Neuronal and respiratory muscle activity during inspiration and expiration:

Transcription

1 CONTROL OF BREATHING Outline: Role of brainstem and pons in establishing respiratory rhythm Medullary Respiratory Centers (recent findings) Patterns of Respiratory Neuron Activity Function of Respiratory Neurons Origin of the respiratory rhythm and developmental changes Muscles of respiration Neuronal and respiratory muscle activity during inspiration and expiration: Upper airway structures 1

2 Control of Breathing - Overview: Breathing occurs rhythmically. This rhythmicity is generated within respiratory centers that are located in the medulla and pons. Many respiratory neurons located in the medulla have axons that travel down to the spinal cord and synapse onto interneurons or motor neurons located at the cervical, thoracic or lumbar regions of the spinal cord. The spinal neurons that receive input from the medullary neurons form nerves that exit the spinal cord and innervate the muscles of inspiration and expiration. Once the inspiratory muscles contract a negative pressure is generated which causes air to travel from the atmosphere to our lungs. The depth and frequency of breathing is important because these breathing components help to maintain homeostatic levels of oxygen, carbon dioxide and hydrogen ions in arterial blood. A number of receptors that sense changes in lung volume or arterial levels of oxygen, carbon dioxide or hydrogen ion concentration feedback to the medullary respiratory neurons which influence the depth and frequency of breathing. In addition, temperature and pain influence breathing via other centers (reticular formation) that feedback to the respiratory centers. Additionally, the level of arousal (e.g. wake versus sleep) and emotions will influence breathing. Lastly, breathing is also under voluntary control from the cerebral cortex (i.e. speaking, breath holding). The voluntary pathways that control breathing bypass the respiratory centers in the medulla and directly affect the respiratory motor neurons that are located in the spinal cord. 2

3 Control of Breathing - Role of brainstem and pons in establishing respiratory rhythm: Historical Perspective: Investigators believed initially that control centers located in the medulla and pons generated the rhythmic pattern of breathing. The medullary respiratory center was considered the primary respiratory control center consisting of two neuronal clusters the dorsal respiratory group (DRG) or nucleus tractus solitarius (NTS) and the ventral respiratory group (VRG). Additionally, investigators believed that the pontine respiratory center influenced the output of the medullary respiratory center. The pontine respiratory center was thought to consist of the pneumotaxic center and the apneustic center. Investigators believed that impulses from the pneumotaxic center inhibited inspiratory neurons in the DRG, while impulses from the apneustic center prolonged the activity of the inspiratory neurons. To determine the potential role of the pons and the medulla in the control of breathing, Lumsden completed a series of transection experiments. He showed with the vagi intact that removal of higher brain structures, such as the cerebral cortex, (transection A upper right diagram) did not influence the basic respiratory rhythm. However, a transection made in the upper 1/3 of the pons (transection B upper right diagram) resulted in a slower breathing rate and an increase in tidal volume. A transection made on the border of the pons and medulla (i.e. eliminating inputs from the pneumotaxic & apneustic center) produced a variable breathing pattern (gasping). These results suggested that inspiration is critically dependent on the lower portion of the pons (apneustic center). Additionally, input from the upper portion of the pons may be necessary to inhibit inspiration. 3

4 Control of Breathing - Medullary Respiratory Centers (recent findings): No specific groups of neurons have been found in the region that was historically referred to as the apneustic center. Thus, theories regarding this center have been abandoned. The pneumotaxic center is now referred to as the pontine respiratory group (PRG) and it is comprised of expiratory neurons in the medial parabrachial nucleus and inspiratory neurons in the lateral parabrachial nucleus and Kolliker-Fuse nucleus. The PRG has reciprocal connections with the medulla. Increased activity within the PRG shortens the activity of inspiratory neurons in the medulla. Thus, inspiration will be shortened and expiration will be initiated earlier. This action is known as phase switching and in this manner the PRG causes more breaths to occur within a given time, thereby increasing the rate of breathing. The lower portion of the pons exerts an excitatory influence on inspiratory neurons. Its activity is usually suppressed by the pneumotaxic center. However, in the absence of input from the pneumotaxic center and from lung stretch receptors breathing will stop in full inspiration. In the absence of any influence from the pontine centers, medullary centers often generate a slow, rhythmic gasping pattern of breathing. Groups of cells whose activity is associated with respiration are found throughout the medulla in several different nuclei. However, the major respiratory neurons are concentrated into three recognizable groups comprised of four major nuclei. The groups are i) Dorsal Respiratory Group (DRG) centered in the nucleus tractus solitarius (NTS); ii) Ventral Respiratory Group (VRG) that encompasses the nucleus ambiguous (NA) and the nucleus retroambigualis (NRA) iii) Pre-Botzinger complex (pre-botc) which contains putative pacemaker neurons iv) Botzinger complex (BotC) which is located in and near the nucleus retrofacialis (NRF). The DRG is comprised solely of inspiratory neurons. The DRG receives afferent information from respiratory related mechanoreceptors and chemoreceptors via the ninth and tenth cranial nerves as well as the spinal cord. Descending afferents from higher brain centers also synapse onto neurons located in the 4

