Studies on the role of the lung deflation reflex

Respiration Physiology (1970) 10, 172-l 83 ; North-Holland Publishing Company, Amsterdam

STUDIES

ON THE ROLE OF THE LUNG DEFLATION

REFLEX

E. A. KOLLER AND P. FERRER Department

of Physiology, University qf Zurich, Switzeriandl

Abstract. The role of the lung deflation

receptors in the respiratory responses to pneumothorax, thoracic compression and anaphylactic bronchial asthma was studied by differential cold block and action potential recording of vagal afferent fibres in spontaneously breathing guinea-pigs. The animals were anaesthetized, or decerebrated at mid-collicular level. Extra-vagal reflexes and pharmacological influences can be excluded. The marked inspiratory effect of forced lung deflation is not affected by cold block of the pulmonary stretch receptors, and is hence essentially different from the weak inspiratory effect brought about by the decrease of lung volume during normal expiration. The marked inspiratory effect, which is characterized by tachypnoe and compensatory increase of lung volume, is mediated by lung deflation receptors, excited specifically by any decrease of lung volume below the normal relaxation volume. The deflation reflex can also be produced by acute increase of lung volume associated with uneven distribution of the inspired air, such as occurs during anaphylactic bronchial asthma in the guineapig. In such animals expiratory airflow is impeded and air-trapping is produced, so that “expiratory self-compression” of the lungs cramped in the thoracic cage occurs. This expiratory pulmonary compression leads to excitation of the lung deflation receptors, resulting in a marked inspiratory reaction, thereby overruling the pulmonary inflation reflex as long as bronchial obstruction and hence expiratory disturbances occur. A complex vicious circle is set up, comprising structural changes (emphysema and microscopic atelectasis) and functional disturbances (rapid and shallow breathing, i.e., the marked inspiratory effect). The lung deflation reflex plays no part in the self-regulation of breathing and should be regarded as a nociceptive reflex tending to prevent and suppress pulmonary compression and pulmonary collapse. Anaphylactic bronchial asthma Lung deflation reflex Pneumothorax

Thoracic compression Uneven ventilation Vagal respiratory reflexes

The foundation for studies on the role of the vagus in the reflex control of breathing was laid by HERINC (1868) and BREUER (1868) when they showed that lung inflation elicits an inhibito-inspiratory reflex, which is mediated by this nerve and leads to Acceptedfor 1 Address

publication 16 April 1970.

for reprints: Zurich, Switzerland.

