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Lauzon, RESPIRATION A.-M. Ph.D. Class notes 2008 Reference textbooks: Human Physiology by Widmaier, Raff, Strang Respiratory Physiology- the essentials by West "The Normal Lung" by Murray I STRUCTURE OF THE LUNGS AND CHEST WALL A. Function of Respiration The primary function of respiration is gas exchange. In mammals, gas exchange occurs in the lungs. During inspiration, air rich in O2 is inhaled into the lungs. During expiration, CO2 produced during the oxidative processes of the body is exhaled from the lungs. Both gases are transported by the blood. Therefore, both the cardiovascular system and the respiratory system are involved with supplying body cells with O2 and eliminating their waste product, CO2. B. The respiratory tract Air flows through a series of air passages that connect the lungs to the nose and mouth. Inhaled air passes over a complex series of surfaces when it goes through the nose: the nasal septum and the nasal turbinates. These surfaces clean the air of big dust particles. From the nose, warmed and moistened air flows through the common passages for air and food, the pharynx, and then continues through the larynx. Air finally reaches the periphery of the lungs via the trachea and bronchi (figure 1). The lungs and the airways share the chest cavity with the heart, the great vessels, and the esophagus. The airways consist of a series of tubes that branch and become narrower, shorter and more numerous as they penetrate into the lungs. The trachea divides into 2 main bronchi, each of which divides into lobar and segmental bronchi. The right main bronchus has 3 lobar bronchi (the right lung has 3 lobes), while the left main bronchus divides into only 2 bronchi (the left lung has only 2 lobes). The segmental bronchi divide further into smaller branches. The smallest airways without alveoli are the terminal bronchioles (figure 2). The respiratory tract Figure 1 turbinates clean air pharynx larynx trachea two main bronchi one bronchi for each of three lobes on right side. 3 lobar bronchi left hand side has two lobes. 2 lobar bronchi then segmental bronchi....finally alvioli surrounded by capillaries * pleural space filled with a small amount of fluid. - couples the lungs with the chest * Subdivisions of the conducting airways and terminal respiratory units Figure 2 * Notes: Pleural surfaces A way to visualize the apposition of the two pleural surfaces is to put a drop of water between two glass microscope slides. The two slides can easily slide over each other but are very difficult to pull apart. lubrication between the lungs (Human Physiology by Widmaier, Raff, Strang) and the chest. but they are coupled The pressure in the pleural space is negative. This will become clearer after the discussion of pneumothorax (figure 35). *Note: These figures will be discussed in detail in section VII on the mechanics of breathing. They are included here because in class, as we discuss the anatomy of the respiratory system, we will briefly address the function of the pleural space. The pleural - couples the lungs to the chest space when you pull on the chest, the lungs will move with it as well The pump analogy The pneumothorax - the pressure in the pleural space is negative w.r.t outside - as you breathe, the pressure in the pleural space becomes more negative - pleural space - similar concept to having two microscope slides together with water in between them - water is non-compressable - if a hole is made in the pleural space, air will flow in, and you lose the coupling of the chest and the lungs C. Conducting and Respiratory Zones The airways are divided into 2 zones: the conducting zone (made up of the conducting airways) and the respiratory zone (figure 2). The conducting airways consist of the airways from the mouth and nose openings, all the way down to the terminal bronchioles. These airways conduct air from the atmosphere to the respiratory part of the lungs. The conductive airways do not contribute to gas exchange, and are thus said to compose the anatomical dead space. The respiratory part of the lungs (the respiratory zone) begins where the terminal bronchioles divide into respiratory bronchioles, which have some alveoli opening into their lumena (figure 3). Beyond the respiratory bronchioles are the alveolar ducts lined with alveoli. The alveolated region of the lungs is the site of gas exchange, and is called the respiratory zone. Because of such abundant branching of the airways, the respiratory zone makes up most of the lungs. The smallest physiological unit of the lungs (distal to the terminal