5 DRG. DRG neurons discharge immediately prior to inspiration. These inspiratory neurons are of two types. One type (Iα) are inhibited by lung inflation and the another type are excited by lung inflation (Iβ). DRG neurons relay their activity to phrenic motor neurons in the cervical spinal cord that control the contraction of the diaphragm. DRG inspiratory neurons also inhibit expiratory neurons in the VRG and the PRG. The VRG contain inspiratory and expiratory neurons that behave in a fashion similar to the neurons that comprise the DRG. The NA contains premotor inspiratory neurons that mainly supply external intercostal and accessory muscles, as well as, motor neurons to the laryngeal muscles and parasympathetic neurons to the bronchioles and heart. The rostral part of the NRA (rnra) is comprised of inspiratory neurons while the caudal portion is comprised of expiratory neurons (cnra). The VRG expiratory neurons activates the expiratory muscles (abdominal and internal intercostal) when expiration becomes active, but also sends inhibitory activity to suppress inspiratory neurons during expiration. This ends the inspiratory phase and contributes to termination of inspiration (inspiratory off-switch). The BotC is rostral to the NA and is composed almost exclusively of expiratory neurons together with vagal and glossopharyngeal motor neurons. It receives sensory input relayed via the NTS and has an inhibitory effect on inspiratory neurons in the DRG and the VRG and spinal motor neurons (e.g. phrenic motor neurons). The Pre-BotC has been identified as the anatomical site of central pattern generator neurons. This region lies caudal to the BotC and contains pacemaker neurons that generate spontaneous activity without synaptic input. This region is discussed in more detail below (see origin of respiratory rhythm). Control of Breathing - Patterns of Respiratory Neuron Activity 5

6 As well as location, respiratory neurons are also classified according to their pattern of activity. As mentioned above neurons can be classified based on whether they discharge during inspiration or expiration. However, the pattern of discharge (firing frequency) also varies so that neurons can be classified according to this designation. To date the firing frequency of neurons have been classified as augmenting, decrementing or constant. Close examination of the respiratory cycle and the activity of the types of respiratory neurons show that respiration has more than 2 distinct phase (i.e. inspiration and expiration). More specifically, the expiratory phase of the cycle can be divided into early (E1 or post-inspiration) or late subdivisions (also known as E2 or pre-inspiration). Control of Breathing - Function of Respiratory Neurons While the function of the inspiratory phase as the pump muscle driving phase is well understood, the subdivision of the expiratory phase is not. The purpose of the post-inspiratory phase is to control airway muscle activity so that expiratory resistance to flow prolongs inflation of the lungs to allow for better gas mixing. The late expiratory activity simply functions to ensure that inspiration is not activated inappropriately. The function of a respiratory neuron is related to its axonal projections and connections. Whether the neuron is inhibitory, excitatory, a cranial motoneuron, a pre-motor neuron, or an afferent relay neuron will determine its connections. There are several ways of determining connections and three are illustrated above. In (A), anatomical methods have been used to find connections. In this study, a VRG inspiratory neuron and a phrenic motoneuron were stained with different dyes and their morphology reconstructed to show that the medullary neuron probably projects to and synapses with the phrenic motoneuron. Connections can also be inferred from the patterns of neuronal activity. In (B) it can be seen that phrenic motoneuron activity coincides with that of a VRG inspiratory neuron, suggesting that the VRG neuron is the source of the phrenic drive. While anatomical techniques can show likely connections and connections can 6

7 be inferred from the correlation of patterns of activity, only electrophysiological techniques like crosscorrelation and spike-triggered averaging can demonstrate functional connections. In (C) the crosscorrelation of the activity of a single VRG inspiratory neuron and the phrenic nerve discharge shows a peak after a short delay for transmission that indicates a monosynaptic excitatory connection. In (D) a triggered average of the intracellular potential of phrenic motoneurons reveals an inhibitory post-synaptic potential, demonstrating the inhibitory connection from the triggering Botzinger complex expiratory neuron. While the above figure shows how connections between individual neurons may be discovered, this technique can be extended by recording from multiple groups of neurons simultaneously using arrays of multiple electrodes. Thus, the behavior and interconnections of large numbers of neurons can be studied. Origin of the respiratory rhythm and developmental changes Much of the early work that resulted in the identification of respiratory neurons was completed in adult cats. These findings lead to the development of a number of network models of respiratory rhythm generation that featured mutual inhibition between populations of respiratory neurons (see above figure left- side). However, more recently in vitro rat preparations have been used to study the activity, connection and functions of respiratory neurons. As shown in the above figure (right side), the superfused brainstem-spinal cord preparation has rhythmic phrenic and cranial nerve activities and a transverse medullary slice also shows rhythmic hypoglossal nerve activity. This preparation has lead to the finding that two intrinsic generators may be responsible for the development of the respiratory rhythm, at least in the neonatal rat. One area in which intrinsic rhythm has been recorded is known as the rostral ventral lateral medulla (RVLM) and the second area in which rhythmic activity has been located is known as the Pre-botzinger complex. The intrinsic nature of the neurons in the pre-botzinger complex is shown in the top figure on the next page (left-hand side). That the rhythm is intrinsic is demonstrated by its persistence after blockade of GABA and glycine inhibition with strychnine and bicuculine, respectively. 7

