Received 2002-07-29    Accepted 2002-08-26

This work is supported by National Institutes of Health (HL-58727) and American Lung Association (CI-18-N).

*Corresponding author.

Department of Medicine (Pulmonary),

University of Louisville,

ACB-3, 530 S. Jackson St.,

Louisville, KY 40292.

Tel: 1-502-852-5146;

Fax: 1-502-852-1359;

E-mail: j0yu0001@gwise.louisville.edu

 

Acta Physiologica Sinica  

Dec. 2002, 54 (6), 451-459

 

Brief Review

An overview of vagal airway receptors

Jerry YU

Departments of Medicine, and Physiology and Biophysics,   University of Louisville, Louisville, KY 40292, USA

 

Abstract:    Breathing is critically depending on a variety of sensory feedbacks from multiple sources for its optimal performance. The sensory information from the lung and airways probably provides one of the most important feedbacks to adjust the respiratory controller to generate optimal breathing movements. Since Breuer and Hering made the seminal report regarding role of the vagus nerve in control of breathing in 1868, airway sensory receptors have been a subject for intensive and extensive studies. After more than a century investigation, our knowledge accumulates immensely, however, our understanding of the nature of these sensory receptors is still far from complete. This brief review provides an overview on this topic.

 

Key words: sensory   nerve;  mechanoreceptor; reflex; lung

 

呼吸道迷走神经感受器概述

於  峻

路易斯维尔大学内科系与生理系, 美国肯塔基州 40292

 

摘  要:    肺以及气道与外界环境之间存在着巨大的界面, 因此需要有效的防御反射机制。呼吸道感受器是肺部神经反射的起始点, 其重要性不言而喻。采用组织、解剖与电生理学方法, 经过一个世纪的研究, 我们对于呼吸道感受器的认识, 特别对其结构的认识, 仍然有限。据电生理实验结果, 肺部感受器至少可被分为三大类: 慢适应感受器、快适应感受器以及C纤维感受器。按血供来源, 后者又可分为气道(体循环)与肺(肺循环)两类。近来发现呼吸道中存在着第四类感受器, 它们由迷走神经的Aδ 传入纤维传递冲动, 其放电活动不同于上述各类, 对肺充气反应阈值高, 故称之为高阈值Aδ 感受器。功能上前两类基本属于机械性感受器, 而后两类可归为化学敏感性感受器。另外, 用组织学方法, 观察到气道内有一些神经内分泌细胞, 它们可以散在分布, 亦可集聚成小体。这些神经上皮小体受多种神经支配, 其结构复杂, 形态酷似感受器。虽然我们对其形态了解颇深,  但对其放电形式一无所知。本文对以上各类感受器进行了评述与探讨。

 

关键词: 感觉神经;  机械性感受器;  反射; 肺

中图分类号: Q423

 

Background

The lung and airways have a huge surface area that is in communication with the external environment. Therefore, their defense mechanisms, including neural reflexes, must be effective. Pulmonary sensory receptors are the initiating sites for the reflexes, which signifies the importance of understanding the receptors. Changes in the mechanical and chemical environment of the respiratory tract elicit sensory activities that can be sent locally to control airway tone, secretion, and perfusion. Sensory information can also be transmitted through both sympathetic and vagal nerves to the central nervous system to initiate reflexes. Little is known about reflex effects evoked through sympathetic afferent pathways, but their influence is felt to be modest[1-3]. Vagal afferent pathways comprise the major route for transmitting the sensory information. Based on electrophysiological studies on the intact animal, airway receptors can be categorized into at least three types[1]: slowly adapting pulmonary stretch receptors (SARs)[4], rapidly adapting receptors (RARs)[5], and C fiber receptors (CFRs)[6]. Some receptors, such as those having a high threshold to inflation pressure and innervated by Aδ fibers, cannot be classified into any of the three categories, and their taxonomy is yet to be established[7]. For convenience, these unclassified receptors are referred as high threshold Aδ fiber receptors (HT-AFRs). In addition, neuroepithelial bodies (NEBs) are also recognized as sensory organs innervated by vagal afferents[8].

