Changes in strength of lung inflation reflex during prolonged inflation.

Recovery from respiratory inhibition produced by the lung inflation reflex was studied in anesthetized dogs, paralyzed and ventilated with a respiratory pump. During constant ventilation the lungs were periodically inflated using positive end-expiratory pressure, while the respiratory motor output was monitored in the phrenic nerve. Inhibition of the phrenic discharge was followed by gradual recovery throughout 8-min inflation periods despite constant blood gases. Recording afferent potentials in a vagus nerve indicated that adaptation of pulmonary stretch receptors contributed to the initial recovery of the phrenic discharge, but this recovery continued after the receptor discharge had stabilized. The phrenic discharge also recovered after initial inhibition in two situations which avoided stretch receptor adaptation: a) when the stretch receptor discharge from the separate lungs was alternated in an overlapping manner by asynchronous pulmonary ventilation, and b) during continuous electrical stimulation of a vagus nerve. Phrenic activity was temporarily increased above its control value after periods of lung inflation, asynchronous ventilation and vagal stimulation. It is concluded that the lung inflation reflex gradually attenuates during prolonged stimulation due to both stretch receptor adaptation and changes within the central pathways.     

Response of slowly adapting pulmonary stretch receptors to reduced lung compliance

We examined the steady-state response of slowly adapting pulmonary stretch receptors (SAPSRs) to reduced lung compliance in open-chest cats with lungs ventilated at eupneic rate and tidal volume (VT) and with a positive end-expiratory pressure (PEEP) of 3-4 cmH2O. Transient removal of PEEP decreased compliance by approximately 30% and increased transpulmonary pressure (Ptp) by 1-2.5 cmH2O. Reduction of compliance significantly decreased SAPSR discharge in deflation and caused a small increase in discharge at the peak of inflation; it had little effect on discharge averaged over the ventilatory cycle. Increasing VT to produce a comparable increase in Ptp significantly increased peak discharge. Thus unlike rapidly adapting receptors, whose discharge is increased more effectively by reduced compliance than by increased VT, SAPSRs are stimulated by increased VT but not by reduced compliance. We speculate that the most consistent effect of reduced compliance on SAPSRs (the decrease in deflation discharge) was due to the decreased time constant for deflation in the stiffer lung. This alteration in firing may contribute to the tachypnea evoked as the lungs become stiffer.     

Rapidly adapting receptors monitor lung compliance in spontaneously breathing dogs

We examined the ability of rapidly adapting receptors (RARs) to monitor changes in dynamic lung compliance (Cdyn) in anesthetized spontaneously breathing dogs by recording RAR impulses from the vagus nerves. We decreased Cdyn in steps through the physiological range by briefly restricting lung expansion with an inflatable cuff around the chest and recording the response after deflating the cuff; we restored Cdyn to control by hyperinflating the lungs. Of 45 RARs, 34 were stimulated by a 40 +/- 2% reduction in Cdyn, their inspiratory discharge increasing on average more than threefold. Two-thirds of responsive RARs were stimulated by less than or equal to 20% reductions in Cdyn; in most, firing increased proportionately with lung stiffness (1/Cdyn) as Cdyn was decreased further. Stimulation by reduced Cdyn was not simply a function of the concomitant increase in transpulmonary pressure, because similar increases in pressure produced by increasing tidal volume produced smaller increases in firing. RAR stimulation was unaffected by atropine and, hence, was not dependent on neurally mediated changes in bronchomotor tone. Our results indicate that during spontaneous breathing RARs provide a signal inversely proportional to Cdyn.     

Rapidly adapting receptor activity in dogs is inversely related to lung compliance

We examined the response of pulmonary rapidly adapting receptors (RAR's) to changes in dynamic lung compliance (Cdyn) in the physiological range. RAR impulse activity was recorded from the cervical vagus nerves in anesthetized open-chest dogs whose lungs were ventilated at constant rate and tidal volume (VT), with a positive end-expiratory pressure (PEEP) of 3-4 cmH2O. After hyperinflation to produce maximal Cdyn, RAR's were silent or fired sparsely and irregularly. Reducing Cdyn in steps by briefly removing PEEP increased firing proportionately, and RAR's began to discharge vigorously in inflation. Activity was restored to control by hyperinflating the lungs. Activity also increased when we increased inflation rate, and hence the rate of change of airway pressure (dP/dt), by reducing inflation time, keeping VT and cycle length constant. RAR's were stimulated more when dP/dt was increased by reducing compliance than when dP/dt was increased by increasing inflation rate. We conclude that RAR's are sensitive to changes in Cdyn and speculate that excitatory input from RAR's may help to maintain VT as the lungs become stiffer.     