8 Recent studies have examined how these two intrinsic rhythm generators interact. A typical experimental preparation used to study this interaction is shown above (right-hand side). (A) shows that lumbar motoneurons have a pre-i pattern of activity, and the investigators in this study traced the pathway of origin from pre-i inspiratory neurons in the medulla to lumbar expiratory motoneurons via caudal VRG expiratory neurons. µ-opiods were used to suppress the rhythmic drive to the phrenic nerves from the pre-botzinger inspiratory neurons. (B) When phrenic activity was absent, the inspiratory inhibition of abdominal expiratory activity was also absent, demonstrating that an inhibitory connection to the RVLM pre-i neurons must exist, probably originating from the pre-botzinger inspiratory neurons. These experiments also demonstrate the expiratory nature of the RVLM pre-i rhythm generator. 8

9 The primary role of the two generators may vary with the RVLM pre-i generator being primarily responsible for controlling hypoglossal motoneuron activity, whereas the pre-botzinger generator assumes control of the phrenic motoneurons. Moreover, the role of these intrinsic pacemakers may become more defined during developmental changes. This idea is supported by recent findings which showed that manipulation of lung inflation can produce changes in hypoglossal activity independent of phrenic activity (see A lower diagram on previous page). Given that this finding was in the adult, a looser coupling of the two rhythm generators might exist in the adult compared to the neonate. This suggestion is substantiated by recent findings, which showed that phrenic pre-motor neurons do not drive hypoglossal motoneurons, supporting the idea of divided control functions. The idea that the two pacemakers are loosely coupled in adults is further confirmed by findings, which show that the onset of hypoglossal nerve activity significantly precedes the onset of phrenic nerve activity in the adult but not in the neonate where the two controllers may be more tightly coupled (see B lower diagram on previous page). The relative importance of the intrinsic pacemakers may also vary between the neonate and adult, since unlike the pacemakers, interconnections appear to have a strong influence on the breathing rhythm in adults. In other words, the respiratory rhythm is disrupted when inhibition is blocked. The balance between the two generators in controlling the respiratory rhythm may not only change with development but may also change with conditions. The recording shown in C (lower diagram on previous page) was made in a 39-day old juvenile rat in situ preparation. It shows that the change from an augmenting to a decrementing phrenic bursting pattern appears to result from the presence of pre-inspiratory activity. In this case, the preparation had been used for several hours and its condition was likely deteriorating. Similar effects, induced by hypoxia, have been noted previously. So it is possible that gasping may be the result of the RVLM pre-i rhythm generator becoming more active and dominating the control of the phrenic motor output. It has been suggested that the RVLM rhythm generator may be the oldest, from an evolutionary point of few, and thus it may not succumb to deteriorating conditions as rapidly as the pre-bot. rhythm generator. Control of Breathing - Muscles of respiration: Mechanically, pulmonary ventilation is accomplished by altering intrapulmonary pressure, which occurs in response to contraction of the inspiratory muscles (inspiration), and the passive recoil of the lungs (expiration). The inspiratory muscles are comprised of the 9

10 diaphragm and the external intercostal muscles. The diaphragm is innervated by the phrenic nerve which is formed by axons that originate from motoneurons located within the ventral horn of the C 3 -C 5 segment of the spinal column. The external intercostal muscle is innervated by the external intercostal nerves, which are formed by axons that originate from motoneurons located within the ventral horn of the T 1 -T 12 segment of the spinal column. The expiratory muscles are comprised of the rectus abdominus and the internal intercostal muscles. These muscles are activated at increased levels of minute ventilation. The former responds to efferent input from motoneurons in the L 1 -L 5 segment of the spinal column, and the latter responds to efferent input from motoneurons in the T 1 -T 12 segment of the spinal column. Cyclical neural input to the respiratory muscles establishes the rhythmic pattern of breathing. This neural input originates from the respiratory control centers that reside in the brain. Control of Breathing - Neuronal and respiratory muscle activity during inspiration and expiration: During normal quiet breathing (eupnea), active inspiration lasts approximately 1-2 seconds, and passive expiration lasts 2-3 seconds, or longer. Resting respiratory frequency in adults is normally in the range of breaths per minute. During inspiration the inspiratory neurons in the DRG and rvrg discharge and send signals to the cervical and thoracic levels of the spinal cord. The motor neurons that receive these signals form nerves which innervate the diaphragm and external intercostal muscles. During inspiration the diaphragm pulls downward, the external intercostals pull the ribs upward and outward. During heavy breathing (i.e. exercise) the accessory muscles in the neck stabilize the ribs. These muscles receive input from cranial motor neurons located in the medulla. During quiet breathing expiration is passive. This passive response is brought about through termination of inspiration, largely via inhibitory signals generated by expiratory neurons located in the BotC. Signals from the BotC will inhibit inspiratory neurons in both the medulla and the spinal cord. During passive expiration, the inspiratory muscles relax and the compliance of the chest wall returns the ribs to their relaxed position expelling air. The expiratory neurons located in the cnra are primarily responsible for generating the increased drive necessary for forced expiration. These neurons have axons which travel down to the level of the spinal cord and synapse onto motor neurons located in the lower region of the thoracic (internal intercostal muscles) and lumbar (abdominal muscles) spinal cord. During forced expiration the internal intercostals can pull the ribs downward and inward and the rectus abdominis and the external oblique muscles pull the chest wall down, compressing the chest gas volume. 10