Little is known about the structure of pulmonary receptors[8]. No claim has been made as to the configuration of RAR or CFRs.  There is disagreement in the few studies of the structure of SARs[9-12]. Our understanding of pulmonary receptor physiology is greatly impeded by lack of morphological information, and there is virtually no information on the correlation of receptor structure with its function. Advances in confocal microscopy and immunohistochemistry permit detailed examination of receptor morphology for the first time (Fig. 1)[13]. In contrast to receptor morphology, emanations of the vagus are better understood. Histological studies revealed that approximately 10000 vagal fibers originate from the lungs and lower airways[14]. Two thousand of these fibers are myelinated A fibers, and 8000 are unmyelinated C fibers.  Approximately 60% of the myelinated fibers are SARs and the remaining 40% are RARs[15]. Vagal sensory neurons are psuedounipolar; their cell bodies are located in the nodose and jugular ganglia. These primary visceral afferents terminate in the caudal two-thirds of the nucleus of the tractus solitarius (NTS).  The various vagal afferents terminate in different topographical regions of the NTS[16].  The relayed information in the NTS is further processed in the central nervous system to evoke reflex actions through efferent pathways that, among other things, regulate breathing, airway caliber, airway perfusion and mucous secretion.

Sensory properties of pulmonary receptors are conventionally studied by recording the single fiber activity of vagal afferents[7]. Chemical stimulants are delivered to the receptive field by right atrial injection or aerosol inhalation. The role of pulmonary afferents in a given reflex is determined by examining responses to a stimulus selective for a single type of receptor. Most of what is known about the vagal sensory system is derived from this type of study. There are also in vitro preparations that permit evaluating pulmonary receptor properties at the cellular and ionic levels under better controlled conditions. Information is also beginning to be collected in isolated cell preparations of primary sensory neurons in the nodose and jugular ganglia. This reduced preparation will certainly shed light on mechanisms of sensory activation; however, it is not our focus here.

 

Slowly adapting pulmonary stretch receptors (SARs) 

SARs are mechanoreceptors that are insensitive to chemicals. SARs are mainly stimulated by increased airway pressure. In addition to sensing sustained changes in pressure, SARs also sense rate of change in pressure[17]. They are the best known of the airway receptors, being easily identified for study because of their characteristic discharge patterns. These patterns form one basis for classification[4]. Low-threshold SARs fire throughout the respiratory cycle, and high-threshold SARs fire only during the inspiratory phase. Low-threshold receptors are mainly located in central airways, high-threshold receptors are found more in peripheral airways. However, the division is not absolute. For example, low-threshold SARs can be converted to high-threshold when lung compliance decreases; the low-threshold pattern returns after compliance is restored by lung inflation[18]. According to their response to constant pressure inflation of the lungs, SARs also are classified as typeⅠ and typeⅡ. In typeⅠ the discharge tends to plateau at inflation pressures above 10 cm H2O, while in type Ⅱ the receptor response to lung inflation is relatively linear and positively correlates with inflation pressure up to 30 cm H2O. It is suggested that type Ⅰ receptors operate in parallel with smooth muscle fibers, while type Ⅱ    receptors operate in series[19]. However, the existence of two types of SARs can not be confirmed by other investigators[20].

Fig.1.  

Immunohistochemical approach to examine airway sensory innervation. A is examined under fluorescent microscope, and the bar indicates 100 μm. The rest figures are confocal images. A-D are unpublished images from our laboratory, and E is adapted from a report[13] with permission. A, B and C illustrate neuroepithelial bodies (NEBs). A and C are immunohistochemical staining with antibody against CGRP. B, a projection image showing double staining for CGRP (red, Cy-3 fluorescence) and PGP (green, FITC fluorescence). Note that NEBs are often located at airway openings and protrude into the airways (A and B) and are innervated by nerve fibers with different chemical compositions (B). C is a single image in a bronchiole, showing inter-relationship of the neuroendocrine cells within a NEB. D, a single image of a lobular bronchus, showing densely distributed varicose nerve fibers, which are immunoreactive with SP. These varicose nerves are present in all airways, but the density is much higher in the central than the peripheral ones. E, a presumptive SAR in the trachea, which is immunoreactive to Na+/K+-ATPase. This receptor is embedded in the smooth muscles, which run horizontally, and more or less parallel the long axis of the receptor structure.