Department

of Physiology,

172

University of Zurich, Ramistrasse

69, 8001

THE LUNG DEFLATIONREFLEX expiration,

whereas relaxation

of the lungs evokes a vagal excite-inspiratory

173 effect, so

that a rhythmic pattern of alternate active inspiration and passive expiration is set up. It was only later that improved methods led to the conclusion that during uninfluenced spontaneous breathing, inspiration as well as expiration depends on a decisive factor, namely the “frequency effect” of the pulmonary stretch receptors (WYSS, 1939, 1950). It is pulmonary stretch receptor activity which ensures the self-regulation of breathing by the vagus. This has been shown in guinea-pig by selective afferent stimulation of the pulmonary stretch receptor fibres (OBERHOLZER, RICCI and STEINER, 1955) or by recording the spontaneous afferent activity of the vagus (FERRER and KOLLER, 1968). These studies indicate that high frequency discharges fired by the pulmonary stretch receptors during the inspiratory phase of normal breathing, produce the inhibito-inspiratory effect (the lung inflation reflex), while lessening of these stretch receptor discharges during expiration evokes a weak inspiratory reaction (the so-called “Lungen-Entdehnungsreflex”). However, as BREUER(1868) has already shown, forced deflation of the lungs, i.e., reduction of the functional residual capacity (FRC) below the normal expiratory level, also produces inspiratory stimulation (the lung deflation reflex). This author showed that the forced expiratory movement produced by suction of air from the trachea or by pneumothorax, is instantly interrupted by a strong inspiratory effect, which may lead to inspiratory tetanos, provided a certain degree of lung collapse has occurred. It is today clear that the strong inspiratory reaction to lung deflation is entirely different from the weak inspiratory effect caused by lessening of inflation (in other words, lessening of the inhibito-inspiratory impulses of the pulmonary stretch receptors) during normal expiration. Electrophysiological studies have thrown muchlight on the strong inspiratory effect produced by lung deflation. ADRIAN (1933), who recorded spontaneous action potentials in single afferent fibres of the vagus nerve in rabbit and cat, showed that suction of air from the lungs or increasing the extrathoracic pressure, stimulates at expiration a fresh set of end organs which are not stimulated by the normal movements of the lungs. Characteristics of the afferent vagal fibres specifically stimulated by lung deflation are: High stimulation threshold; independence of the strong inspiratory effect of stimulation rate (WYSS and RIVKINE, 1950; FERNANDEZ DE MOLINA and WYSS, 1950); and slow conduction velocity, averaging below 6 m/set (PAINTAL, 1953, 1955). The receptors from which the fibres arise are apparently situated in the respiratory bronchioles or distal to them, since they are stimulated or sensitized by ether inhalation or by drugs injected into the pulmonary circulation (PAINTAL, 1955, 1957a, b). The strong acceleratory and inspiratory effect produced by deflation fibres sensitized by phenyl diguanide is abolished by cooling the vagi to temperatures below 3 “C (DAWES, MOTT and WIDDICOMBE, 1951). The lung deflation fibres are very fine and they outnumber the other fibres carried by the pulmonary vagus. Their specificity appears to be small (MILLS, SELLICK and WIDDICOMBE, 1969), since the lung deflation reflex has so far not been clearly differentiated from the respirathe respiratory and cardiovascular responses to tory “pulmonary chemoreflex”,

174

E. A. KOLLERAND P. FERRER

multiple pulmonary embolism, and the paradoxical reflex of HEAD (1889). Observations on the lung deflation reflex have been mostly carried out on cat and rabbit. The reader is referred to the publications of PAINTAL (1963), WIDDICOMBE (1964) and WYSS (1964) for further data on the subject. The lung deflation

fibres investigated

in cat by PAINTAL (1957a, b, 1969), in rabbit

by HOMBERGER(1968) and in guinea-pig by FERRER and KOLLER (1968) are the only afferent fibres studied by action potential recording that seem likely to mediate the deflation reflex. The aim of the present investigation, carried out on spontaneously breathing animals with intact thorax, was to differentiate this reflex from the vagal reflexes mediating the self-regulation of respiration. To accomplish this, the action potentials in single afferent filaments of the vagus and the respiratory responses were recorded simultaneously. The role played by the lung deflation reflex in general or local pulmonary alterations was also investigated, care being taken to exclude pharmacological influences and extravagal reflex responses. Methods The experiments were carried out on over 100 guinea-pigs anaesthetized with urethane (1 to 1.5 g/kg) or decerebrated by high-frequency coagulation. A tracheal cannula was inserted, as well as a jugular veinous catheter for injection of drugs (urethane, atropine, albumen). Pleural pressure was measured through a left sinus phrenico-costalis catheter, which was also used when inducing a pneumothorax. The techniques used have been fully described in preceding papers (KOLLER, 1967a, b; FERRER and KOLLER, 1968; KOLLER and JENNY, 1969). Spontaneous respiration was recorded by means of a body plethysmograph into which a tracheal cannula was fitted through which the animal continued to breath room air. In some experiments the intraplethysmographic pressure was maintained constant, and changes in lung volume were recorded (volume displacement plethysmograph).

In other

experiments

the intraplethysmographic

volume

was maintained

constant (constant volume plethysmograph) in order to register: a) changes of pressure due to the respiratory excursions of the spontaneously breathing animal; or b) artificially produced changes of pressure (by raising or lowering the intraplethysmographic pressure) in order to evoke respiratory reflexes. Changes in tracheal cannula sidepressure were recorded at the same time. Afferent activity was studied in the left cervical vagus nerve. Filaments of this nerve measuring 4-6 mm in length were prepared and sectioned at their central end, the nerve remaining otherwise intact. The spontaneous afferent activity of one or several nerve fibres was then led off from two platinum hook-electrodes in simple bipolar arrangement and recorded simultaneously with the tracheal cannula side-pressure and the plethysmographic pressure (see above). Cooling of the vagus was performed by means of thermodes measuring 10 mm in length. Reversible and differential vagus block was obtained by perfusing the thermodes at a constant rate with alcohol cooled to temperatures between 0 and 4 “C or 4 and 8 “C respectively, or warmed to 40 “C. Owing to the fact that difficulties are encountered