11 Control of Breathing - Upper airway structures: In order for air to enter or exit the lungs the upper airway must remain open. The upper airway s ability to remain unobstructed depends in part, on whether the anatomy of the upper airway is compromised. The middle (MT) and inferior turbinates (IT) that are located in the nasopharynx function to warm, clean and humidify the air as it passes through the nose and into the lungs. If the turbinates are extremely large they can reduce or completely block airflow through the nose. Similarly, if the tongue (T) or uvula (U) is enlarged, the upper airway could become partially or completely obstructed. Likewise, a soft palate that is abnormally compliant (i.e. floppy) could also lead to upper airway obstruction. Upper airway muscles play an important role in maintaining upper airway patency. These muscles are shown below. The function of each muscle will not be reviewed. However, note that three primary muscles control the position of the tongue. The genioglossus, styloglossus and the hyoglossus. Contraction of the genioglossus causes the tongue to protrude. In contrast, contraction of the hyoglossus and styloglossus cause the tongue to retract. These muscles interact in a complex fashion to ensure that the tongue does not obstruct the upper airway. Tonic and phasic activity can be recorded from tongue muscles. Unlike the respiratory neurons that have axons that travel from the medulla to the spinal cord, the hypoglossal nucleus is comprised of neurons whose axons form the hypoglossal nerve that exits at the level of the medulla and innervates the tongue muscles. 11

12 VENTILATION AND MECHANICS OF BREATHING Outline: Functional anatomy of the respiratory system Pulmonary mechanics of the lungs and chest wall Lung pressures and pressure gradients Determinants of lung compliance Lung and chest wall compliance Dynamic lung compliance and airway resistance Airway Diameter Dynamic and Static Lung Volumes Lung Disease and Static Lung Volumes 12

13 Ventilation and Mechanics of Breathing - Functional anatomy of the respiratory system: Once the muscles of inspiration contract a negative pressure is generated. If the upper airway remains patent, air will travel from the atmosphere into the lungs. The right lung has three lobes (upper, middle and lower) while the left lung has two lobes. Air travels from the atmosphere to lung alveoli, where gas exchange occurs, via the tracheo-bronchial tree. The tracheo-bronchial tree is comprised of 23 generations. The first 16 generations lack alveoli and consequently gas exchange does not occur within these generations. The first 16 generations are referred to as the conducting zone and the volume of air normally found in this zone is referred to as the anatomical deadspace of the system. The remaining 7 zones are referred to as the respiratory zone. Within this zone alveoli branch off from bronchioles and consequently gas exchange occurs within the respiratory zone. Numerous branching in the respiratory zone is accompanied by a rapid increase in the total cross-sectional area. As a result, the forward velocity of gas during inspiration is very slow and gaseous diffusion becomes the chief mode of ventilation. Ventilation and Mechanics of Breathing - Pulmonary mechanics of the lungs and chest wall: P = -5 P = 0 P = 0 P = 0 P = 0 P = 0 13

14 The volume of air that enters the lung will depend in part on the negative pressure that is generated. This concept is covered later in the syllabus. The volume of air that enters the lung will also depend on the individual properties of the lung and chest wall, and the manner in which the lung and chest wall interact. Use of a simple physical spring model (see lower left-hand diagram on previous page) will aid in understanding the physical interactions between the lungs and the chest wall. The lungs are modeled as a spring being stretched and trying to recoil back to a shorter length. This is true even at residual volume (RV) which is the volume remaining in the lungs following maximal expiratory effort. Alternatively, the chest wall is modeled as a spring that is being compressed and is constantly trying to expand back to its maximum length. When the lungs and chest wall are coupled, which is normally the case, lung volume is larger and the chest wall volume is smaller than would be the case if the lung and chest wall were uncoupled. Consequently, the lung normally has an inward directed recoil force while the chest wall has an outward directed force. As a result, the space between the lungs and the chest wall (the intrapleural space) has a negative pressure (- 5 cmh 2 O) relative to atmospheric pressure (see lower righthand diagram on previous page). At the end of a normal expiration, the outward recoil force of the chest wall offsets the inward recoil force of the lungs. This equilibrium state is referred to as functional residual capacity (FRC). There are conditions that alter the normal physical forces that govern the interaction between the lung and chest wall. For example, the lungs can lose some of there elastic recoil in certain pulmonary diseases, such as emphysema. When this occurs the outward force of the chest wall overcomes the inward recoil forces of the lungs resulting in an increase in FRC. Another example is the alterations that occur following a pneumothorax. When the chest wall becomes uncoupled from the lungs, as it often does in response to blunt force injury, intrapleural pressure becomes the same as atmospheric pressure and the lung and chest wall becomes uncoupled. Under this condition, the lung collapses to a minimum volume while the chest wall expands to its maximum volume (i.e. 80 % of vital capacity). Under these conditions, mechanical ventilation of the lungs is necessary to maintain adequate gas exchange. Ventilation and Mechanics of Breathing Lung pressures and pressure gradients By convention the pressure difference is measured as inside outside. The recoil pressure of the chest wall (P cw ) is the difference between pleural pressure (P pl ) and atmospheric pressure (P atm ). The recoil pressure of 14