 

SARs are functioning at birth[21] and are responsible for the Hering-Breuer reflex. They provide information about stretch of the lung on a cycle by cycle basis and thus influence the rate and depth of breathing[22]. Reflex effects include inhibition of inspiration, bronchodilation, and tachycardia. In addition, activation of SARs can cause systemic vasodilation, including the microvasculature by withdrawal of sympathetic activity[23]. Activation of SARs also stimulates expiratory muscle activity[24], which could be one of the reasons that expiration is active in patients with chronic obstructive lung disease.

    Recently, an excellent marker (Na+/K+-ATPase) has been identified for detecting airway receptors[13]. By combining the immunohistochemical technique with confocal microscopy, the morphology of airway receptors can be examined in detail (Fig. 1). Furthermore, by recording discharges from an axon to identify a specific receptor ending, then further dissecting the receptor and processing the tissue immunohistochemically for confocal microscopy, we found the structure of typical SARs. The procedure can also be used with neural tracing techniques to identify the receptor[25]. The SAR is buried in the wall of small airways. The parent axon feeds to multiple structures that have many arborizations, forming knob-like terminal endings. Many investigators claim to have observed the SAR in parallel with the smooth muscle[9,12]. However, it has never been stated which part or axis of the receptor is parallel to the muscle, and why that particular axis should be considered as a sensory axis. In the peripheral airway, the direction of smooth muscle fiber is irregular; therefore, it is hard to envision a parallel relationship. If the terminals are the basic sensory devices, they may stretch in any direction. Thus, the receptor can be activated no matter how it is oriented in relation to the smooth muscle.

 

Rapidly adapting receptors (RARs)

RARs, by definition, are mechanoreceptors but are believed to be activated by many endogenous and exogenous chemical substances as well[5,26,27]. As their name suggests RARs are sensitive to dynamic changes. Since first identified by Knowlton and Larrabee[15], RARs have been variously termed “deflation receptors”, “cough receptors”, “pulmonary flow receptors” and “irritant receptors”. These multiple terms create confusion, and most investigators now prefer “rapidly adapting receptors” because this term describes their properties rather than their function, which is uncertain. Although afferent properties of RARs and SARs differ, they overlap in all aspects, including their conduction velocities[28]. No matter how the receptors are categorized, each classification has limitations. One way to resolve the dilemma is to view myelinated mechanoreceptors as a heterogeneous group in a spectrum, with typical SARs at one end and RARs at the other[28]. To establish this view, morphological and functional evidence is needed. Unfortunately, up till now we do not know the morphology of RARs. Using the new approach, we observed some afferents located in the epithelium and in the lamina propria, forming leaf-like terminals. They could be RARs. Since physiological classification is not clear, caution is needed when linking a morphological type to the RAR.

RARs have little activity during eupnea, therefore were not thought to be important to normal breathing control. However, low activity could exert a tonic influence on the respiratory center, especially when activities in different RARs are synchronized. Indeed, RAR activity increases and is synchronized as lung compliance decreases within physiological range[29]. Thus, RARs may signal the need to expand the lungs to restore compliance[30]. RARs are thought important in producing reflex effects during lung abnormalities such as pulmonary embolism, pneumothorax, pulmonary congestion, edema, and atelectasis[27,31-34].  Stimulation of RARs reportedly enhances inspiration, causes sighs or augmented breaths, shortens expiratory time, induces cough, increases airway secretions, and produces mucosal vasodilatation[35-39]. RARs are also believed by Kappagoda and his group[40] to sense fluid flux, a function that has been ascribed to CFRs[2]. Activation of RARs is believed to constrict airways; however, this view does not have a substantial basis and has been challenged[41].

RARs are also thought to be chemosensitive[5]. They respond to a variety of endogenous and exogenous substances, such as histamine, ammonia,  5-HT, and etc. In addition to direct stimulation, chemical stimulation can be secondary to changes in lung mechanics produced by these agents[42-44].

Researchers are often perplexed when they try to understand the physiological role of RARs. Their sensitivities to a wide variety of mechanical and chemical stimuli, along with a spectrum of responses, make the RAR reflex system non-specific. The question arises whether the receptors identified as RAR actually constitute a heterogeneous group, or have many subtypes. Careful review of the literature shows that RARs are not rigorously defined. Certainly, some of the afferent property and reflex effects ascribed to RARs belong to HT-AFRs (see Section on HT-AFRs) and other receptor types. 