THE

LUNG DEFLATIONREFLEX

175

when measuring the temperature of the vagi within the plethysmograph, measurement was made of the temperature of the in- and outcoming alcohol. A system of hot or cold water coils, inserted into the plethysmograph, counterbalanced the action of the thermodes and maintained the plethysmographic pressure and volume constant. Vagal respiratory reflexes were evoked as follows: a) The lung deflation reflex, by inducing a graded and reversible pneumothorax. The product of volume and pressure in the plethysmograph was maintained constant by withdrawing from the plethysmograph the volume of air blown into the intrapleural space. b) Lung deflation and inflation reflexes, by compression and subsequent distension of the thorax (WILSON and HAMMOUDA, 1928). Distension was produced by withdrawing air from the plethysmograph, thus causing a negative pressure around the animal. Increased extrathoracic pressure was produced by reversing the procedure. The intraplethysmographic pressure was controlled and recorded by a water manometer. c) Reversible bronchial asthma in animals sensitized to egg albumen, by inhalation of the antigen aerosol (HERXHEIMER, 1952). At onset of increased bronchial resistance, a marked inspiratory reaction mediated by afferent vagus fibres subserving inspiration occurs (KOLLER, 1967b, 1969). The three foregoing reflexes only occur with intact vagi and before a change in ventilation has had any effect. Extravagal proprioceptive influences can be excluded (FERRER and KOLLER, 1968). Results The marked inspiratory effects due to the lung deflation reflex can be differentiated from the weak inspiratory effect brought about by release of the inflation reflex during the expiratory phase of normal breathing, by progressively cooling the vagus nerves. Typical records may be seen in fig. 1. At Pt induction of a left-side pneumothorax causes a reduction of the FRC below the normal expiratory level, manifested by a forced expiratory movement, which is suddenly interrupted by accelerated and shallow respiration, i.e., the marked inspiratory effect. As a result, partial compensation of the reduced lung volume occurs. The inspiratory effect is not abolished by cooling the vagi to a temperature of 4-8 “C (fig. lA, signal a), although such a procedure - when normal breathing has been restored by withdrawal of pneumothorax (PJ) - does block the pulmonary stretch receptors (fig. lB, signal a), so that the guinea-pig presents the appearance of a vagotomized animal. The marked inspiratory effect of pneumothorax is hence not mediated by the vagal stretch receptors subserving the self-regulation of breathing. Cooling the vagi to 04 “C (fig. 1A, signal b) abolishes the effect and shows that it is mediated by an entirely different set of fibres - the so-called lung deflation fibres, and this is also shown by recording spontaneous afferent activity in the vagal filaments. In fig. 2 during uninfluenced spontaneous breathing (a) the afferent neurogram of the left cervical vagus shows the activity of a single pulmonary stretch receptor, i.e.,

176

E. A. KOLLER

AND P. FERRER

Fig. 1. Separation of the lung deflation reflex from the respiratory effects of the lung stretch receptors (firing at low rates) by differential cold block of the vagi in the guinea-pig. A: Deflation reflex elicited by pneumothorax. Pt : Injection of 2 ml air into the left sinus phrenicocostalis. Pi: Withdrawal of pneumothorax by air suction. a) Cooling the vagus nerves to 4-8 “C (cold block of the lung stretch fibres). b) Cooling the vagus nerves to O-4 “C {cold block of the lung deflation fibres). b’) Rewarming of the nerves. R: Control, normal spontaneous breathing a) Cooling the vagus nerves to 4-8 “C. a’) Rewarming of the nerves Body plethysmography; volume calibrated in ml; inspiration upward.