15 the lungs (P L or transpulmonary pressure) is the difference between the alveolar pressure (P A ) and the pleural pressure (P pl ). When there is no airflow (closed nose and mouth) P A and the pressure measured at the mouth are the same. Hence, the pressure gradient across the entire respiratory system (P rs ) is the difference between the alveolar pressure (P A ) and atmospheric pressure (P atm ). The pressure across the respiratory system (P rs ) is also the sum of the pressure of its two components, the lung (P L ) and chest wall (P cw ). During inspiration, the diaphragm contracts, and the chest wall and the lungs expand. As the lungs are pulled further away from their resting position (which is below residual volume), Ppl becomes more subatmospheric. Consequently, lung volume is increased and gas in the lungs is decompressed, and pressure in the alveoli (P A ) drops below atmospheric pressure. The created negative pressure gradient between the airways and atmosphere generates airflow to the lungs. As inspiration proceeds, the lungs fill up with air, and the pressure gradient and air flow gradually decrease. At the end of inspiration airflow stops because P A is equal to atmospheric pressure (no pressure gradient). At the onset of expiration, the diaphragm relaxes, elastic recoil of the respiratory system compresses the gas in the lungs, thereby increasing P A. The positive pressure gradient between the lungs and the atmosphere is reversed and air from the lungs is pushed out to the atmosphere. As lung volume decreases, Ppl slowly returns to its resting level. At the end of expiration (i.e. at FRC) airflow and P A are 0 (ml/sec and cmh 2 O, respectively), and Ppl is about -5 cmh 2 0. Ventilation and Mechanics of Breathing Determinants of lung compliance The volume of air that enters or exits the lungs for a given change in pressure ( V/ P = compliance) will depend in part on the properties of the lung and chest wall. We will consider the compliance of these two structures separately prior to considering the compliance of the structures when they are coupled. 15

16 In the experiment shown above a lung was excised and placed into an airtight container. Subsequently, changes in lung volume and container pressure were measured. Pressure in the container was decreased and then increased in a step-wise fashion and changes in lung volume were plotted. Decreasing pressure outside the lung (i.e. intrapleural pressure) expanded the lung. Changes in lung volume were less at high lung volumes for a given pressure change. When pressure was returned to atmospheric pressure lung volume decreased, however, it followed a different path. This property is referred to as hysteresis and is the result of changes in surface tension created from the air-fluid interface in the alveoli. The shape of the compliance curves is determined by elastic forces caused by surface tension, and elastic forces caused by the lung. Lung composition and compliance: Elastic behavior of the lung itself is determined by the composition and arrangement of the collagen and elastin fibers of the lung. The construction of the lung is such that inflation of one alveoli tends to augment the inflation of adjacent alveoli (interdependence). These tissue factors account for about 1/3 of the compliance behavior of the lung. Surface tension and lung compliance: The majority of static compliance behavior is determined by surface tension. Each alveolus is an air-water interface. Surface tension is a result of unequal attraction between gas molecules and liquid molecules. Water molecules will have more attraction for each other than for air molecules. Thus, there is a tendency to decrease the surface area of the air water interface (to contract ). In an alveolus, this means that surface tension tends to promote deflation (collapse). Quantitatively, surface tension is responsible for 2/3 of the compliance behavior of the lungs. 16

17 The importance of surface tension at a gas-liquid interface is illustrated by the two static compliance curves illustrated above. This experiment shows the effect of inflating the isolated lung with air versus saline. The air inflated lung requires large positive pressures and exhibits hysteresis (i.e. the path followed during expiration is different from that taken during inspiration). At low lung volumes, a greater pressure is required to produce a volume change when the lung is inflated with air versus saline. This implies that the air-fluid interface on the alveolar surface affects lung expansion. In contrast, the saline-inflated lung requires much less positive pressure and exhibits no hysteresis. Note that the slope of the P-V curve (i.e. compliance) is greater during saline inflation. This is the result of very low surface tension which will be discussed below. Surface tension is a force generated by the physical - chemical nature of the interaction between the air-fluid interface in the alveoli. This force has the effect of collapsing alveoli to the smallest possible surface area. This inward directed force accounts for approximately 2/3 of the inward elastic recoil of the lung. This relationship is described by LaPlace s Law (P = 2T/r) where T is the surface tension and r is the radius. The balance between tension within the wall of the alveolus (produced by the air-fluid interface) and the pressure inside the alveolus determines the size of the alveolus. If surface tension is the same in two alveoli then the smaller alveolus will have a higher pressure and it will empty into the larger alveolus. If surface tension remains constant, the pressure within the alveolus is inversely related to the radius. Thus, if a large alveolus is connected to a small one, the gas will flow down its pressure gradient from the small alveolus to the large alveolus. This will result in collapse of the small bubble. This condition rarely occurs in the normal healthy lung due to the lung s production of surfactant. 17

18 Surfactant, surface tension and lung compliance: Surfactant gives the alveoli a variable surface tension, so that at small volumes the surface tension is low. Surfactant (DPPC-dipalmitoyl phosphatidyl choline) is secreted by type II epithelial cells in the alveoli of normal lungs. The major component of surfactant is primarily a phospholipid (dipalmitoyl phosphatidylcholine). This molecule has a hydrophobic portion and a hydrophilic portion. This serves to orient the molecule at the air-water interface. Surfactant is a surface-active agent in water that acts to decrease surface tension at the air-water interface of the alveolus. In doing so, surfactant i) decreases surface tension ii) decreases work of breathing iii) increases compliance iv) stabilizes alveolar size v) dries the alveoli 18