 

C fiber receptors (CFRs)

Unmyelinated C fibers account for 80 percent of all vagal afferents. They are immunoreactive with many neuropeptides, including substance P (SP)[45], forming net work structures in the large airways (Fig. 1). The reasoning that C fiber endings lie in dense networks is consistent with the physiological observation that their receptive fields cover large areas (personal observation). CFRs are chemosensitive, but respond only to extreme mechanical stimulation[22]. Therefore, they are unlikely to be activated by cyclic changes in lung mechanics under physiological conditions[46]. CFRs can be divided into pulmonary and bronchial types according to their blood supplies. Pulmonary CFRs are also called juxtacapillary or J receptors because of their presumptive location in the lung interstitium next to the pulmonary capillary[2]. There are some differences in properties and reflex effects of bronchial and pulmonary CFRs[22], but in general they are very similar to each other and often treated as a single group. CFRs are stimulated by a variety of chemicals such as capsaicin, hydrogen ions, and phenyldiguanide. Their superficial location in the airway lumen and sensitivity to mediators, such as bradykinins and prostaglandins, underline their role in airway defense.

CFRs have low discharge frequency and an irregular firing pattern[47]. They are activated alongside RARs in many pathological conditions, including pneumothorax, pulmonary congestion, and microembolism. The typical CFR reflex response is a triad of apnea followed by rapid shallow breathing, bradycardia and hypotension[22]. These afferents may also inhibit skeletal muscle activation and evoke dyspneic sensation[48]. CFRs reflexly induce bronchoconstriction[49], airway secretion [50,51] and bronchial vasodilation[36,39]. In addition to the conventional reflex pathway through central nervous system, CFRs may produce local axon reflexes, eliciting what has been termed neurogenic inflammation of the airways[52]. Accordingly, tachykinins and other neuropeptides are released, leading to regional bronchoconstriction, vasodilation, protein extravasation, and chemotaxis of various inflammatory cells. There is evidence suggesting that CFRs are sensitized during airway mucosal injury or inflammation by direct action of released mediators[53]. These receptors may play a part in airway hyper-responsiveness. Some investigators believe that activation of CFRs can induce cough, others disagree[6]. It is still a controversial issue.

 

High threshold Aδ fiber receptors (HT-AFRs)

Certain vagal afferents fit no known category of receptors[54]. These fibers have conduction velocities of 4-15 m/s, and in this regard, belong to the Aδ afferents. Yet they share many characteristics of pulmonary CFRs, including low resting discharge frequency, chemosensitivity, and insensitivity to mechanical stimulation (Fig.2). However, in rabbits they are not activated by phenyldiguanide, an agent that activates CFRs in this species[55]. HT-AFRs are activated by hypertonic saline (Fig.2), hydrogen peroxide, and bradykinin[7,54]. These receptors may play an important role in pathological conditions because their activation evokes the excitatory lung reflex[56]. This reflex includes tachypnea and hyperpnea, increased inspiratory time and inspiratory duty cycle, shortened expiratory time, and reduced expiratory activity. All these reflex effects on breathing stress the inspiratory muscles[57].  Thus, activation of the reflex is a promoting factor for inspiratory muscle fatigue.

    It is not surprising that RARs get much more ‘credit’  than HT-AFRs because most researchers assume that there are only three types of airway receptors. Actually, some responses ascribed to RARs may instead belong to HT-AFRs. Because of the assumption that there are only three types of airway receptors, many investigators ascribe reflex effects to RARs by default whenever SARs and CFRs are ruled out. For the same reason, some afferent properties, such as chemosensitivity, ascribed to RARs may belong to HT-AFRs. It is not uncommon, during vagal afferent recording, to classify any airway receptor that is chemosensitive but not mechanosensitive as a CFR. Because HT-AFRs and CFRs share many properties, it is hard to distinguish them without measuring conduction velocity. There is no doubt that in the research literature some HT-AFRs have been mistakenly classified as CFRs because of the assumption of only three receptor types.

 

Fig.2. 