Effects of lung inflation on pulmonary arterial blood volume in intact dogs.

The isolated effects of alterations of lung inflation and transmural pulmonary arterial pressure (pressure difference between intravascular and pleural pressure) on pulmonary arterial blood volume (Vpa) were investigated in anesthetized intact dogs. Using transvenous phrenic nerve stimulation, changes in transmural pulmonary arterial pressure (Ptm) at a fixed transpulmonary pressure (Ptp) were produced by the Mueller maneuver, and increases in Ptp at relatively constant Ptm by a quasi-Valsalva maneuver. Also, both Ptm and Ptp were allowed to change during open airway lung inflation. Vpa was determined during these three maneuvers by multiplying pulmonary blood flow by pulmonary arterial mean transit time obtained by an ether plethysmographic method. During open airway lung inflation, mean (plus or minus SD) Ptp increased by 7.2 (plus or minus 3.7) cmH2O and Ptm by 4.3 (plus or minus 3.4) cmH2O for a mean increase in Vpa by 26.2 (plus or minus 10.7) ml. A pulmonary arterial compliance term (Delta Vpa/Delta Ptm) calculated from the Mueller maneuver was 3.9 ml/cmH2O and an interdependence term (Delta Vpa/Delta Ptp) calculated from the quasi-Valsalva maneuver was 2.5 ml/cmH2O for a 19% increase in lung volume, and 1.2 ml/cmH2O for an increase in lung volume from 19% to 35%. These findings indicate that in normal anesthetized dogs near FRC for a given change in Ptp and Ptm the latter results in a greater increase of Vpa.     

Interstitial fibrosis and collateral ventilation

Interstitial fibrosis may increase resistance to collateral flow (Rcoll) because of decreased lung volume and destruction of collateral channels or it may decrease Rcoll because of emphysematous changes around fibrotic regions. In addition, if interstitial fibrosis involves a small region of lung periphery, interdependence from surrounding unaffected lung should produce relatively large changes in volume of the fibrotic region during lung inflation. We studied the effects of interstitial fibrosis on collateral airflow by measuring Rcoll at functional residual capacity (FRC) in nine mongrel dogs before and 28 days after the local instillation of bleomycin into selected lung segments. In six of these dogs Rcoll was also measured at a higher lung volume (transpulmonary pressure = 12 cmH2O above FRC pressure). Rcoll increased in fibrotic lung segments following local treatment with bleomycin. With lung inflation (high transpulmonary pressure) Rcoll fell a similar proportion in fibrotic and nonfibrotic lung regions. These observations suggest that collateral resistance increases in fibrotic segments because lung volume decreases or because collateral pathways are involved directly in the fibrotic process. Compensatory increases in collateral communications do not occur. In addition, pulmonary interdependence does not cause disproportionate increases in volume and decreases in Rcoll of the fibrotic region during lung inflation.     

Dynamic lung compliance in newborn and adult cats

Static (Cstat) and dynamic (Cdyn) lung compliance and lung stress relaxation were examined in isolated lungs of newborn kittens and adult cats. Cstat was determined by increasing volume in increments and recording the corresponding change in pressure; Cdyn was calculated as the ratio of the changes in volume to transpulmonary pressure between points of zero flow at ventilation frequencies between 10 and 110 cycles/min. Lung volume history, end-inflation volume, and end-deflation pressure were maintained constant. At the lowest frequency of ventilation, Cdyn was less than Cstat, the difference being greater in newborns. Between 20 and 100 cycles/min, Cdyn of the newborn lung remained constant, whereas Cdyn of the adult lung decreased after 60 cycles/min. At all frequencies, the rate of stress relaxation, measured as the decay in transpulmonary pressure during maintained inflation, was greater in newborns than in adults. The frequency response of Cdyn in kittens, together with the relatively greater rate of stress relaxation, suggests that viscoelasticity contributes more to the dynamic stiffening of the lung in newborns than in adults. A theoretical treatment of the data based on a linear model of viscoelasticity supports this conclusion.     

