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J Appl Physiol 101: 986-992, 2006. First published May 4, 2006; doi:10.1152/japplphysiol.00161.2006
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HIGHLIGHTED TOPIC
Reflexes From the Lungs and Airways

Pulmonary sensory and reflex responses in the mouse

J. W. Zhang,1 J. F. Walker,1,3 J. Guardiola,1 and J. Yu1,2

1Pulmonary Division, Department of Medicine, and 2Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky; and 3Department of Respiratory Therapy, Bellarmine University, Louisville, Kentucky

Submitted 8 February 2006 ; accepted in final form 17 April 2006


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
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 REFERENCES
 
Mouse model research is proliferating because of its readiness for genetic manipulation. Little is known about pulmonary vagal afferents in mice, however. The purpose of this study was to determine whether their pulmonary afferents are similar to those in large animals. Single-unit activity was recorded in the cervical vagus nerve of anesthetized, open-chest, and mechanically ventilated mice. We evaluated airway sensory activity in 153 single units; 141 were mechanosensitive, with 134 inflation receptors and 7 deflation receptors. The remaining 12 receptors were chemosensitive and mechanically insensitive, showing low basal firing frequency and behaving like C-fiber or high-threshold A{delta}-receptors. In separate studies, phrenic activity was recorded as an index of respiratory drive to assess pulmonary reflexes. Lung inflation produced a typical Hering-Breuer reflex, and intravenous injection of phenylbiguanide produced the typical chemoreflex resulting in apnea, bradycardia, and hypotension. These reflexes were blocked by bilateral vagotomy. We conclude that mice possess a similar set of airway sensors and pulmonary reflexes as typically found in larger animals.

mice; lung receptors; airway sensors; sensory receptor; vagal afferent

AIRWAY RECEPTORS INITIATE important reflexes to regulate breathing and defend against the entry of harmful substances into the lung (6). Their role in cardiopulmonary function has been studied extensively in various animal species, including humans (10). There are four types of airway sensory receptors: slowly adapting pulmonary stretch receptors (SARs) (23, 28), rapidly adapting receptors (RARs) (25), C-fiber receptors (7, 18), and high-threshold A{delta}-receptors (25, 29). The sensory behavior of each receptor type is variable, and each can be further divided into subcategories. These receptors have been found in all mammals examined so far, although their proportions vary among species.

Recently, techniques to genetically modify intact animals have been developed that provide new opportunities to reveal molecular mechanisms of body function (9). The mouse is the most common species for gene manipulation, and its use in physiological studies is rapidly increasing. Such an approach can be expanded into breathing control (11), airway receptor function (17), and vagal afferent nerve neurochemistry (8). Despite great advances in understanding the afferent properties and reflex functions of airway receptors (5, 18), little is known about airway sensory behavior in the mouse. The major goals of the present study were 1) to characterize the airway sensors operating in the mouse by direct electrical recording of single-unit activity in the vagus and 2) to determine whether the mouse produces typical pulmonary reflexes, such as the chemoreflex and Hering-Breuer reflex, in response to pulmonary sensory receptor activators known to operate in other species.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
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General.   Fifty-six mice (C57BL/6, 25–40 g) were anesthetized with pentobarbital sodium (0.5 mg ip). Supplemental doses were administered as needed to prevent eye blink, withdrawal reflexes, and fluctuations in arterial blood pressure. Body temperature was maintained using a heating pad. In addition, the right femoral artery was cannulated with a PE-50 polyethylene tube to monitor arterial blood pressure using a Statham pressure transducer. The femoral vein was also cannulated with polyethylene tubing (PE-10 connected to a syringe with a 30-gauge needle) for administering drugs. A midline incision in the neck was performed for tracheal cannulation with polyethylene tubing (PE-90). The mouse was then mechanically ventilated (model 683, Harvard Apparatus, South Natick, MA), maintaining airway opening pressure at ~10 cmH2O on inspiration. Airway opening pressure was monitored through a port proximal to the Y connection between the ventilator circuit and the endotracheal tube, keeping apparatus dead space to a minimum (~230 µl). Ventilation was set at ~90 cycles/min, with an inspiration-to-expiration ratio of 1:1.3. The chest was opened widely in the midline. For some experiments, the ventilator was fitted with a separate air entrainment jet on the expiratory limb to generate controlled negative end-expiratory pressure. Airway pressure, raw single-unit activity, and rate meter output (spikes/sec) were recorded on a thermochart recorder (Astro-Med, West Warwick, RI). In some experiments, the nerve signals were recorded along with airway pressure by a MacLab computerized data-acquisition system.

