P < 0.01 compared with the corresponding response at BT (36°C). [Modified, with permission, from reference ().]


Figure 13. Voltage shifts of TRPV1 activation curves by temperature and capsaicin. (A) Voltage dependence of the open probability of TRPV1 channels at 17°C (triangles) and 42°C (circles). The inset shows the respective current families obtained from a voltage‐step protocol (holding potential 0 mV, voltage steps of 100‐ms duration from –120 to +160 mV in 40‐mV increments). Note the leftward shift of the activation curve toward negative potentials by increasing the temperature. (B) The same voltage protocol as in A, and the temperature was held at 24°C. Activation of TRPV1 by capsaicin (100 nmol/L; circles) also caused a pronounced leftward shift of the activation curve. [Modified, with permission, from reference ().]


Figure 14. Expression of P2X2 and P2X3 receptors in capsaicin‐sensitive pulmonary neurons isolated from nodose ganglion but not from jugular or dorsal root ganglia. (A) Inward currents were elicited by α,β‐methylene ATP (30 μmol/L; bars) in pulmonary (DiI‐labeled) nodose ganglion (left), jugular ganglion (middle), and dorsal root ganglion (DRG; right) neurons. Neurons were capsaicin sensitive. Standard ruptured patch whole cell recordings were made at room temperature. Holding potential was –60 mV. (B) Comparison of peak α,β‐methylene ATP‐elicited current density revealed a significant overall difference among the three populations of neurons (1‐way ANOVA, P < 0.001); and significant differences between nodose (n = 10) and jugular (n = 14) populations (P < 0.05; Tukey test) and between nodose and DRG (n = 7) populations (P < 0.05). Single‐cell RT‐PCR analysis of 24 lung‐specific nodose neurons (C), 22 lung‐specific jugular neurons (D), and 13 lung‐specific DRG neurons (E). Message for P2X2 and P2X3 was analyzed in TRPV1‐positive neurons. β‐actin was used as a positive control. Top, middle, and bottom bands of the ladder represent 300, 200, and 100 bp, respectively. Lanes +, –, and B indicate positive control from whole trigeminal ganglion, no‐RT control, and a representative bath control, respectively. [Modified, with permission, from reference ().]


Figure 15. Involvement of cholinergic reflex in the bronchoconstriction evoked by increasing airway temperature in patients with asthma. (A) Representative responses of specific airway resistance (SRaw) to hyperventilation of humidified room air (open circles; 20‐22°C, 65‐75% relative humidity) and hot air (closed circles; 49°C, 75‐80% relative humidity) in an asthmatic patient (left) and a healthy subject (right). Each point represents the data averaged over four consecutive breaths. During hyperventilation (shaded bars), the subjects breathed at 40% of maximal voluntary ventilation for 4 min of a gas mixture of 4.5% CO2 balance air. Only one experiment was performed in each subject on the same day. (B) Effect of pretreatment with ipratropium aerosol (500 mg; 2.5 ml of 0.02% solution) on hot humid air‐induced bronchoconstriction in asthmatic patients. Left: representative SRaw responses obtained in an asthmatic patient. Ipratropium and placebo aerosols were administered in a double‐blind fashion, and the response to hot air challenge was tested 90 min after the aerosol inhalation; the two tests were performed about a week apart. Right: average data collected from all six asthmatic patients comparing the peak SRaw responses to hot humid air challenge after ipratropium and placebo pretreatments. Baseline and peak SRaw were averaged over eight and four consecutive breaths before and after hyperventilation of hot air, respectively, in each subject. * denotes significantly different (P < 0.05) from the baseline. # denotes significant difference (P < 0.05) comparing the corresponding data between ipratropium and placebo pretreatments. Data are means ± SEM. [Modified, with permission, from reference ().]


Figure 16. Effect of ovalbumin sensitization on TRPV1 expression in neurofilament (NF)‐positive and NF‐negative neurons with DiI labeling in nodose ganglion. (A) Percentages of NF‐positive and NF‐negative neurons in DiI‐labeled pulmonary neurons. (B) Percentages of TRPV1‐positive neurons in NF‐positive and NF‐negative neurons labeled with DiI. Open bars, average data obtained from control rats (n = 4); filled bars, sensitized rats (n = 4). Values are means ± SEM. * denotes P < 0.05, significant difference in responses between control and sensitized rats. (C) Representative 20× photographs of triple‐labeling immunohistochemistry of NF, DiI, and TRPV1 in nodose ganglia of both control and sensitized rats. The first column from left, NF staining in blue; second, DiI labeling in red; third, TRPV1 staining in green; fourth, the merged image. Arrows are added to depict colocalization of NF staining, DiI labeling and TRPV1 staining in the same neurons. Asterisk depicts the neuron with colocalization of NF staining and DiI labeling, but without TRPV1 staining. Scale bar, 100 μm. [Modified, with permission, from reference ().]


Figure 17. Sympathetic afferent activity recorded from a multifiber preparation in the right second thoracic white ramus. The afferents respond to increases in tracheal pressure during positive‐pressure ventilation. Signal‐to‐noise ratio was electronically enhanced. TP, tracheal pressure; NA, nerve activity. [Modified, with permission, from reference ().]
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Corrigendum

 

LuYuan Lee, Jerry Yu. Sensory Nerves in Lung and Airways. Compr Physiol 2014, 4: 287-324. doi: 10.1002/cphy.c130020

Pages numbers called out throughout the article (i.e., “see page xx”) have been corrected to reflect the actual published page numbers instead of the place-holder page numbers from the page proof. The publisher regrets this error.


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Lu‐Yuan Lee, Jerry Yu. Sensory Nerves in Lung and Airways. Compr Physiol 2014, 4: 287-324. doi: 10.1002/cphy.c130020