discharge sequences characterized by maximal rates during the inspiratory phase and minimal rates during expiration. During the marked inspiratory effect produced by induction of a small pneumothorax (b), slight lessening in rate of discharge of the stretch receptor occurs, and the new set of fibres, stimulated at expiration, become active. The spikes are of low amplitude, cannot be identi~ed as units and appear to be related to the slow, i.e., end-phase of expiration. If extra-thoracic pressure is now increased (c), the discharges of the lung deflation fibres increase in rate and the bursts finally merge. If intra-plethysmographic pressure is, however, decreased to subatmospheric values, causing thoracic distension (d), the discharges of the lung deflation fibres no longer occur and respiration becomes expiratory in type, although the pneumothorax is still maintained. Block of the afferent impulses from the pulmonary stretch receptors produces minimal reduction of the marked inspiratory reaction to pneumothorax. And this holds true if thoracic compression is resorted to instead of pneumothorax, which means that lessening of pulmonary stretch receptor activity cannot be responsible for the marked

THE LUNG DEFLATION REFLEX

177

Fig. 2. Vagus afferent discharges at inspiration (pulmonary stretch receptor) and at expiration (pulmonary deflation receptors) during pneumothorax (b) combined (at c) with compression of the thorax. a) Control. Stretch receptor activity during unin~uenced spontaneous breathing. b’J Reduced stretch receptor activity and stimulation of deflation receptors during accelerated respiration of inspiratory type, as concomitant responses to left-side pneumothorax (2 ml). c) Increased deflation receptor activity and inspiratory reaction in response to pneumothorax combined with thoracic compression. 4 Increased stretch receptor activity and expiratory reaction to thoracic distension. (Note absence of deflation receptor discharges.) From top to bottom: Tracheal cannula side-pressure (inspiration downward), afferent vagal neurogram combined at c and d with pressure curve from the body-pietbysmograph.

inspiratory reaction. The latter hence appears to be closely related to deflation receptor activity, since the slight inspiratory effect due to lessening of stretch receptor activity and the frequency effect of the stretch receptors firing at low rates (see above) need not to be taken into account. Stimulation of the lung deflation fibres (see fig. 2b and c) does indeed result in quickening of breathing as well as in augmentation of the inspiratory-expiratory duration relationship, in other words in the marked inspiratory effect. Pneumothorax and thoracic compression are easily understood examples of the lung deflation reflex. More difficult to understand - and at first sight paradoxical - is the fact that the deflation fibres also mediate the inspiratory reaction due to the acute increase of lung volume in anaphylactic bronchial asthma. This has, however, been amply demonstrated by vagal cold block, differentiated afferent vagal stimulation and

178

E. A. KOLLER

AND P. FERRER

Fig. 3. Vagal afferent neurogram during the lung deflation reflex elicited by anaphylactic bronchial asthma(b) combined with pneumothorax (at c) as well as thoracic compression (at d). a) Control. Uninfluenced spontaneous respiration. b) Deflation receptor discharges and respiratory responses to antigen inflation. cl Increased deflation receptor activity and increased inspiratory reaction after inducing pneumothorax (3 ml), combined at d) with thoracic compression. 4 During subsequent thoracic distension, increased stretch receptor discharges and expiratory reaction. (Note the absence of deflation discharges.} From top to bottom: Tracheal cannula side-pressure (inspiration downward), ECG (Einthoven 1) at c, d and e, afferent vagat neurogram combined at d and e with pressure curves from the bodyplethysmograph.

recording of spontaneous afferent impulses in vagal filaments. In fig. 3 during uninfluenced spontaneous breathing (a), the afferent vagal neurogram shows the activity of a single pulmonary stretch receptor, and of pressoreceptors synchronous with cardiac rhythm. After inhalation of the antigen aerosol, an asthma attack occurs (b). It has practically no effect on the activity of the stretch receptor, although breathing compared with normal - is accelerated and inspiratory in type. During the expiratory

THE LUNG DEFLATIONREFLEX phase, however,

a new type of action potential

appears.