Afferent studies.   A series of airway sensory units was recorded using conventional techniques (20, 27). The left or right vagus nerve was isolated from its surrounding connective tissue low in the neck under a dissecting microscope. The nerve was placed on a miniaturized bipolar platinum electrode (0.12-mm outer diameter) and immersed in mineral oil. Nerve activity was fed to a high-impedance probe and Grass band-pass amplifier (HIP 511J, Grass; 30 Hz to 3 kHz) and displayed on a dual-beam storage oscilloscope (model 5113, Tektronix), with audio monitoring through a loudspeaker. Spikes exceeding the selected threshold voltage were consecutively counted in 0.1-s bin widths by a rate meter analyzer. The airway sensors encountered by direct vagal nerve recording were classified according to their discharge pattern and characteristics described in large animals (27). Because of the short length of the vagus nerve in the mouse, nerve conduction velocity was not available.

Based on adaptation index, the airway mechanoreceptors in the series were divided into RARs (>75%), intermediate receptors (40–74%), and SARs (0–39%). Adaptation index was calculated using procedures described by Widdicombe (26). Total discharge frequency during second 2 of inflation was subtracted from peak discharge frequency; this value was then divided by the peak discharge frequency and multiplied by 100.

Receptor fields were identified by gently probing the external surface of the lung and airways with a cotton swab. No attempt was made to identify sensory fields more precisely. When a mechanoreceptor was identified, airway opening pressure was increased in 10-cmH2O increments to assess receptor responsiveness.

Reflex studies.   Pulmonary chemoreflexes were examined by assessing phrenic nerve activity or inspiratory muscle activity through external intercostal muscle electromyogram. Cardiovascular variables were also monitored. The right or left phrenic nerve was separated from its surrounding tissue in the neck and transected, placing the desheathed, central end of the nerve on a bipolar silver electrode. Alternatively, inspiratory activity was recorded with bipolar needle electrodes inserted into the muscle. The electrodes were connected to a Grass (model P 511) amplifier, with nerve or muscle activity monitored by a loudspeaker. Moving time averaged signals were obtained through an integrator (model 73PD integrator, Grass; time constant, 50 or 200 ms).

To activate C fibers, phenylbiguanide (PBG; 100 µg/ml, 20 µl) was administered intravenously after cannulating the left femoral vein with polyethylene tubing (PE-10 attached to a syringe by a 30-gauge needle). The Hering-Breuer reflex was evaluated while assessing inspiratory activity in response to constant airway opening pressures of 10, 15, and 20 cmH2O. It has been reported that the strength of the Hering-Breuer reflex is increased during anesthesia (5). In the present study, we examined the reflex at three levels during a time span of 5 min, to avoid the effects of anesthesia. The experiments were carried out in spontaneous breathing mice for PBG studies but in open chest and mechanically ventilated mice for Hering-Breuer reflex studies.

All data are expressed as means ± SE, with statistical significance determined by paired t-test or one-way ANOVA at {alpha} ≤ 0.05. All procedures were approved by the University of Louisville Animal Care and Use Committee and followed American Physiological Society guidelines.