19 The lower diagram on the previous page shows the effect of surfactant on alveolar stability. To understand the diagram, we must re-consider Laplace s Law: P = 2T/R P is the intra-alveolar pressure, T is the tension of the alveolus (resistance that acts to preserve the integrity of the surface), and R is the radius of the alveolus. In the example shown at the top of the figure (see bottom figure previous page), the alveoli are assumed to be without surfactant. Thus, the surface tensions are equal. Based on the above equation, you can see that the smaller alveolus will have a larger intraluminal pressure. Because gas flows from regions of high pressure to low pressure, gas will flow from the smaller alveolus to the larger alveolus. (One alveolus will be deflated or collapsed). When alveoli are collapsed, they are said to be atelectic. The bottom example (see bottom figure previous page) shows the effects of surfactant on surface tension. First, look at the alveolus on the right. Note that the presence of surfactant decreased the surface tension by approximately 4 times. The result of this alteration is a significant decrease in the intra-alveolar pressure from 8 cmh 2 O to 2 cmh 2 O. The importance of this change is evident when you assess the pressure in the larger alveolus (left). In the larger alveolus, the intraluminal pressure is 4 cm H 2 O. Thus, gas will flow from the larger alveolus to the smaller. The result will be two alveoli of equal size. Thus, deflation (atelectasis) is prevented. The bottom example shows that surface tension was lower in the small alveolus than in the large. This is similar to what happens to surface tension in the experimental apparatus shown in the middle of the page. Note that as the relative surface area is reduced, surface tension is decreased in the presence of surfactant. This probably has to do with the fact that surfactant is concentrated as surface area is reduced. Compliance of the total lung: As stated previously compliance of the lung is defined as the change in lung volume divided by the change in lung distending pressure (C L = V/ P). Under normal conditions - C L = V/ P where P = Palv-Ppl (for lung) and Ppl-Patm (for chest wall). For example if V = 1L and P = 5 cmh 2 O then C L = 0.2 L/cmH 2 O. 19

20 Compliance is usually measured during expiration above FRC. Compliance is increased by destruction of the elastin and collegen content of the lung. This occurs in obstructive lung disease (i.e. emphysema). Several factors also decrease compliance including i) high lung volume ii) respiratory diseases (restrictive diseases) iii) alveolar edema iv) deficiency of surfactant. Changes in pulmonary compliance in disease states: Static pressure-volume (P-V) curves and dynamic tidal P-V loops illustrate the effects of certain respiratory diseases on lung compliance, lung volumes and airway resistance. Airway resistance is the predominate feature in obstructive disease (asthma, emphysema), whereas decreased compliance is most obvious in restrictive diseases (pulmonary fibrosis and respiratory distress syndrome). 20

21 Ventilation and Mechanics of Breathing Lung and chest wall compliance The interaction between the lung and chest wall can be observed if the P-V relationship of both the lung and chest wall is plotted together. In this experiment, the subject inspires or expires into a spirometer and then relaxes their respiratory muscles while airway pressure is measured. The points are then plotted to create the graph above (SOLID LINE) that shows the relaxation P-V relationship. Functional residual capacity occurs when the relaxation pressure of the lung and chest wall is atmospheric and the expansion force of the chest wall opposes the recoil force of the lung. Thus, FRC is the equilibrium volume when the elastic recoil of the lung is balanced by the normal tendency of the chest wall to expand. The DOTTED LINES represent the P-V curves for the lung alone and the chest wall alone. If the outward force generated by the chest wall was absent, then airway pressure at FRC would be positive owing to the elastic recoil force of the lung. If on the other hand, the inward recoil force of the lung was absent, then airway pressure at FRC would be negative owing to the outward expansion force of the chest wall. Note, also that the relaxation pressure for the chest wall (i.e. atmospheric pressure) occurs at 80 % VC. This means that under normal conditions the outward expansion force generated by the chest wall aids in inspiration. If the subject increases lung volume above this point airway pressure increases. This is due to the greater inward recoil force of the lung. The chest wall, on the other hand, is closer to where it wants to be and thus contributes less outward elastic recoil force then at FRC. If the subject expires from FRC and relaxes then airway pressure will be negative. This is due to the small inward recoil force of the lung and the large expansion force of the chest wall. Ventilation and Mechanics of Breathing - Dynamic lung compliance and airway resistance In the previous discussion, we considered the static lung and chest wall compliance (i.e. when air is not moving). The factors principally responsible for these measures are the elastic properties of the lung and chest wall, and surface tension. However, we must consider compliance of the lung and chest wall when air is moving (i.e. dynamic compliance). The additional factors that influence the dynamic compliance measures are airway resistance, tissue resistance and inertia. Of these three, airway resistance is quantitatively the most important. 21

22 The above diagram shows simultaneous changes in lung volume, intrapleural pressure, gas flow, and alveolar pressure during normal inspiration and expiration. The graph of intrapleural pressure shows the actual pleural pressure (AB`C), and the pleural pressure required to overcome only the elastic characteristics of the lung (ABC). The difference in pressures is due to the additional work expended to overcome resistance to air flow. Airway resistance can be calculated using Poiseuille s Law. This law describes the pressure-flow characteristics for laminar flow in a tube: V = Pπr 4 8ηl where P is the pressure, r is the tube radius, η is fluid viscosity and l is tube length. Since resistance is driving pressure divided by flow then we can arrange this equation to calculate resistance: R = 8ηl πr 4 As the equation shows Poiseulle s law predicts that resistance to laminar flow (of air or a Newtonian fluid) is directly proportional to viscosity and tube length and inversely proportional to tube radius. Therefore, small changes in tube radius can have large effects on resistance. 22