The question

179 arises whether

the lung deflation receptors have come into play, in which case induction of a pneumothorax combined with subsequent thoracic compression would reinforce the expiratory discharges as well as the resultant inspiratory effects. The tracings show that such effects do in fact occur after induction of a small pneumothorax (c) followed by thoratic compression (d), and are abolished by thoracic distension (e). The afferent impulses recorded in a vagal filament during an anaphylactic asthma attack arise from a small, so far undefined portion of the left lung in which structural and functional changes bring about the marked inspiratory effect, i.e., the lung deflation reflex. This does not mean, however, that the pulmonary disturbances signalized are uniform. On the contrary, as tracings carried out in over 100 experiments show, the activity recorded comprises both deflation receptor and stretch receptor activation, corresponding to either deflation or inflation of the undefined lung portions. Examination of the in vivo fixed lungs of asthmatic guinea-pigs revealed emphysema as well as microscopic atelectasis scattered throughout the lungs, in other words, disturbances of the air content. These histological findings are therefore in close agreement with the electrophysiological data. Discussion The results reported prove that pneumothorax as well as thoracic compression in the intact guinea-pig produces accelerated respiration, inspiratory in type, associated with partial compensation of lung volume reduction, findings already partially described by TROELSTRAand HEEMSTRA(1956/57) and HOMBERGER(1968) in rabbits. This marked inspiratory effect occurs as long as the pulmonary vagi are intact, and is independent of extravagal influences. It represents an inspiratory response to lung volume reduction below the relaxation volume and is due to excitation of lung deflation receptors, since the weak inspiratory effect brought about by lessening of stretch receptor activity, and the “frequency effect” of afferent vagal impulses (WY%, 1939) can be excluded by means of differential cold block. A quantitative analysis of the respiratory effect produced on the one hand by deflation receptor activity and on the other by low-rate stretch receptor discharges, is at present being carried out. The fact that a plethysmographic pressure of at least + 3 to + 5 cm H,O or unilateral pneumothorax of at least 2 ml is required to excite the lung deflation receptors, means that the decrease in lung volume below normal expiratory level in the lung examined must correspond to normal tidal volume and that intrapleural pressure, measured in the sinus phrenico-costalis, must become slightly positive. The lung dellation receptors thus appear to be excited by negative transpulmonary pressure (FERRER and KOLLER, 1968), which would justify the German term “lung collapse receptors”. The recent work of PAINTAL (1969), showing that the so-called type J pulmonary receptors in cat are excited by application of local pressure on the lungs after opening the chest, lends support to these findings. It should be made clear that the lung deflation fibres always mediate the same reaction, i.e., the marked inspiratory effect, although they

180

E. A. KOLLERAND P. FERRER

comprise fibres of various types, ranging from A 6 to C fibres, as shown by WYSS and RIVKINE (1950) in rabbit, and apparently arise from various sites, lung parenchyma as well as vascular and bronchiolar structures (PAINTAL, 1955, 1957b, 1969; WYSS, 1964). The marked

inspiratory

effect in anaphylactic

bronchial

asthma

of guinea-pig

is

also due to excitation of the lung deflation receptors. The excitation appears to be due to disturbances of pulmonary air content and air distribution, which arise from the expiratory check-valve mechanism and complicate the bronchiolar obstruction. Since the expiratory airflow is impeded in the affected lung areas, air-trapping and regional overinflation occur. The overinflated alveoli during the expiratory rise of intrathoracic pressure compress the normally relaxed alveoli and the still collapsible bronchioles; the effect is, excitation of the lung deflation receptors. If bronchiolar obstruction, and thus uneven distribution of the inspired air, is removed (by thoracic distension in spontaneously breathing animals or by raising the inflation pressure in artificially ventilated preparations), the marked inspiratory effect no longer occurs. The sighs, so typical for an asthma attack, serve the same purpose. Like short, repeated strong inflations, they render deep, passive expiration possible by readjusting the regional intrapulmonary pressures and reopening the blocked alveolar areas (REYNOLDS, 1962). The whole process can often be followed in the afferent vagal neurogram as transient regression after the sigh - of the increased stretch receptor activity produced by the asthma attack. If the mechanical factors just discussed, and the histological and neurophysiological data are compared, it is obvious that all three appear to agree. This is probably not due to a coincidence, but strongly suggests that we are dealing with related events, in which the mechanical and histological factors bring about the neurophysiological effects. In this connection, it is of interest that PAINTAL (1957b) in cat described endings of lung deflation fibres in respiratory bronchioles, atria and alveoli, the structures which are predominantly involved in asthma. The importance of the lung deflation fibres in the respiratory and circulatory effects of anaphylactic bronchial asthma as reported in guinea-pig by KOLLER (1967b, 1968, 1969), has recently also been demonstrated in rabbit by KARCZEWSKI and WIDDICOMBE (1969), who stated that anaphylaxis stimulates lung deflation and irritant receptors which mediate much of the reflex responses. The respiratory reflexes in anaphylactic bronchial asthma of the guinea-pig have been dealt with elsewhere (KOLLER, 1969). However, it would be well to compare the role played by pulmonary stretch receptor activity i.e., the lung inflation reflex and the role played by the lung deflation reflex during an acute attack, in view of the acute increase in lung volume which then occurs. Because pulmonary stretch receptor impulses reach the respiratory center in great numbers during the air-trapping of an acute asthma attack or anaphylactic shock (BUCHER, 1952; KARCZEWSKI, 1962), it might be assumed that the acute increase of lung volume abolishes the inspiratory effect due to excitation of the deflation receptors. That this, however, is not so, was demonstrated by selective electrical stimulation of the stretch fibres during an asthma attack. The results showed that the greater the increase in lung volume, the smaller