   RESULTS
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Afferent studies.   A total of 215 single units were encountered in 56 mice. Among them, 153 sensory units were identified in the lung [~3 receptors (1–5 receptors) per mouse]: there were 141 mechanosensors and 12 chemosensors; 134 of the mechanosensors were inflation-stimulated, and 7 were purely deflation receptors. The distribution of the 134 inflation receptors was 101 typical SARs, 23 RARs, and 10 intermediate receptors (Fig. 1). In general, resting activity in inflation receptors was inversely related to adaptation rate, that is, slower receptor adaptation rate yielded higher discharge frequency.


Figure 1
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  		Fig. 1. Adaptation index and basal discharge frequency in the 3 types of mechanoreceptors: rapidly adapting pulmonary stretch receptors (RARs), intermediate receptors, and slowly adapting pulmonary stretch receptors (SARs). Note that the average discharge frequency is much higher in SARs than RARs, with the intermediate receptors in between. However, there is significant overlap among the 3 types. Values are means ± SE. Imp, impulses.

 
SARs were the most frequently observed type (n = 101), accounting for 66.0% of the total units examined. Of these, 85 were high threshold (Fig. 2), and 16 were low threshold (Fig. 3). In 44 SARs, we completed protocols for lung inflation at three different levels (10, 20, and 30 cmH2O), as well as lung deflation to 0 cmH2O. SAR activity increased during lung inflation and decreased during deflation. The increased response is graded as inflation pressure increases (Figs. 2 and 4). Most (28 of the 44 SARs) became silent during all or some of the deflation phase, although some (16 of the 44) fired tonically at a low rate at 0 cmH2O (17.9 ± 2.4 impulses/s, n = 16).


Figure 2
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  		Fig. 2. Single unit activity in a typical SAR recorded from the left cervical vagus nerve in an anesthetized, open chest, and mechanically ventilated mouse. Traces are impulses per second counted at a bin width of 0.1 s (IMP/s), impulses of sensory activity (IMP), and airway pressure Paw. A–C: receptor responses to different inflation pressures. D and E: responses to lung deflation at constant pressures of 0 and –5 cmH2O, respectively. F: fast-speed recording with the left segment half the speed of the right.

 

Figure 3
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  		Fig. 3. Typical low-threshold SAR recorded from an anesthetized, open-chest, and artificially ventilated mouse. The receptor discharged throughout the ventilatory cycle, peaking during inspiration. Discharge continued at a low frequency when the ventilator stopped (A), with little adaptation (adaptation index <5%) in response to constant pressure inflation (B).

 

Figure 4
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  		Fig. 4. SAR response to changes in lung mechanics examined under 4 different constant airway pressures (0, 10, 20, and 30 cmH2O). Values are means ± SE; n = 44. SAR activity increased as the inflation pressure increased. These graded increases were statistically significant, P < 0.0001 (ANOVA).

 
Twenty-three RARs were observed. As classically described, these RARs discharged irregularly under resting conditions. Compared with SARs, they fired at lower basal frequency (Fig. 1) and higher activation threshold. The RARs discharged at high initial frequency during constant pressure inflation and adapted rapidly. Figure 5 shows a RAR that did not respond at low inflation (10 cmH2O) and had only a sluggish, irregular response at 20 cmH2O. A brisk, rapidly decelerating discharge rate ensued when the lung was inflated to a high level (30 cmH2O). This particular RAR had cardiac modulation on active negative pressure deflation to –5 cmH2O. In addition, seven purely deflation receptors were recorded (4.9% of the of the mechanosensitive receptor sample). They responded only to active lung deflation and usually had cardiac modulation. Their activity ceased during lung inflation (Fig. 6).


Figure 5
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  		Fig. 5. RAR unit recorded from an open-chest and mechanically ventilated mouse. The activity shows a low and irregular discharge pattern at baseline. It has a high inflation threshold, not discharging at 10-cmH2O pressure (A) and adapting rapidly to pressures of 20 and 30 cmH2O (B and C). This unit does not respond to constant end-expiratory pressure of 0 cmH2O (D), but it shows cardiac modulation and continues to discharge during lung deflation to –5 cmH2O (E). The adaptation index is 97%.

