Functional morphology and physiology of slowly adapting pulmonary stretch receptors.код для вставкиСкачать
THE ANATOMICAL RECORD PART A 270A:11–16 (2003) Functional Morphology and Physiology of Slowly Adapting Pulmonary Stretch Receptors EDWARD S. SCHELEGLE* Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California–Davis, Davis, California ABSTRACT Since the original work by Hering and Breuer (1868) on slowly adapting pulmonary stretch receptors (SARs), numerous studies have demonstrated that these receptors are the lung vagal afferents responsible for eliciting the reﬂexes evoked by moderate lung inﬂation. SARs play a role in controlling breathing pattern, airway smooth muscle tone, systemic vascular resistance, and heart rate. Both anatomical and physiological studies support the contention that SARs, by their close association with airway smooth muscle, continuously sense the tension within the myoelastic components of the airways caused by lung inﬂation, smooth muscle contraction, and/or tethering of small intrapulmonary airways to the lung parenchyma. As a result, the receptor ﬁeld location within the tracheobronchial tree of a SAR plays an important role in its discharge pattern, with variations in airway transluminal pressure and airway smooth muscle orientation being important modulating factors. The disruption of airway myoelastic components in various pulmonary diseases would be expected to alter the discharge pattern of SARs, and contribute to changes in breathing pattern and airway smooth muscle tone. Anat Rec Part A 270A:11–16, 2003. © 2003 Wiley-Liss, Inc. Key words: vagus nerve; slowly adapting pulmonary stretch receptors; control of ventilation SARs are a category of neural afferent endings that innervate the tracheobronchial tree. Their original designation was based on the observation that an increase in airway wall tension increases receptor discharge, i.e., there is a rhythmic pattern of discharge during eupneic breathing (dynamic property), and this increase in discharge slowly adapts as airway wall tension is maintained (static property). The rhythmic discharge of eupneic breathing is characterized by a mounting discharge during inspiration and a declining discharge during expiration. The pattern of SAR discharge during eupneic breathing and lung inﬂation is a direct consequence of their anatomical location within the tracheobronchial tree and the orientation of their receptor endings in relation to airway wall structures. The ﬁrst documented role for SARs was as the afferent “input” for evoking the HeringBreuer inﬂation reﬂexes. These reﬂexes are characterized by an early termination of inspiration when the lungs are inﬂated during inspiration, and a prolongation of the expiratory pause when a prolonged inﬂation is applied at the end of inspiration (Fig. 1). In addition, these receptors © 2003 WILEY-LISS, INC. have been implicated in the regulation of airway smooth muscle tone, the regulation of systemic vascular tone and heart rate, and the pathophysiology of restrictive lung disease. Historically, SARs have played an interesting role in physiology. Hering and Breuer’s (1868) description of the vagus nerves’ function in the “self steering” of breathing is arguably the ﬁrst description of a negative feedback loop playing a role in the regulation of a normal body function. With our current understanding of biological systems and *Correspondence to: Edward S. Schelegle, Ph.D., Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California–Davis, One Shields Ave., Davis, CA 95616. Fax: (530) 752-7690. E-mail: firstname.lastname@example.org Received 24 April 2002; Accepted 5 September 2002 DOI 10.1002/ar.a.10004 12 SCHELEGLE homeostatic mechanisms, it is hard to imagine a time when the notion of a feedback loop would be novel. The studies of Hering and Breuer (1868) were followed by the descriptions of Stirling (1876), Krause (1876), and Berkeley (1893) of myelinated nerves within the lung that are distributed to the bronchial smooth muscle. Later, Larsell (1921) and Larsell and Dow (1933) described afferent nerve endings terminating in bundles of airway smooth muscle in rabbit, dog, and human lung. They described coarse ﬁbers that end in plate-like masses in airway smooth muscle bands. The terminal branches of these nerves terminate between and wrap around the smooth muscle. Smaller bands of muscle are partially encircled by the terminal twigs, with their terminal knobs located between individual muscle cells. In the same year that Larsell and Dow reported their anatomical studies of the human lung, Adrian (1933) published his studies on the afferent impulses in the vagus nerve and their affect on breathing. This