THE

the expiratory

r_u~c DEFLATION

181

REFLEX

effect elicited by afferent vagal stimulation

at high-rates

(loo-190

c/set).

The reverse holds true for the inspiratory effect evoked by low-rate stimulation (2040 c/set). No change in receptor sensitivity could be established to explain these paradoxical effects (KOLLER, 1967b). As expiratory airflow is impeded and air-trapping is produced, “expiratory self-compression” of the lungs cramped in the thoracic cage occurs. This sets up a vicious circle in which, on the one hand, pulmonary overinflation and collapse, on the other, the marked inspiratory effect with tachypnoe, follow one another as long as bronchiolar obstruction prevails. This chain of events is due to the fact that the inspiratory-inhibition i.e., the lung inflation reflex due to high-rate afferent discharges of the stretch receptors, is overruled by the marked inspiratory effect produced by the lung deflation receptors. In other words, the lung deflation reflex takes priority over the inflation reflex (WYSS and RIVKINE, 1950) during an acute asthma attack. The lung deflation reflex should be regarded as a nociceptive reflex. It consequently does not participate in self-regulation of respiration, which means that it is entirely different from the reflexes mediated by the pulmonary stretch receptors. It may be classed with the “Fremdreflexe der Atmung” (HESS, 1931). The role of the deflation reflex is to prevent pulmonary compression or collapse and compensate lung volume reduction. Conclusions The lung deflation reflex plays a dominant role in the respiratory responses to pneumothorax, thoracic compression and anaphylactic bronchial asthma in the guinea-pig.

a

b

C

d

Fig. 4. Schematic representation of the excitation of lung deflation receptors by lessening the FRC below the relaxation volume or by increasing the lung volume in an unevenly ventilated lung. a) Control. Normal lung at expiration with uniformly relaxed terminal lung units. b) Lung at expiration after induction of a small pneumothorax.

c) Lung at expiration compressed by rising extrathoracic pressure. d) Lung at expiration “self-compressed” during an asthma attack. The small circles represent the terminal lung units, the large circle represents the thoracic cage (see text).

Fig. 4 is a schematic representation of the lung-thorax system. The large circle represents the thoracic cage. The small circles within the large one represent lung units i.e., alveoli, acini or lobuli, as the lung deflation receptor fields have so far not been definitely localized. a) shows normal lung conditions, represented by uniformely distended circles at FRC level; b) partially collapsed lung in pneumothorax; c) lung during thoracic compression and d) lung “self-compressed” in thoracic cage at

182

E. A. KOLLER AND P. FERRER

expiration in asthma attack. b), c) and d) have one factor in common, namely, reduction in volume of whole lung or portions thereof below physiological relaxation level (small grey circles). Obviously the parts of the lungs concerned are not all located at the periphery or at the centre, but are randomly distributed. The reduction in lung volume leads to excitation of the lung deflation receptors, resulting in a marked inspiratory reaction. The latter represents or pulmonary compression.

a defence mechanism

against

lung collapse

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