bronchiole) is the acinus (figure 3). smooth muscle Acinus Figure 3 the smooth muscles around the airways mean trouble. don't know why they're there. these are the muscles that contract during asthma -decreasing the luma DON'T HELP TO BREATHE AT ALL. Acinus (Reproduced from Netter, F.H.: The CIBA Collection of Medical Illustrations, vol. 7). D. Functions of the Conducting Airways The conducting airways have 4 main functions: 1. Defense against bacterial infection and foreign particles: the epithelial lining of the bronchi has hair-like projections called cilia. The epithelial glands secrete a thick substance, mucous, which lines the respiratory passages as far down as the bronchioles. Foreign particles stick to the mucous and the cilia constantly sweep the mucous up into the pharynx. - mucoual cillial elevator - paralyzed by nicotine 2. Warm and moisten inhaled air. 3. Sound and speech are produced by the movement of air passing over the vocal cords. 4. Regulation of air flow: smooth muscle around the airways may contract or relax to alter resistance to air flow. E. Function of the Respiratory Zone The respiratory zone is the site of gas exchange between the air in the alveoli and the blood in the pulmonary capillaries. There are roughly 300 million alveoli in the human lungs, and each alveolus may be associated with as many as 1000 capillaries. F. Blood Supply The lungs have two circulations: the pulmonary circulation (figures 4 & 5), bringing mixed venous blood (blood that comes from different body organs with different metabolic activities) to the lungs (figure 4), allowing for the blood to get oxygenated, and then back to the left heart, and the bronchial circulation (figure 5), supplying oxygenated blood from the systemic circulation to the tracheobronchial tree (this circulation allows for the airways to get oxygenated). 1) Pulmonary circulation: Blood to the pulmonary capillaries is supplied via the pulmonary artery, which originates from the right ventricle (figures 4 and 5). Branches of the pulmonary artery run with the airways. When the alveoli are reached, arterioles divide into a capillary bed. The pulmonary arteries supply with blood all capillaries within the alveolar walls, which constitute the respiratory surface of the lungs where the gas exchange takes place. Oxygenated blood (from the alveolar capillaries) leaves the lungs and returns to the left heart via the pulmonary veins (figures 4 and 5). 2) Bronchial circulation: Bronchial arteries from the aorta supply the airway walls (figure 4). The bronchial circulation is part of the systemic circulation. pulmonary circulation pulmonary artery pulmonary vein to left heart Figure 4 The pulmonary and bronchial circulations. (Reproduced from Netter, F.H.: The CIBA Collection of Medical Illustrations, vol. 7). Figure 5 G. Alveolar Cell Types There are three alveolar cell types (Figure 6): 1. Epithelial type I and II cells: Alveoli are lined by epithelial type I and II cells. Together, all the alveolar epithelial cells form a complete epithelial layer sealed by tight junctions. Little is known about the specific metabolic activities of type I cells. Type II cells produce pulmonary surfactant, a substance that decreases the surface tension of the alveoli (see sections VII- F & G). 2. Endothelial cells: Endothelial cells constitute the walls of the pulmonary capillaries. These cells may be as thin as 0.1 micron. 3. Alveolar macrophages: These remove foreign particles that may have escaped the mucociliary defense system of the airways and found their way into the alveoli. Alveolar-capillary membrane Figure 6 H. Respiratory Muscles The lung tissue is elastic, but it is unable to expand or contract by itself. Air has to be sucked into the lungs (see figure 40). This function is powered by the respiratory muscles of the chest wall. There are 2 types of respiratory muscles: inspiratory and expiratory (figure 7). everything on this slide is important Figure 7 passive, chest relaxes increases longitudinal length, elevates rib cage and sternum depress ribs abdominal muscles pushes the abdomen in, lifting the diaphragm Reproduced from Netter, F.H.: The CIBA Collection of Medical Illustrations, vol. 7. Inspiratory muscles: The main inspiratory muscle is the diaphragm. It is innervated by the phrenic nerves from cervical segments 3, 4 and 5. Contraction of the diaphragm causes its dome to descend and the chest to expand longitudinally. At the same time, its contraction elevates the lower ribs because of the vertically oriented attachments of the diaphragm to the costal margins. Contraction of the external intercostal