Phasic pulmonary stretch receptor feedback modulates both eupnea and gasping in an in situ rat preparation

The perfused in situ juvenile rat preparation produces patterns of phrenic discharge comparable to eupnea and gasping in vivo. These ventilatory patterns differ in multiple aspects, including most prominently the rate of rise of inspiratory activity. Although we have recently demonstrated that both eupnea and gasping are similarly modulated by a Hering-Breuer expiratory-promoting reflex to tonic pulmonary stretch, it has generally been assumed that gasping was unresponsive to afferent stimuli from pulmonary stretch receptors. In the present study, we recorded eupneic and gasplike efferent activity of the phrenic nerve in the in situ juvenile rat perfused brain stem preparation, with and without phrenic-triggered phasic pulmonary inflation. We tested the hypothesis that phasic pulmonary inflation produces reflex responses in situ akin to those in vivo and that both eupnea and gasping are similarly modulated by phasic pulmonary stretch. In eupnea, we found that phasic pulmonary inflation decreases inspiratory burst duration and the period of expiration, thus increasing burst frequency of the phrenic neurogram. Phasic pulmonary inflation also decreases the duration of expiration and increases the burst frequency during gasping. Bilateral vagotomy eliminated these changes. We conclude that the neural substrate mediating the Hering-Breuer reflex is retained in the in situ preparation and that the brain stem circuitry generating the respiratory patterns respond to phasic activation of pulmonary stretch receptors in both eupnea and gasping. These findings support the homology of eupneic phrenic discharge patterns in the reduced in situ preparation and eupnea in vivo and disprove the common supposition that gasping is insensitive to vagal afferent feedback from pulmonary stretch receptor mechanisms.     

Effect of lung inflation on lung blood volume and pulmonary venous flow

Phasic changes in lung blood volume (LBV) during the respiratory cycle may play an important role in the genesis of the respiratory wave in arterial pressure, or pulsus paradoxus. To better understand the effects of lung inflation on LBV, we studied the effect of changes in transpulmonary pressure (delta Ptp) on pulmonary venous flow (Qv) in eight isolated canine lungs with constant inflow. Inflation when the zone 2 condition was predominant resulted in transient decreases in Qv associated with increases in LBV. In contrast, inflation when the zone 3 condition was predominant resulted in transient increases in Qv associated with decreases in LBV. These findings are consistent with a model of the pulmonary vasculature that consists of alveolar and extra-alveolar vessels. Blood may be expelled from alveolar vessels but is retained in extra-alveolar vessels with each inflation. The net effect on LBV and thus on Qv is dependent on the zone conditions that predominate during inflation, with alveolar or extra-alveolar effects being greater when the zone 3 or zone 2 conditions predominate, respectively. Lung inflation may therefore result in either transiently augmented or diminished Qv. Phasic changes in left ventricular preload may therefore depend on the zone conditions of the lungs during the respiratory cycle. This may be an important modulator of respiratory variations in cardiac output and blood pressure.     

Alveolar liquid pressures in newborn and adult rabbit lungs

To study the effects of lung maturation and inflation on alveolar liquid pressures, we isolated lungs from adult and newborn rabbit pups (1-11 days old). We used the micropuncture technique to measure alveolar liquid pressure at several transpulmonary pressures on lung deflation. Alveolar liquid pressure was greater than pleural pressure but less than airway pressure at all transpulmonary pressures. Alveolar liquid pressure decreased further below airway pressure with lung inflation. At high transpulmonary pressure, alveolar liquid pressure was less in newborn than in adult lungs. To study the effects of edema, we measured alveolar liquid pressures in newborn lungs with different wet-to-dry weight ratios. Alveolar liquid pressure increased with progressive edema. In addition, we compared alveolar liquid and perivenular interstitial pressures in perfused newborn lungs and found that they were similar. Thus alveolar liquid pressure can be used to estimate perivenular interstitial pressure. We conclude that the transvascular pressure gradient for fluid flux into the interstitium might increase with lung inflation and decrease with progressive edema. Furthermore, this gradient might be greater in newborn than adult lungs at high inflation pressures.     