An HT-AFR recorded from the right cervical vagus nerve in an anesthetized, open-chest, mechanically ventilated rabbit. The traces are: IMP, receptor activity; Paw, airway pressure. A-C are the receptor responses to different inflation pressure. D is the response to lung deflation (removal of positive-end-expiratory pressure), which is indicated by the bar on the top. E and F are consecutive recording, showing stimulation of the HT-AFR by injecting 8.1% NaCl (0.02 ml) into the receptor field, which is located at the edge of the right middle lobe. The injection is denoted by the black arrow on top of the trace in E. This receptor has sporadic and irregular activity at the baseline, does not respond to deflation of the lung. Moreover, it is insensitive to mechanical stimulus, exhibited by a high threshold to lung inflation and low peak firing rate at lung inflation to 30 cm H2O even when the lung compliance was very low (indicated by very high tracheal pressure swing in C). Afferent of this receptor has a conduction velocity of 7.3 m/s, therefore, it is classified as high threshold Aδ fiber receptor.

 

Neuroepithelial bodies (NEBs)

NEBs were first described seven decades ago[58]. They are groups of neural endocrine cells, often located at the airway openings, widely distributed in the epithelium along intrapulmonary airways, and richly innervated (Fig. 1). The nerve fibers that innervate the NEBs originate from local ganglia, the spinal cord and nodose ganglia[59,60], suggesting both vagal and sympathetic sensory and perhaps efferent autonomic innervation. NEBs can be targeted by many specific antibodies for immunochemical staining [calcium gene related peptide (CGRP), substance P (SP), protein gene peptide (PGP) to name a few]. In contrast to the airway receptors described above, the anatomical structure of NEBs has been described[58], yet no sensory response has ever been shown[8]. There is abundant speculation as to the function of NEBs[61], for example as oxygen sensors[58]. Since NEBs are innervated by vagal afferents[59], the afferent activities, although unrecognized, may have been recorded from the vagus by neurophysiologists. NEBs may be innervated by one of the four receptor types mentioned above. The question is by which one. From a morphological stand point, NEBs resemble chemosensitive rather than mechanosensitive receptors. Their activation may release mediators including 5-HT, which is a stimulant to some small afferent fibers. Thus, it has long been suspected that NEBs interact with afferent of RARs or CFRs[59]. Because mechanosensitive receptors, such as SARs and RARs, are abundant in the extra pulmonary airways, where there are fewer NEBs than lobular and segmental airways, it is unlikely that NEBs are associated with SARs or RARs. The CFR could be the candidate, however. Myelinated vagal afferents are believed to innervate the NEB[59]. Since the HT-AFR has myelinated afferents and chemosensitivity, and is located mostly in the intrathoracic airways, it is the best candidate for the NEB. In addition to the possibility of being a sensor itself, another potential function of NEB, which may relate to pulmonary reflex, is modulation of airway receptors by releasing its mediators.

 

Receptors studied in in vitro

Using conventional procedures to administer chemical stimulants (right atrial injection or aerosol) to airway receptors limits the concentration of the agent used for activation. Therefore, an in vitro preparation was developed to assess afferent properties of lung receptors[62, 63]. The airways, intact vagus nerve, and nodose and jugular ganglia are excised and then superperfused with physiological solutions. While nerve activities in the nodose or jugular ganglia are recorded, the bathing solution can be changed easily to alter chemical concentration. In comparison to in vivo procedures, this technique allows better control of the chemical environment at the receptor field.  Much information has been obtained as to the effects of different agents on various ion channels[62,63]. In in vitro preparations, afferents are categorized by their conduction velocities and divided into C fibers and Aδ fibers[62,63]. In guinea pigs, these afferents may have a topographical segregation. For example, hypertonic saline stimulates Aδ fibers whose cell bodies are located in the jugular, but not in the nodose ganglion. However, common to all in vitro preparations, there is the uncertainty whether the phenomena observed would occur in vivo. The results obtained in the reduced preparation need to be reconciled with those from the intact animals. It is likely that the Aδ fibers described in vitro include SARs, RARs and HT-AFRs. The hypertonic sensitive Aδ fibers in the jugular ganglion may be HT-AFRs.

Recently, a new technique (direct injection of stimulants or inhibitors into the receptive field) was developed to examine the airway receptor[64], which complements the conventional in vivo techniques and the in vitro preparation. It helps to selectively identify the targeted receptor; therefore, it increases certainty of interpretation by avoiding complications due to effects from widespread dissemination of the agent. In addition, pinpoint identification permits dissection of a single receptor for morphological study[25]. Comprehensively analyzing information collected by using conventional methods, in vitro preparations, and local injection, we should have a better picture of the pulmonary receptor physiology.