 

Figure 6
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  		Fig. 6. Single-unit activity of a receptor discharging during deflation but not inflation. Characteristic of this type of receptor is clear cardiac modulation superimposed on respiratory modulation. Note the receptor continues to discharge with clear cardiac modulation when the ventilator is stopped (A) and when the lungs are deflated (B). The receptor stopped discharge during lung inflation at constant pressures of 10 and 30 cmH2O (C and D). BP, arterial blood pressure.

 
Twelve receptors (7.8%) were identified as chemosensitive or as nociceptors (C-fiber or high-threshold A{delta}-receptors). In six of these receptors, we injected PBG intravenously: four were stimulated (Fig. 7), whereas the remaining two did not respond. In two receptors, we injected hypertonic saline (8.1%, 20 µl, through a 30-gauge needle) directly into the receptive field, stimulating both. These nociceptors had low basal firing frequency (3.3 ± 0.5 imp/s; n = 12) and irregular firing patterns. Compared with the mechanosensors (SARs and RARs), these receptors were much less sensitive to lung inflation or deflation (Fig. 8, B and C, and Fig. 9 B and C). For example, during lung inflation to 20 cmH2O, the chemosensitive receptors discharged at 13.3 ± 3.3 impulses/s during their peak response, whereas the SARs and RARs discharged at 157.5 ± 3.9 and 58.2 ± 7.4 impulses/s during their peak response. During lung inflation, some chemosensitive receptors discharged with a few action potentials. The adaptation index for such receptors would fall into the rapidly adapting range; however, these receptors cannot be classified as RARs because they were not sensitive to lung mechanical stimulation. Figures 8 and 9 illustrate a presumptive high-threshold A{delta}- and C-fiber receptor, respectively.


Figure 7
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  		Fig. 7. Unit response to intravenous injection of phenylbiguanide (100 µg/ml, 20 µl). Injection was made at time 0. Unit activity [expressed as impulses per second (imp/s)] exhibits a surge discharge within the first few seconds, then subsides rapidly, and returns to the control level 30 s after the injection. Values are means ± SE; n = 4.

 

Figure 8
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  		Fig. 8. Single unit activity of a chemosensitive receptor (see Fig. 1 legend for abbreviations). This receptor is located in the peripheral airway of the left lung and activated immediately with local injection of hypertonic saline (8% NaCl, 10 µl, indicated by the arrow on the top) (A). Receptor activity reverted to control level 30 s after the injection. This receptor is not stimulated by negative pressure deflation (B) and not very sensitive to lung inflation (C). This sensory receptor may be a high-threshold A{delta}-receptor.

 

Figure 9
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  		Fig. 9. A presumed C-fiber located in the left lung in response to intravenous injection of phenylbiguanide (100 µg/ml, 20 µl) in an anesthetized and artificially ventilated mouse. The response is intense but short lived (~10 s) (A). This receptor is not stimulated by negative pressure deflation (B) and not very sensitive to lung inflation (C).

 
Reflex studies.   A typical chemoreflex response to intravenous injection of PBG, a C-fiber activator, was observed. PBG produced usual chemoreflex effects, including apnea, bradycardia, and hypotension, that were often followed by rapid and shallow breathing (Fig. 10). The response characteristics are listed in Table 1. The Hering-Breuer reflex was also observed, with inspiratory inhibition in response to lung inflation at a constant airway pressure. Inspiratory activity became silent for a period during lung inflation and lasted longer as inflation pressure increased (Fig. 11). The inspiratory pause lasted 3.3 ± 0.6, 14.1 ± 3.3, and 26.6 ± 4.0 s, respectively, at 10-, 15-, and 20-cmH2O lung inflation (n = 15, P = 0.0001). Both the chemoreflex and Hering-Breuer reflex were blocked by bilateral vagotomy.