was the ﬁrst study of the discharge pattern of single vagal afferent ﬁbers arising from the lung. Adrian reported that the main group of sense organs in the lung behave no differently than the muscle spindles and stretch receptors found in other parts of the body. This main group of sense organs shows a serial discharge of impulses when they are stretched, and adapt very slowly. Adrian (1933, p. 355) stated that “[T]he stretch receptors in the lung resemble those in skeletal muscle in their effect on the central nervous system. Both inﬂuence it to cut short the movement which has stimulated them, and in so doing prevent the inconvenience or damage which might from unrestrained motor activity.” Adrian’s studies were followed by those of Knowlton and Larrabee (1946), in which they analyzed the discharge pattern of pulmonary volume receptors. Knowlton and Larrabee (1946) identiﬁed two distinct pulmonary volume receptors: SARs and rapidly adapting receptors (RARs). It was thus 65 years after the ﬁndings of Hering and Breuer (1868) were reported that the afferent arm of the feedback loop they described was physiologically identiﬁed, and 78 years after that the nomenclature we use today to identify these ﬁbers as SARs was devised. The description of the discharge pattern of SARs following numerous stimuli reported by Knowlton and Larrabee (1946) and later by Widdicombe (1954a, b) form the foundation on which all further studies of the physiologic function of SARs are based. The early studies of Widdicombe (1954a, b), in which reﬂex responses were isolated to different areas of the tracheobronchial tree, and the newly developed technique of nerve cooling was used to produce selective conduction block of nerve ﬁbers when combined with the extensive study of single-ﬁber discharge patterns under numerous conditions, provided us with initial insights into the full physiologic function of SARs. These initial studies provided the ﬁrst information (and the impetus for numerous physiologic studies) concerning 1) the distribution of SARs within the tracheobronchial tree; 2) the effect of airway distribution on discharge pattern and physiological response; 3) the response of SARs to changes in airway resistance and lung compliance, and in turn their inﬂuence on airway smooth muscle tone; and 4) the response of SARs to changing CO2 levels delivered to them. The remainder of this review will brieﬂy examine the later studies that extended these observations, and conclude with a discussion of the possible role of SARs in disease. These mostly physiological studies occurred in parallel with anatomical studies (Elftman, 1943; von During et al., 1974; Yamamoto et al., 1995) of the innervation of the airway smooth muscle by the afferent end organs (originally described by Larsell (1921)). The study of Bartlett et al. (1976) provided the best localization of functional SARs to airway smooth muscle. As a result, these anatomically described afferent endings remain the presumptive end organs responsible for the discharge pattern of SARs recorded in the vagus and only grossly localized to the tracheobronchial tree. In order to identify the speciﬁc receptors and stimuli that play a role in setting breathing patterns and evoking the Hering-Breuer inﬂation reﬂexes, several investigators (Widdicombe, 1954a; Miserocchi et al., 1973; Miserocchi and Milic-Emili, 1975; Bartlett et al., 1976; Ravi, 1986) attempted to quantitate the relative distribution of SARs within the lower airways. These investigators used a combination of single nerve ﬁber recording techniques with locally applied stimuli to determine the anatomical location of the receptor being studied. The results of these studies indicate that a considerable variation between mammalian species exists in the distribution of SARs along the tracheobronchial tree. Using the combined observations of Miserocchi et al. (1973) and Bartlett et al. (1976) in dogs, the distribution of SARs is 18.8% in the extrathoracic trachea, 34.4% in the intrathoracic trachea, 9.0% in the bronchus, and 36.1% in the intrapulmonary airways. Similarly, using the combined observations of Ravi (1986) and Widdicombe (1954b) in the cat, the distribution SARs is 0.8% in the extrathoracic trachea, 2.1% in the intrathoracic trachea, 13.2% in the extrapulmonary bronchus, and 83.9% in the intrapulmonary airways. Keller et al. (1989) reported that in the guinea pig, 92% of the SARs identiﬁed were located in small intrapulmonary airways and only 8% were located in the large airways, including the trachea, main bronchi, and lobar bronchi. Given their location in the tracheobronchial tree, and the different forces acting upon them during the ventilatory