 

Future directions

As in other research areas, with advancement of techniques, information about pulmonary receptors at the molecular and cellular levels has begun to appear. This research area needs integration with research at the whole body level. Advances in immunohistochemistry, the development of neural tracers, and technology in microscopy will permit histological description of pulmonary receptors, and will allow us to determine the chemical nature of the receptors. In parallel, the interrelationship among the receptor structure, chemical codes and function needs to be tackled. The underlying mechanisms for mechanical and chemical transduction at receptors need exploring. Activities recorded in a single afferent fiber may come from multiple receptor endings (i.e., a receptor may have multiple encoders). Exploring the integration of the sensory activities during action potential generation should provide significant information for understanding the sensory system. In short, the structure-function relationship, the activation mechanisms at the cellular level, the molecular composition and genetic make-up of the airway receptors will be available in the coming decades.

 

REFERENCES

[1]  Coleridge HM, Coleridge JCG. Pulmonary reflexes: neural mechanisms of pulmonary defense.  Annu Rev Physiol,  1994,56:69-91.

[2]  Paintal AS. Vagal sensory receptors and their reflex effects.  Physiol Rev, 1973,53:159-227.

[3]  Sant'Ambrogio G, Sant'Ambrogio FB. Reflexes from the upper airway, lungs, chest wall, and limbs. In: Crystal RG, West JB, Weibel ER, Barnes PJ, eds.The Lung: Scientific Foundations. New York: Raven, 1997,1805-1819.

[4]  Schelegle ES, Green JF. An overview of the anatomy and physiology of slowly adapting pulmonary stretch receptors.  Respir Physiol, 2001,125:17-31.

[5]  Sant'Ambrogio G, Widdicombe J. Reflexes from airway rapidly adapting receptors.  Respir Physiol,  2001,125:33-45.

[6]  Lee LY, Pisarri TE. Afferent properties and reflex functions of bronchopulmonary C-fibers.  Respir Physiol,  2001,125:47-65.

[7]  Zhan WZ, Yu J. Respiratory Reflexes. In: Yao T, ed. Human Physiology, 3rd ed. Beijing, China: People's Health Publisher, 2001,1504-1512.

[8]  Widdicombe JG. Airway receptors.  Respir Physiol,  2001,125:3-15.

[9]  Baluk P, Gabella G. Afferent nerve endings in the tracheal muscle of guinea-pigs and rats.  Anat  Embryol (Berl.), 1991,183:81-87.

[10]  Düring Mv, Andres KH, Iravani J. The fine structure of the pulmonary stretch receptor in the rat.  Z Anat Entwicklungsgesch, 1974,143:215-222.

[11]  Krauhs JM. Morphology of presumptive slowly adapting receptors in dog trachea.  Anat Rec,  1984,210:73-85.

[12]  Yamamoto Y, Atoji Y, Suzuki Y. Nerve endings in bronchi of the dog that react with antibodies against neurofilament protein.  J Anat,  1995,187:59-65.

[13]  Wang YF, Yu J. Na+/K+-ATPase as a marker for detecting pulmonary sensory receptors.  Acta Physiol Sin,   2002,54:390-394.

[14]  Agostoni E, Chinnock JE, Daly MD, Murray JG. Functional and histological studies of the vagus nerve and its branches to the heart, lungs and abdominal viscera in the cat.  J Physiol, 1957,135:182-205.

[15]  Knowlton GC, Larrabee MG. A unitary analysis of pulmonary volume receptors.  Am J Physiol,  1946,147:100-114.

[16]  Jordan D. Central nervous pathways and control of the airways.  Respir Physiol, 2001,125:67-81.

[17]  Sant'Ambrogio G. Nervous receptors of the tracheobronchial tree.  Annu Rev Physiol, 1987,49:611-627.

[18]  Yu J, Pisarri TE, Coleridge JCG, Coleridge HM. Response of slowly adapting pulmonary stretch receptors to reduced lung compliance.  J Appl Physiol, 1991,71:425-431.

[19]  Miserocchi G, Sant'Ambrogio G. Responses of pulmonary stretch receptors to static pressure inflations.  Respir Physiol, 1974,21:77-85.

[20]  Ogilvie MD, Bogen DK, GalanteRJ, Pack AI. Response of stretch receptors to static inflations and deflations in an isolated tracheal segment.  Respir Physiol, 1989,75:289-307.