Influence of CPAP on reflex responses to tracheal irritation in anesthetized humans

We investigated the effects of lung inflation during continuous positive airway pressure breathing (CPAP) on airway defensive reflexes in 10 enflurane-anesthetized spontaneously breathing humans. The airway defensive reflexes were induced by instillation into the trachea of 0.5 ml of distilled water at two different levels of end-expiratory pressure (0 and 10 cmH2O CPAP). The tracheal irritation at an end-expiratory pressure of 0 cmH2O caused a variety of reflex responses including apnea, spasmodic panting, expiration reflex, cough reflex, an increase in heart rate, and an increase in blood pressure. Lung inflation during CPAP of 10 cmH2O did not exert any influence on these reflex responses in terms of the types, latencies, and durations of reflex responses although the intensity of the expiration reflex and cough reflex was augmented by lung inflation. Our results suggest that the pulmonary stretch receptors do not play an important role in the mechanisms of airway defensive reflexes in humans.     

Differences in regional vascular conductances in isolated dog lungs

The distribution of pulmonary blood flow is influenced by gravity, regional lung expansion, and hypoxic pulmonary vasoconstriction. However, these factors cannot completely explain the three-dimensional distribution of blood flow in the lung. The present study was designed to see whether anatomically related factors could contribute. Regional blood pressure vs. flow curves were determined in 100-230 small parenchymal samples (0.3-0.4 ml) from 12 isolated perfused dog lungs held at constant inflation pressure. In each region four blood flows were measured using radioactively labeled microspheres, and the four corresponding regional perfusion pressures were determined by correcting the measured perfusion pressure for hydrostatic effects. There were considerable differences in the slopes of the pressure vs. flow curves among lung regions. Dorso-caudal regions of the lung had higher vascular conductances than ventrocephalad regions, independent of the vertical orientation of the lung or the inflation volume during injections of microspheres. Thus the distributions of regional vascular conductances were related to the anatomic location and were not related to gravity, nor were they caused by nonuniformities in regional lung expansion or by hypoxic vasoconstriction or edema.     

Tonic pulmonary stretch receptor feedback modulates both eupnea and gasping in an in situ rat preparation

The perfused in situ juvenile rat preparation produces phrenic discharge patterns comparable to eupnea and gasping in vivo. These ventilatory patterns of eupnea and gasping differ in multiple aspects, including most prominently the rate of rise of inspiratory activity. Because gasping, but not eupnea, appeared similar after vagotomy in spontaneous breathing preparations, it has been assumed that gasping was unresponsive to afferent stimuli from pulmonary stretch receptors. In the present study, efferent activity of the phrenic nerve was recorded during eupnea and gasping in the in situ juvenile rat preparation. Gasping was induced in hypoxic-hypercapnia or ischemia. An increase in the pressure of tonic lung inflation from 1 to 10 cmH2O caused a prolongation of the duration between phrenic bursts in both eupnea or gasping. Bilateral vagotomy eliminated these changes. We conclude that the neural substrate mediating the Hering-Breuer reflex is retained in the in situ preparation and that the brain stem circuitry generating the respiratory patterns responds to tonic activation of pulmonary stretch receptors in a similar manner in eupnea and gasping. These findings support the homology of eupnea-like phrenic discharge patterns in the reduced in situ preparation and eupnea in vivo and disprove the common supposition that gasping is insensitive to vagal afferent feedback from pulmonary stretch receptor mechanisms.     