Figure 10
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  		Fig. 10. Dose responses in cardiopulmonary reflexes evoked by bolus intravenous injection of a pulmonary C-fiber activator, phenylbiguanide, in a spontaneously breathing mouse. ENG (Integ), integrated phrenic nerve activity. A, B, and C: responses to phenylbiguanide doses of 0.2, 0.6, and 1.8 µg (in 20 µl iv), respectively. {blacksquare}, Time of injection. Note that heart rate and respiratory rate decrease, with a slight decrement in BP. At the 1.8-µg dose, cardiopulmonary responses became significant, and there was a 2.5-s respiratory pause. The slopes of dose response (heart rate or respiratory pause) curve are the reflex sensitivities.

 

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  		Table 1. Cardiopulmonary responses to intravenous injection of PBG

 

Figure 11
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  		Fig. 11. Assessment of respiratory drive by recording phrenic efferent activity in an open-chest and mechanically ventilated mouse. ENG (Integ), integrated phrenic neurogram; Paw, airway pressure. Shown is the Hering-Breuer reflex initiated at different inflation pressures (10, 20, and 30 cmH2O in A, B, and C, respectively) in the mouse, demonstrating how this reflex is evaluated in the model.

 

   DISCUSSION
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 REFERENCES
 
Most airway receptor behavior has been described in larger animals such as dogs (13, 14, 20), cats (22, 30), and rabbits (15, 19, 27). There are fewer reports in guinea pigs (1, 4) and rats (2, 12, 24) [and very few in the mouse, where we know of only one that describes the afferent properties of airway SARs in vivo (3)], in addition to some in vitro recordings (16, 17). The airway sensory receptors that have been characterized in rats behave similarly to those in larger animals, with some differences. For example, many receptors that were activated purely during deflation are found in the rat (2, 12), yet are rare in larger animals (28). In the present studies, we systematically searched for airway sensors in the mouse, demonstrating an array of known vagal sensors. Lung sensory behavior in the mouse is similar to large animals and especially the rat. A brief report on the airway sensory receptors in the mouse has been communicated (31).

Mechanoreceptors are categorized based on their adaptation index into RARs, SARs, and intermediate receptors. In the present series, we identified 23 RARs, 101 SARs, and 10 intermediate receptors, accounting for 17.1, 75.4, and 7.5% of inflation mechanoreceptors, respectively. Intermediate receptors have been observed in other species (26). It has been proposed that the myelinated vagal afferents be viewed as a heterogeneous group behaving in a spectrum, where typical RARs and SARs represent two extremes (27). In the mouse, RARs behave similarly to other species. Their discharge is irregular and adapts rapidly to a maintained volume or pressure stimulus. As mechanosensors, RARs sense dynamic changes in lung mechanics; their activity increases significantly as lung compliance decreases (13, 21).

The most frequently encountered sensors in the series were the slowly adapting receptors. Their characteristic discharge pattern is readily accessible for study. However, if the distribution of pulmonary afferents in the mouse is similar to other species (18), the chemosensitive receptors are probably the largest group. We do not know whether C-fiber receptors outnumber mechanoreceptors in the mouse; the chemosensors account for only 7.8% of the receptors recorded in this series. Possibly, for technical reasons, they are relatively inaccessible.

SARs can be divided into high-threshold and low-threshold types (22), and both were identified in the mouse. It should be emphasized that this distinction is not exclusive and that the discharge pattern may change from one type to another (28). The SAR shown in Fig. 2 illustrates this point. This behavior can be explained by the coexistence of multiple encoders in a sensory unit (28). There is clearly a rapidly adapting component during lung inflation to 30 cmH2O, but not at 10 cmH2O; it can be identified at 20-cmH2O inflation.