23 There are a number of factors that influence airway resistance: Branching patterns and physical dimensions of the airway (i.e. airway geometry and the impact of lung volume on the surrounding tissue). Airway Resistance (cm H 2 O/L/sec) Lung Volume (L) The chief site of airway resistance is located in the intermediate-sized bronchi. Because of the increase in cross-sectional area the small airways contribute relatively little to airway resistance. Additionally, as lung volume increases airway resistance decreases and conductance (i.e. the reciprocal of resistance) increases. The reduction in resistance occurs primarily because increasing lung volume provides radial traction to the surrounding lung tissue, which decreases the possibility that the airway would collapse leading to an increase in airway resistance. Airway smooth muscle tone 23

24 Airway resistance is altered by a variety of endogenous mediators. Airway smooth muscle tone is affected by noxious stimuli that activate receptors located beneath the epithelium of smooth muscle. Axons from these receptors travel to the medulla via the vagus nerve. Consequently, efferent fibers within the vagus nerve will be stimulated and cause bronchial smooth muscle constriction. The parasympathetic nervous system mediates the reflex modulated by the release of acetylcholine at muscarinic receptors on the muscle cell. Parasympatholytic drugs (i.e. atropine or glycopyrrolate) may block the efferent response to stimulation of this reflex arc. The sympathetic system (shown to the far right in the above diagram) plays a role in modulating bronchial smooth muscle tone, and some direct innervation is present as shown in the diagram. However, the presence of circulating catecholamines is probably more important to airway resistance as direct innervation is not extensive in most species. Agonists at the beta-2 receptor are used therapeutically to treat bronchoconstriction (i.e. albuterol, clenbuterol). The nonadrenergic noncholinergic system may also play a role in modulating smooth muscle tone, and vasoactive intestinal peptide (VIP) has been shown to be a bronchodilator. Nitric oxide may also play a role in modulation of bronchial smooth muscle tone. A variety of inflammatory mediators can alter airway tone. Histamine and serotonin are two mediators that can be released from mast cells in response to IgE-mediated degranulation of mast cells. Lipid mediators {leukotrienes (LTB4), sulfidopeptide leukotrienes (LTC4, LTD4, LTE4)} and prostaglandins are also released. Mucus production Airflow patterns Airflow changes from laminar to turbulent flow when airflow velocity is increased. Even during normal tidal breathing airflow is turbulent in the upper airways, although flow is always laminar in the small airways (< 2 mm internal diameter). During turbulent flow, particles move in irregular and constantly varying paths forming eddies. Resistance to airflow increases in response to turbulent flow. Flow is turbulent when Reynold s number is greater than

25 Reynold s number: Re = 2rvd η where r is radius, v is average air flow velocity, d is density and η = viscosity. Decreased elastic recoil of the lung Obstructive lung disease, such as emphysema, results in loss of alveolar tissue and thus a reduction of the inward elastic recoil of the lung. This results in collapse of small airways during expiration and increased airway resistance. Ventilation and Mechanics of Breathing - Airway Diameter The loss of elastic recoil is not the only factor that may result in the collapse or compression of the airways. Another important modifier of airway diameter is dynamic compression of airways. Dynamic compression results in a limitation of flow during much of expiration. The graph above indicates that flow peaks early during forced exhalation from total lung capacity and then decreases throughout the reminder of exhalation. C shows the flow tracing during a submaximal expiratory effort. Note that over much of the trace, there is no difference in flow compared to A (maximal effort). Likewise, when flow is forced at a relatively low lung volume, peak flow is lower, and flow rate diminishes similar to that in A and C. Thus, gas flow during much of expiration is limited and is independent of effort. The reason for this limitation is compression of airways by the increase in intrathoracic pressure that occurs during exhalation. 25