[21]  Fisher JT, Sant'Ambrogio G. Location and discharge properties of respiratory vagal afferents in the newborn dog.  Respir Physiol,  1982,50:209-220.

[22]  Coleridge JCG, Coleridge HM. Afferent vagal C fibre innervation of the lungs and airways and its functional significance.  Rev Physiol Biochem Pharmacol, 1984,99:1-110.

[23]  Yu J, Roberts AM, Joshua IG. Lung inflation evokes reflex dilation of microvessels in rat skeletal muscle.  Am J Physiol, 1990,258:H939-H945.

[24]  Russell JA, Bishop B. Vagal afferents essential for abdominal muscle activity during lung inflation in cats.  J Appl Physiol,  1976,41:310-315.

[25]  Wang Y, Cheng Z, Zhang J, Yu J. A novel approach to investigate pulmonary receptors.  FASEB J,  2002,16:453 (abstract).

[26]  Pack AI. Sensory inputs to the medulla.   Annu Rev Physiol, 1981,43:73-90.

[27]  Coleridge HM, Coleridge JCG. Reflexes evoked from tracheobronchial tree and lungs. In: Cherniack NS, Widdicombe JG, eds. Handbook of Physiology. 2nd ed. Bethsda: American Physiological Society, 1986,395-430.

[28]  Yu J. Spectrum of myelinated pulmonary afferents.  Am J Physiol  Regul Integr Comp Physiol, 2000,279:R2142-R2148.

[29]  Yu J, Coleridge JCG, Coleridge HM. Influence of lung stiffness on rapidly adapting receptors in rabbits and cats.  Respir Physiol, 1987,68:161-176.

[30]  Jonzon A, Pisarri TE, Coleridge JC, Coleridge HM. Rapidly adapting receptor activity in dogs is inversely related to lung compliance.  J Appl Physiol, 1986,61:1980-1987.

[31]  Widdicombe JG. The activity of pulmonary stretch receptors during bronchoconstriction, pulmonary oedema, atelectasis and breathing against a resistance.  J Physiol, 1961,159:436-450.

[32]  Sellick H, Widdicombe JG. The activity of lung irritant receptors during pneumothorax, hyperpnea and pulmonary vascular congestion.  J Physiol,  1969,203:359-381.

[33]  Mills JE, Sellick H, Widdicombe JG. Activity of lung irritant receptors in pulmonary microembolism, anaphylaxis and drug-induced bronchoconstrictions.  J Physiol.  1969,203:337-357.

[34]  Armstrong DJ, Luck JC, Martin VM. The effect of emboli upon intrapulmonary receptors in the cat.  Respir Physiol,  1976,26:41-54.

[35]  Yu J, Schultz HD, Goodman J, Coleridge JCG, Coleridge HM, Davis B. Pulmonary rapidly adapting receptors reflexly increase airway secretion in dogs.  J Appl Physiol, 1989,67:682-687.

[36]  Pisarri TE, Coleridge HM, Coleridge JC. Reflex bronchial vasodilation in dogs evoked by injection of a small volume of water into a bronchus.  J Appl Physiol, 1993,75:2195-2202.

[37]  Karlsson JA, Sant'Ambrogio G, Widdicombe JG. Afferent neural pathways in cough and reflex bronchoconstriction.  J Appl Physiol,  1988,65:1007-1023.

[38]  Davies A, Roumy M. The effect of transient stimulation of lung irritant receptors on the pattern of breathing in rabbits.  J Physiol,  1982,324:389-401.

[39]  Coleridge HM, Coleridge JC. Neural regulation of bronchial blood flow.  Respir Physiol,  1994,98:1-13.

[40]  Ravi K, Kappagoda CT. Reflex effects of pulmonary venous congestion: Role of vagal afferents.  NIPS,  1990,5:95-99.

[41]  Yu J, Zhang JF, Roberts AM, Collins LC, Fletcher EC. Pulmonary rapidly adapting receptor stimulation does not increase airway resistance in anesthetized rabbits.  Am J Respir Crit Care Med,   1999,160:906-912.

[42]  Bergren DR. Sensory receptor activation by mediators of defense reflexes in guinea-pig lungs.  Respir Physiol,  1997,108:195-204.

[43]  Kou YR, Lee LY. Mechanisms of cigarette smoke-induced stimulation of rapidly adapting receptors in canine lungs.  Respir Physiol,  1991,83:61-75.