Inhibition of skeletal muscle activity by lung expansion in the dog

The ability of lung expansion to reflexly decrease skeletal muscle activity was tested in anesthetized dogs. In animals whose left lung was vascularly isolated but neurally intact, the left lung was inflated statically to 40 cmH2O pressure or cyclically with tidal volumes of 10, 20, or 30 ml/kg. Responses to these stimuli were compared with those of injecting 120 or 240 micrograms capsaicin into the left pulmonary artery. Skeletal muscle activity was assessed from the electromyogram (EMG) response of the left hindlimb muscles and from the monosynaptic reflex response to a periodic patellar tendon tap of the right leg (knee jerk). Static inflation and cyclic inflations above 10 ml/kg resulted in significant decreases in both EMG and knee jerk responses. The results indicate that lung expansion is capable of initiating a reflex decrease in skeletal muscle activity. Capsaicin injections caused responses that were similar to those caused by lung inflation, suggesting that at least part of this skeletal muscle reflex response to lung inflation can be attributed to the stimulation of pulmonary C-fibers that could be caused by stretch of the lung.     

Sustained sensitivity modifications induced by brief length perturbations in the crayfish slowly adapting stretch receptor

These experiments in the slowly adapting stretch receptor of crayfish test the effects of brief length perturbations (i.e., pulses) when presented in isolation at different constant elongations or superimposed on trapezoidal stretches of different amplitudes. Within "in vivo" lengths, during static responses, perturbations reduced firing rates to below control values and, in extreme cases, could silence the receptor. This effect, or "down-step," was sustained, occurred above a threshold pulse amplitude and background stretch, and increased with both stimulus characteristics, but was not present during dynamic responses. Beyond "in vivo" lengths, and in a few cases within those limits but close to the extremes, the receptor was silent but perturbations could restore activity. Lengthening pulses were more effective than shortening ones in generating after-effects. Perturbations change, during indefinitively long periods, the receptor's length or static sensitivity acting as a negative feedback which tends to maintain the discharge rate within fixed values. Perturbations disclose marked nonlinearities, which suggest that the classical view of a proportional control in the reflex loop in which the receptor participates may not operate in natural conditions.     

Pulmonary rapidly adapting receptors reflexly increase airway secretion in dogs

We attempted to determine whether stimulation of pulmonary rapidly adapting receptors (RARs) increase tracheal submucosal gland secretion in anesthetized open-chest dogs. Electroneurographic studies of pulmonary afferents established that RARs but not lung C-fibers were stimulated by intermittent lung collapse during deflation, collapse being produced by removing positive end-expiratory pressure (PEEP, 4 cmH2O) or by applying negative end-expiratory pressure (NEEP, -4 cmH2O). We measured tracheal secretion by the "hillocks" method. Removing PEEP or applying NEEP for 1 min increased secretion from a base line of 6.0 +/- 1.1 to 11.8 +/- 1.7 and 22.0 +/- 2.8 hillocks.cm-2.min-1, respectively (P less than 0.005). After PEEP was restored, dynamic lung compliance (Cdyn) was 37% below control, and secretion remained elevated (P less than 0.05). A decrease in Cdyn stimulates RARs but not other pulmonary afferents. Hyperinflation, which restored Cdyn and RAR activity to control, returned secretion rate to base line. Secretory responses to lung collapse were abolished by vagal cooling (6 degrees C), by pulmonary vagal section, or by atropine. We conclude that RAR stimulation reflexly increases airway secretion. We cannot exclude the possibility that reduced input from slowly adapting stretch receptors contributed to the secretory response.     

A model of non-uniform lung parenchyma distortion

A finite element model of mammalian lung parenchyma is used to study the effect of large non-uniform distortions on lung elastic behaviour. The non-uniform distortion is a uni-axial stretch from an initial state of uniform pressure expansion. For small distortions, the parenchymal properties are linearly isotropic and described by two elastic moduli. However, for large distortions, the parenchyma has anisotropic non-linear elastic properties described by five independent elastic moduli dependent on the degree of distortion; they are computed for a range of distortions and initial pressures. Ez, the Young's modulus in the direction of stretch, increases significantly with distortion (epsilon(z)) while Ex, the Young's modulus in the plane perpendicular to the stretch, is approximately constant. The greater the initial pressure, the bigger the difference between the two moduli at larger distortion strains. The shear modulus G(xz) is approximately independent of degree of distortion except at the highest initial pressure. The Poisson's ratio, nu(xz) is approximately constant with distortion strain for lower initial pressures, but increases significantly with epsilon(z) at higher pressures. Model predictions of the relation between G(xz) and initial uniform inflation pressure show a good correlation with reported experimental data for small distortion strains in a range of species. The model also exhibits similar behaviour to the experimentally measured uni-axial large deformations of a tri-axially pre-loaded block of parenchyma (Hoppin et al., 1975, Journal of Applied Physiology 39, 742-751).     