cycle, it is not surprising that extra-/intrathoracic and extra-/intrapulmonary SARs have different patterns of discharge. In addition, these different populations of receptors respond differently to applied lung inﬂation and deﬂation. Intrathoracic SARs have a rhythmic pattern of discharge during eupneic breathing that is characterized most often by a mounting discharge during inspiration and a declining discharge during expiration. In contrast, extrathoracic tracheal receptors exhibit a more irregular pattern of discharge and may exhibit in a few receptors a mounting discharge during expiration. The large group of SARs with inspiratory rhythmic discharge pattern has been further characterized based on whether they continue to discharge during expiration. Sant’Ambrogio and Sant’Ambrogio (1982) discussed the different terminology used to describe these receptor populations. For the purposes of this review, we use the terminology ﬁrst proposed by Paintal (1973) and refer to SARs with discharge activity during expiration as “low-threshold” receptors and those that are silent during expiration as “high-threshold” receptors (Fig. 2). SARs demonstrating these discharge patterns have been shown in cats (Ravi, 1986), dogs (Miserocchi and Sant’Ambrogio, 1974), and rats (Bergren and Peterson, 1993; Davies et al., 1996). In addition to the observed differential distribution of low- and high-threshold receptors in extra- and intrapulmonary airways, extra- and intrapulmonary SARs have FUNCTIONAL MORPHOLOGY AND PHYSIOLOGY OF SARs Fig. 1. Response to lung hyperinﬂation applied at the end of inspiration in a dog with (A) vagus nerves intact and (B) after bilateral vagotomy. Note the prolonged expiration with (A) the vagus nerves intact, indicating the presence of the Hering-Breuer inﬂation reﬂex. Note that (B) after bilateral vagotomy the Hering-Breuer reﬂex is absent, and that prior to and after hyperinﬂation, respiratory frequency is decreased and tidal volume (VT) is increased. This illustrates not only the role of the vagus in the Hering-Breuer inﬂation reﬂex, but also the inﬂuence of the vagus nerves in determining the eupneic breathing pattern. VT, tidal volume; ABP, arterial blood pressure; PTP, transpulmonary pressure. been shown to respond differently to positive and negative pressures applied to the airway. Miserocchi and Sant’Ambrogio (1974) found that 58% of extrapulmonary receptors in the dog showed a plateau in discharge frequency in response to an applied airway pressure above 10 cm H2O. Of these receptors, 88% were located in extrapulmonary airways, with 100% being located in airways ⬎ 1 mm in diameter. The remaining type of SARs described had an increasing discharge frequency to applied airway pressures up to 30 cm H2O. Of these receptors 57% were located within intrapulmonary airways and showed a more even distribution throughout the airway levels studied. In comparison, a negative pressure applied to the airway has been shown to selectively activate extrathoracic SARs (Bartlett et al., 1976; Widdicombe, 1954b). Considering the large variation in the distribution of SARs, and their varying pattern of discharge, it becomes important to understand the relative contribution these different populations of receptors have on reﬂex responses, including the control of breathing. Interestingly, despite their relatively high percentage in the dog, extraand/or intrathoracic tracheal receptors do not appear to contribute signiﬁcantly to inﬂation reﬂexes or the control of breathing (Russell and Bishop, 1976; Lloyd, 1979; Lloyd and Cooper, 1980; Rao et al., 1981). In rabbits, however, tracheal receptors may act to delay the activation of the 13 Fig. 2. Response of (A) a low-threshold SAR and (B) a high-threshold SAR (high amplitude spikes) to the application of 15 cm H2O inﬂation pressure to the airway in an anesthetized, closed-chest, mechanically ventilated rat. Bar at the bottom of ﬁgure represents 2 sec. Note the presence of expiratory discharge activity in the (A) low-threshold SAR prior to inﬂation. AP, action potential; PTP, transpulmonary pressure. inspiratory off-switch and facilitate post-inspiratory endexpiration diaphragm activity, and thus act to modulate the reﬂex response evoked by SARs lower in the airway (Agostini et al., 1985). Whether such differential inﬂuences on the control of breathing exists for any of the other proﬁles of SARs located through the airway tree (i.e., highor low-threshold, deﬂation-sensitive, etc.) is unclear. Coleridge and Coleridge (1986) proposed that low-threshold receptors, which have a low continuous discharge rate during expiration and are primarily located in large bronchi in the cat (Ravi, 1986), contribute