[44]  Yu J, Roberts AM. Indirect effects of histamine on pulmonary rapidly adapting receptors in cats.  Respir Physiol,  1990,79:101-110.

[45]  Solway J, Leff AR. Sensory neuropeptides and airway function.  J Appl Physiol, 1991,71:2077-2087.

[46]  Kaufman MP, Ordway GA, Waldrop TG. Effect of PEEP on discharge of pulmonary C-fibers in dogs.  J    Appl Physiol,  1985,59:1085-1089.

[47]  Pisarri TE, Yu J, Coleridge HM, Coleridge JCG. Background activity in pulmonary vagal C-fibers and its effects on breathing.  Respir Physiol, 1986,64:29-43.

[48]  Paintal AS. Thoracic receptors connected with sensation.  Br Med Bull,  1977,33:169-174.

[49]  Roberts AM, Kaufman MP, Baker DG, Brown JK, Coleridge HM, Coleridge JCG. Reflex tracheal contraction induced by stimulation of bronchial C-fibers in dogs.  J Appl Physiol, 1981,51:485-493.

[50]  Schultz HD, Roberts AM, Bratcher C, Coleridge HM, Coleridge JC, Davis B. Pulmonary C-fibers reflexly increase secretion by tracheal submucosal glands in dogs.  J Appl Physiol, 1985,58:907-910.

[51]  Davis B, Roberts AM, Coleridge HM, Coleridge JCG. Reflex tracheal gland secretion evoked by stimulation of bronchial C-fibers in dogs.  J Appl Physiol, 1982,53:985-991.

[52]  McDonald DM, Mitchell RA, Gabella G, Haskell A. Neurogenic inflammation in the rat trachea. Ⅱ. Identity and distribution of nerves mediating the increase in vascular permeability.  J Neurocytol, 1988,17:605-628.

[53]  Lee LY, Morton RF. Pulmonary chemoreflex sensitivity is enhanced by prostaglandin E2 in anesthetized rats.  J Appl Physiol, 1995,79:1679-1686.

[54]  Yu J, Soukhova GK, Fletcher EC. Unclassified pulmonary afferent maybe responsible for excitatory lung reflex.  FASEB J, 1998,12(5):A782

[55]  Trenchard D. CO2/H+ receptors in the lungs of anaesthetized rabbits.  Respir Physiol, 1986,63:227-240.

[56]  Yu J. Pulmonary reflex may promote ventilatory failure. In: Pandalai SG, ed. Recent Research Developments in Respiratory and Critical Care Medicine. Kerala, India: Research Signpost, 2002,55-68.

[57]  Yu J, Wang Y, Soukhova G, Collins LC, Falcone JC. Excitatory lung reflex may stress inspiratory muscle by suppressing expiratory muscle activity.  J Appl Physiol, 2001,90:857-864.

[58]  Cutz E, Jackson A. Neuroepithelial bodies as airway oxygen sensors.  Respir Physiol, 1999,115:201-214.

[59]  van Lommel A, Lauweryns JM, Berthoud HR. Pulmonary neuroepithelial bodies are innervated by vagal afferent nerves: an investigation with in vivo anterograde DiI tracing and confocal microscopy.  Anat Embryol (Berl.), 1998,197:325-330.

[60]  Adriaensen D, Timmermans JP, Brouns I, Berthoud HR, Neuhuber WL, Scheuermann DW. Pulmonary intraepithelial vagal nodose afferent nerve terminals are confined to neuroepithelial bodies: an anterograde tracing and confocal microscopy study in adult rats.  Cell Tissue Res,  1998,293:395-405.

[61]  Sorokin SP, Hoyt RF. On the supposed function of neuroepithelial bodies in adult mammalian lungs.  News Physiol Sci, 1990,5:89-95.

[62]  Carr MJ, Undem BJ. Ion channels in airway afferent neurons.  Respir Physiol,  2001,125:83-97.

[63]  Fox AJ. Mechanisms and modulation of capsaicin activity on airway afferent nerves.  Pulm Pharmacol,  1995,8:207-215.

[64]  Yu J, Zhang JF, Wang Y, Zhang JW, Fletcher EC. A new approach to assess sensory property of pulmonary afferents to chemicals.  Am J Respir Crit Care,  2001,163:628 (abstract).