26 During inspiration, the transmural pressure gradient between the alveoli and intrapleural space (P A -Ppl) is acting to open the airways. However, during forced expiration intrapleural pressure becomes positive and the transmural pressure gradient is sufficiently negative at some point along the airway to cause collapse. More specifically, the diagram in the top left corner (see bottom figure on previous page) shows pressure in the pleural space, alveolus, intrathoracic airway, and atmosphere at FRC. Note that the transmural (or distending) pressure is also shown for the intrathoracic airway (airway pleural pressure). Note that the distending pressure on the airway is +5 cm H 2 O at this time. During inspiration the diaphragm contracts, pleural pressure decreases, alveolar pressure decreases, and the distending pressure on the airway becomes more positive. These changes in pressure result in the flow of gas into the respiratory system and are initiated by contraction of the diaphragm and external intercostal muscles. Note that the distending pressure on the airway would tend to increase the diameter of intrathoracic airways during inspiration. At end inspiration, the pressure tending to distend the airways is even greater, and the flow of gas has stopped because alveolar, airway and atmospheric pressure are equal. A forced exhalation (bottom right) results in an increase in pleural pressure and alveolar pressure. Pressure in the airway decreases as flow begins, and the distending pressure on the intrathoracic airway becomes negative, and the airways narrow. Please note that raising intrapleural pressure does not increase flow because driving pressure is unaltered. Maximal flow decreases as lung volume decreases because the difference between alveolar and intrapleural pressure decreases and airways become narrower. The relationships seen above may be exaggerated if increased peripheral airway resistance accentuates the pressure drop in the airways. In addition, low lung volume and disruption of the pulmonary parenchyma (i.e. emphysema) contributes to airway collapse. Flow-related collapse occurs in larger bronchi during forced expiration. During coughing, the increased velocity of flow results in increased turbulence (and sound). Increased velocity and turbulence will actually aid in the clearing of secretions from the air passages. Flow-related small airway collapse occurs more easily in certain disease states (i.e. emphysema, asthma). In these diseases, collapse of small airways may occur and result in gas trapping. Ventilation and Mechanics of Breathing - Dynamic and Static Lung Volumes As discussed above, once the diaphragm contracts negative pressure is generated and the volume of air taken into the lungs for a given change in pressure depends on the compliance of the lung and chest wall. There are a number of lung volume measures that can be obtained both under dynamic and static conditions. 26

27 Dynamic Lung Volumes The above diagram shows ventilation in the lung. Inspired ventilation is comprised of deadspace ventilation and alveolar ventilation. Upon exhalation ventilation from the deadspace and the alveolar space combine to form total ventilation. The lung is perfused by pulmonary blood flow. Ventilation (V E ) = frequency (f) * Volume (V T ) Tidal vol. (V T ) = dead space vol. (V D ) + alveolar vol. (V A ) alveolar volume refers to the volume of air entering the alveoli only. Thus minute ventilation can also be written - V T * f = V D * f + V A * f Anatomical dead space refers to structures that do not contribute to gas exchange. Physiological dead space includes alveoli that are not perfused or poorly perfused, leading to wasted ventilation. 27

28 Static Lung Volumes Simple measures of static lung volume can be obtained by having a subject completely fill their lungs and then expire forcefully into a spirometer. The volume of air expired during such a maneuver is known as the forced vital capacity and the volume of air expired in the first second of the maneuver is the known as F E V 1.0. These simple measures allow clinicians to diagnose preliminarily the existence of pulmonary disease. In addition to measures of vital capacity the spirometry tracing will also allow for the measurement of other lung volumes and capacities which are shown in the diagram below. More specifically, inspiratory reserve volume (IRV), inspiratory capacity (IC), expiratory reserve volume (ERV) and tidal volume can be determined via spirometry. If more sophisticated equipment is employed measures of RV can be obtained. Once this measure is obtained total lung capacity (TLC) and functional residual capacity (FRC) can be calculated. As noted below, measures of these volumes and capacities are important because they are altered in response to lung disease (e.g. emphysema and bronchitis). 28

29 Ventilation and Mechanics of Breathing - Lung Disease and Static Lung Volumes The above table and figure show changes in lung volume that occur in response to restrictive and obstructive lung disease. Shown in the table on the next page are examples of restrictive and obstructive lung diseases. Note in the above table, if measures of forced vital capacity are less than normal this reduction in volume may be indicative of lung disease. However, this reduction will not allow you to determine whether the disease is restrictive or obstructive in nature. This is also the case if F E V 1.0 is examined solely to detect the presence of lung disease. However, obstructive and restrictive lung disease can be differentiated by examining the F E V 1.0 /FVC ratio concurrently with FVC and F E V 1.0. More specifically, in obstructive lung disease FVC and F E V 1.0 are reduced. In addition, the F E V 1.0 /FVC is reduced because it is difficult to expire a significant portion of the FVC in the initial second because of the presence of obstructed airways. Conversely, although the FVC and F E V 1.0 are reduced in individuals with a restrictive disease they are capable of expiring a significant percentage of this volume (80 % 90 %) within the initial second because the airway is not obstructed. Other lung volume alterations will also aid in differentiating between an obstructive and restrictive disease. Note that total lung capacity, residual volume and functional residual capacity are all increased in individuals with chronic obstructive pulmonary disease. These lung volumes are increased in part because of the loss of lung elasticity and because air becomes trapped in the obstructed airways. In contrast, total lung capacity, residual volume and functional residual capacity is reduced in individuals with restrictive lung disease (e.g. pulmonary fibrosis) because the lung is unable to inflate adequately. 29

30 Example of Restrictive and Obstructive Lung Diseases I. Restrictive A. Diseases of thoracic cage 1. Kyphoscoliosis 2. Ankylosing spondylitis 3. Closed chest wall trauma B. Diseases of nerve supply to respiratory muscles 1. Polimyelitis 2. Muscular dystrophy 3. Guillain-Barre syndrome 4. Myasthenia gravis C. Abnormalities of pleura and pleural space 1. Pneumothorax 2. Pleural effusion 3. Pleural thickening D. Pathology in lung 1. Fibrosis 2. Space occupying lesions, e.g. cysts II. Obstructive A. Bronchoconstriction 1. Asthma 2. Inhalation of irritants, e.g. cigarette smoke B. Structural changes in airways, e.g. chronic bronchitis C. Obstructions within airways 1. Inhaled foreign body 2. Excess bronchial secretions 30