Effect of alveolar and pleural pressures on interstitial pressures in isolated dog lungs

We report the first direct measurements of perialveolar interstitial pressures in lungs inflated with negative pleural pressure. In eight experiments, we varied surrounding (pleural) pressure in a dog lung lobe to maintain constant inflation with either positive alveolar and ambient atmospheric pleural pressures (positive inflation) or ambient atmospheric alveolar and negative pleural pressures (negative inflation). Throughout, vascular pressure was approximately 4 cmH2O above pleural pressure. By the micropuncture servo-null technique we recorded interstitial pressures at alveolar junctions (Pjct) and in the perimicrovascular adventitia (Padv). At transpulmonary pressure of 7 cmH2O (n = 4), the difference of Pjct and Pady from pleural pressure of 0.9 +/- 0.4 and -1.1 +/- 0.2 cmH2O, respectively, during positive inflation did not significantly change (P less than 0.05) after negative inflation. After increase of transpulmonary pressure from 7 to 15 cmH2O (n = 4), the decrease of Pjct by 3.3 +/- 0.3 cmH2O and Pady by 2.0 +/- 0.4 cmH2O during positive inflation did not change during negative inflation. The Pjct-Pady gradient was not affected by the mode of inflation. Our measurements indicate that, in lung, when all pressures are referred to pleural or alveolar pressure, the mode of inflation does not affect perialveolar interstitial pressures.     

Activation of lung vagal sensory receptors by circulatory endotoxin in rats

Although endotoxin is known to induce various pulmonary responses that are linked to the function of lung vagal sensory receptors, its effects on these pulmonary receptors are still not clear. This study investigated the effects of circulatory endotoxin on the afferent activity of lung vagal sensory receptors in rats. We recorded afferent activity arising from vagal pulmonary C fibers (CFs), rapidly adapting receptors (RARs), tonic pulmonary stretch receptors (T-PSRs), and phasic pulmonary stretch receptors (P-PSRs) in 64 anesthetized, paralyzed, and artificially ventilated rats. Intravenous injection of endotoxin (50 mg/kg; lipopolysaccharide) stimulated 7 of the 8 CFs, 8 of the 8 RARs, and 4 of the 8 T-PSRs studied, while having no effect on the 8 P-PSRs tested. The stimulation started 3-16 min after endotoxin injection and lasted until the end of the 90-min observation period. The evoked discharge of either CFs or RARs was not in phase with the ventilatory cycle, whereas that of T-PSRs showed a respiratory modulation. Injection of a saline vehicle caused no significant change in the discharge of these receptors. Additionally, endotoxin significantly produced an increase in total lung resistance, and decreases in dynamic lung compliance and arterial blood pressure. Our results demonstrate that a majority of lung vagal sensory receptors are activated following intravenous injection of endotoxin, and support the notion that these pulmonary receptors may function as an important afferent system during endotoxemia.     

Airway mechanoreceptor deactivation.

Airway sensors play an important role in control of breathing. Recently, it was found that pulmonary slowly adapting stretch receptors (SARs) cease after a brief excitation following sodium pump blockade by ouabain. This deactivation can be explained by overexcitation. If this is true, mechanical stimulation of the SARs should also lead to a deactivation. In this study, we recorded unit activity of the SARs in anesthetized, open-chest, and mechanically ventilated rabbits and examined their responses to lung inflation at different constant pressures. Forty-seven of 137 units had a clear deactivation during the lung inflation. The deactivation threshold varied from unit to unit. For a given unit, the higher the inflation pressure, the sooner the deactivation occurs. For example, the SARs deactivated at 3.0 +/- 0.3 and 4.8 +/- 0.4 s when the lungs were inflated to constant pressures of 30 and 20 cmH(2)O, respectively (n = 25, P < 0.0001). The units usually ceased after a brief intense discharge. In some units, their activity shifted to a lower level, indicating a pacemaker switching. Our results support the notion that SARs deactivate due to overexcitation.