more to setting expiratory time than high-threshold receptors. Inhibitory effects of changing end-tidal CO2 on SARs have now been observed in dogs and other mammalian species (Mustafa and Purves, 1972; Schoener and Frankel, 1972; Sant’Ambrogio et al., 1974; Bradley et al., 1976; Kunz et al., 1976; Coleridge et al., 1978; Bystrzycka and Nail, 1980; Mitchell et al., 1980) with intrapulmonary high-threshold receptors being the most affected (Ravi, 1985). The results of these studies indicate that this inhibitory effect is limited to end-tidal CO2 below normal. In contrast, Green et al. (1986) demonstrated that when pulmonary arterial CO2 was altered while maintaining tidal volume and breathing frequency constant, the inhibitory effect of CO2 on SAR discharge extends above as well as below normal resting pulmonary arterial CO2. The inhibition of SAR discharge by CO2 has been shown to be independent of changes in pulmonary mechanics (Mustafa and Purves, 1972; Sant’Ambrogio et al., 1974; Coleridge et al., 1978; Green et al., 1986). The possibility that an elevated PCO2 acts by increasing hydrogen ion concentration at the receptor location is supported by those studies that show that treatment with acetazolamide attenuates the CO2-induced inhibition (Sant’Ambrogio et al., 14 SCHELEGLE Fig. 3. Schematic of SAR input traveling in the vagus nerve (vagus n.) into the nucleus tractus solataris (NTS), and the inhibitory inﬂuence on neurons in the nucleus ambiguus (NA) and the nucleus paraambiguus (NPA). The inhibitory inﬂuence on the NPA decreases the output from the spinal motor nucleus (SMN), decreasing the motor output to the respiratory muscles (illustrated is the motor output via cervical spinal nerves 3–5 (phrenic nerve) supplying the diaphragm). The inhibitory inﬂuence on the NA decreases the output via the parasympathetic nerves (PSN) traveling in the vagus nerve to airway ganglia (AG) and decreasing the parasympathetic motor output to airway smooth muscle (ASM). Also shown are the excitatory inﬂuence of increasing ASM tension, and the inhibitory inﬂuence of elevated airway and pulmonary arterial CO2 on SAR. 1974; Ravi, 1985). Matsumoto et al. (1999, 2000) suggested that the CO2-induced inhibition of SARs does not involve a reduced inﬂux of Na⫹ through voltage-gated Na⫹ channels, but may involve the activation of 4-aminopyridine-sensitive K⫹ channels on the nerve terminals of SARs. Numerous investigators have demonstrated an increase in peak inspiratory and/or mean expiratory discharge activity of SARs located below the trachea in several species following the administration of bronchoconstrictive agents (Widdicombe, 1954a; Bartlett et al., 1976; Davenport et al., 1981b; Matsumoto et al., 1990) and vagal parasympathetic efferent stimulation (Matsumoto, 1996). These interventions have been shown to act through the contraction of airway smooth muscle, and not by a direct stimulation of the SAR terminal ending (Matsumoto et al., 1990, 1992, 1993; Matsumoto and Shimizu, 1994; Matsumoto, 1996). In addition to the direct effect of airway smooth muscle contraction upon SAR activity, receptors located peripherally to a site of airway constriction also exhibit an increase in discharge frequency due to resistive loading of the airway (Davenport et al., 1981a) (it has also been shown that an increase in SAR activity relaxes airway smooth muscle by reducing parasympathetic tone to the airway (Widdicombe and Nadel, 1963a, b)). Widdicombe and Nadel (1963b) suggested that SARs play a role in a negative feedback mechanism that acts to limit increases in parasympathetic tone to the airway, and optimize the reciprocal relationship between dead space and airway resistance. The role that phasic activity of SARs plays in determining normal airway tone, and how this may be altered in disease states, such as asthma, have become areas of active study. Recent studies suggest that SARs play important roles in the regulation of breathing pattern and/or airway tone in pathological conditions wherein their sensitivity to normal stimuli is increased due to bronchoconstriction (Widdicombe, 1954a; Bartlett et al., 1976; Davenport et al., 1981b; Matsumoto et al., 1990), airway obstruction (Davenport et al., 1981a), or decreases in lung compliance (Yu et al., 1991). Koller and Ferrer (1973) observed an increase in SAR activity following allergen challenge in a guinea pig model of asthma. More recently, Mansoor et al. (1997b) showed that vagal afferent ﬁbers do not contribute to mild alterations in breathing patterns observed in rats with elastase-induced emphysema, whereas they appear to signiﬁcantly inﬂuence breathing pattern and altered pulmonary reﬂexes in rats with