Sensory units responding purely to deflation were identified, accounting for 4.9% of the mechanosensors recorded (Fig. 6). Although they are found in the rat (2), receptors that respond purely to deflation are rare in large mammals. Some SARs and RARs are activated by lung deflation. Under the current airway mechanoreceptor classification system, receptors having both inflation and deflation activity are termed SARs or RARs, based on their response to lung inflation (28). However, receptors that respond to deflation, whether mixed or pure, may be different receptors from SARs and RARs. For instance, the RAR in Fig. 5 is different from the deflation receptor in Fig. 6. As pointed out, a sensory unit may respond to both lung inflation and deflation because of the coexistence of inflation and deflation encoders. Although it is still an unresolved issue whether one encoder can respond to both inflation and deflation, the coexistence of inflation and deflation encoders does occur (28). Each may be responsible only for a particular stimulus, such as inflation or deflation. Possibly, deflation receptors exert effects opposite to SARs, stimulating inspiration and suppressing expiration. The inflation and deflation receptors may comprise a dual-control system like that operating in the peripheral nervous system. Such a dual system would be effective in high workload and stress situations, providing more vigorous control of breathing (28).

Our studies clearly demonstrate pulmonary chemosensitive receptors in the mouse. Due to technique limitations, we cannot measure the conduction velocity of the vagus nerve, which is the standard to distinguish myelinated from nonmyelinated fibers. We are therefore unable to claim that the recorded receptors are bona fide C-fiber receptors or high-threshold A{delta}-receptors. However, looking at the receptors' contour and discharge sound of action potentials (28), and responses to mechanical stimulation, it seems that both high threshold A{delta}-receptors (Fig. 8) and C-fiber receptors (Fig. 9) are present. These sensory receptors responded to hypertonic saline and PBG as observed in rabbits (29). However, these stimulating agents may not be highly specific. For example, hypertonic saline may also stimulate RARs, whereas PBG may not activate all the C-fiber receptors. In a study, ATP was found to be a better stimulant to identify C fibers than PBG, capsaicin, and bradykinin in an in vitro preparation (16). Nevertheless, our data suggest the presence of chemosensitive sensory receptors in the mouse. Historically, RARs have not been very well classified. Some of the so-called RARs reported in the literature may in fact be high-threshold A{delta} receptors (29). One significant difference is their mechanical sensitivity. RARs are much more sensitive to mechanical stimulation, such as lung inflation, although they have higher activating thresholds than SARs.

In addition to the airway sensors, the typical chemosensitive reflex and Hering-Breuer reflex were also observed in the mouse (Figs. 10 and 11). Nonmyelinated C-fibers are the primary type of chemosensitive vagal pulmonary afferent in the rat lung (12). Their stimulation produces bradycardia, hypotension, and apnea. C fibers play an important role in regulating respiratory and cardiovascular function, especially under abnormal conditions (7, 18). Lung inflation activates SARs, which in turn inhibits central inspiratory activity and terminates inspiration, causing the Hering-Breuer reflex. Across species, animals typically adopt a rate and depth pattern of breathing to optimize alveolar ventilation at minimal energy expenditure. The Hering-Breuer reflex mediated through the SARs may serve the underlying mechanisms.

In conclusion, airway sensors in the mouse closely resemble those in the rat. They include mechanosensors (SARs, RARs, and deflation receptors) and chemosensors (C-fiber receptors and high-threshold A{delta}-receptors). Typical pulmonary reflexes such as the Hering-Breuer reflex and the chemoreflex are also present in the mouse. Because genetic modification of molecules is readily available in the mouse, established techniques to assess the pulmonary afferents and their reflex effects will facilitate our understanding of receptor function at the molecular level.


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This work is supported by grants from the Rett Syndrome Research Foundation and by National Heart, Lung, and Blood Institute Grant HL-58727.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. Yu, Pulmonary Div., Dept. of Medicine. Univ. of Louisville, ACB-3, 530 S. Jackson St., Louisville, KY 40292 (e-mail: j0yu0001{at}louisville.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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