bleomycin-induced pulmonary ﬁbrosis (Mansoor et al., 1997a; Schelegle et al., 2001). Pulmonary ﬁbrosis is characterized by an increased collagen content of the lung parenchyma that is often associated with chronic inﬂammation. The increase in lung collagen results in a decrease in lung volume and compliance. In addition, pulmonary ﬁbrosis may produce a decreased diffusing capacity that can result in hypoxia and hypercapnia. These alterations in lung mechanics and gas exchange are usually associated with a rapid shallow breathing pattern at rest and during exercise, and the sensation of dyspnea. Guz et al. (1970) ﬁrst hypothesized that lung vagal afferents with receptor endings within the airways and parenchyma play a role in the development and maintenance of this abnormal breathing pattern. This hypothesis now seems reasonable given our new knowledge of reﬂexes evoked by SARs in response to experimentally induced alterations in lung compliance and to exogenous inﬂammatory mediators (Coleridge and Coleridge, 1986; Mansoor et al., 1997a). Using selective conduction blocking techniques, Mansoor et al. (1997a) examined the inﬂuence of lung vagal nonmyelinated and myelinated afferents in the rapid shallow breathing pattern present in rats with bleomycininduced pulmonary ﬁbrosis. Mansoor et al. (1997a) found that an alteration in the phasic and/or tonic impulse activity of SARs and/or RARs contribute to the observed rapid shallow breathing in this model of lung ﬁbrosis. In a subsequent study, Schelegle et al. (2001) examined the impulse activity of pulmonary vagal afferents in rats with bleomycin-induced lung ﬁbrosis. Bleomycin treatment resulted in a signiﬁcant increase in the volume sensitivity of high-threshold SARs, while it blunted the sensitivity of these ﬁbers to increasing transpulmonary pressure. In addition, the activity of high-threshold SARs during the deﬂation phase of expiration was signiﬁcantly reduced in bleomycin-treated rats. These observations are consistent FUNCTIONAL MORPHOLOGY AND PHYSIOLOGY OF SARs with previous observations of the effects of acutely induced decreases in lung compliance on SAR discharge patterns in cats and rabbits (Yu et al., 1991). Yu et al. (1991) found that a 30% reduction in lung compliance resulted in a signiﬁcant increase in SAR discharge at peak inﬂation of the ventilator cycle in an experiment in which inﬂation volume was held constant across treatments. The increase in responsiveness of SARs to lung inﬂation volume induced by bleomycin would lead to an increased SAR input to the brainstem at any given lung volume, and would therefore act as an inspiratory “off switch” at a lower inﬂation volume and contribute to a reduced tidal volume and possibly a shorter inspiratory time. Mansoor et al. (1997a) observed a signiﬁcant reduction in the average expiratory frequency for SARs as well, and suggested that a decrease in tonic expiratory activity of SARs may also contribute to the previously observed shortening of expiratory time in this model of chronic pulmonary ﬁbrosis. Widdicombe (1964) pointed out the wide variation in thresholds and potencies of the Hering-Breuer inhibitory reﬂex in research animals, and the perceived lack of inﬂuence that SAR discharge has on resting breathing pattern in man. While we have learned much in recent years, our knowledge is far from complete. Most investigators now believe that in most species, once a certain volume threshold is achieved, the “inspiratory off-switch” provided by stretch receptor input controls tidal volume and inspiratory time. In addition, the expiratory discharge of these receptors may act to determine expiratory time and thus inﬂuence breathing frequency at rest—at least in some species. On the other hand, the role that normal phasic activity of SARs plays in determining normal airway tone is poorly understood. Also poorly understood is the function of SARs in the regulation of breathing pattern and/or airway tone under conditions (such as exercise) in which tidal volume is increased, and the role these receptors play when their activity changes due to bronchoconstriction, airway obstruction, or decreases in lung compliance (Fig. 3). Manning et al. (1992) observed that the sensation of air hunger induced by the inhalation of increased CO2 in humans is modulated by volume feedback from the lung, with greater lung volumes being associated with a reduced rate of air hunger. This observation is consistent with the notion that while SARs may not play a role in setting eupneic breathing patterns in humans, their pattern of discharge in lung disease may act to modulate sensations of air hunger and dyspnea. 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