muscles also raises the ribs during inspiration. As the ribs are elevated, the anterior-posterior and transverse dimensions of the chest enlarge (figure 7). In addition to the diaphragm, the external intercostal muscles, and the parasternal intercartilaginous muscles, the neck muscles (sternocleidomastoid and scalenus muscles) may assist in inspiration. Their major contribution is during high levels of ventilation. Contraction of these muscles is also apparent during severe asthma and other disorders that obstruct the movements of air into the lungs. The neck muscles elevate and fix the uppermost part of the rib cage, elevate the sternum, and slightly enlarge the anterio-posterior and longitudinal dimensions of the chest. Expiratory muscles: In contrast to inspiration, expiration is passive during quiet breathing as a result of the recoil of the lungs and the chest wall. It becomes active at higher levels of ventilation (exercise), or in pathological states when expiratory resistance increases and the movement of airflow out of the lungs is impeded. Muscles involved in active expiration include the internal intercostal muscles and the abdominal muscles. Contractions of these muscles compress the abdominal content, depress the lower ribs, and pull down the anterior part of the lower chest (Figure 7). In effect, they force the diaphragm upwards. They are essential for several body functions: e.g. coughing, singing, talking, vomiting. Forced maximal contraction of the expiratory muscles against a closed glottis (Valsalva's maneuver) can result in an enormous increase in pressure (up to 100 mm Hg) in the thoracic cage and abdomen. If sustained, this would lead to a decrease in venous return to the heart, thus a decrease in cardiac output. Summary of events during inspiration: Inspiration: Diaphragm and intercostal muscles contract Thoracic cage expands Intrapleural pressure becomes more subatmospheric - even more negative pressure created in the pleural space Transpulmonary pressure increases - pressure difference across difference in pressure the lungs increases from inside to outside the lungs Lungs expands Alveolar pressure becomes subatmospheric Air flows into alveoli - air flows along the pressure gradient *Note: This figure will be discussed in detail in section VII on the mechanics of breathing. Summary of events during expiration: Expiration: Diaphragm and external intercostal muscles stop contracting Chest wall moves inwards Intrapleural pressure goes back towards preinspiratory value Transpulmonary pressure goes back towards preinspiratory value Lung recoil towards preinspiratory volume Air in lungs is compressed Alveolar pressure becomes greater than atmospheric pressure Air flows out of the lungs canister with water with an inverted canister with air in it I. Spirometry: Measuring lung volumes can only measure volumes of air that you breathe in and out Clinically, it is useful to be able to measure the volume of air inhaled during inspiration under a number of different circumstances. Subdivisions of the lung volumes can be determined by means of a spirometer (Figure 8): a spirometer measures volumes of inhaled or exhaled gas, so can be used to measure tidal volume, vital capacity, inspiratory capacity, expiratory reserve volume, and inspiratory reserve volume (Figures 8 & 9). It cannot be used to measure functional residual capacity, total lung capacity, or residual volume. Figure 8 you cannot measure functional residual capacity with a spirometer - it can only be used to measure volumes that you can breathe in an out Lung volumes. (Reproduced from West, J.B.: Respiratory Physiology- the essentials). - at rest, one is taking a tidal breath - functional residual capacity is the volume of air that is left in the lungs during tidal breathing, makes sure that there is air left in the lungs at the end of a breath, maximize the amount of gas exchange, maintain air equilibrium - residual volume, there is Figure 9 always some air that is kept in your lungs even if you breath as hard as you can necessary to maintain equilibrium and prevent collapsing of the lungs - total lung capacity = all the air that you can hold in your lungs functional residual capacity J. Measurement of FRC FRC can be measured by helium dilution (Figure 10). Let C1 be the helium concentration in a spirometer of volume V1 and let the subject breath out to FRC. Then, open the valve and ask the subject to breath in and out from the spirometer. After equilibration with the subject's lungs, the concentration in the spirometer is C2. Since the total amount of helium is conserved, we have: C1 x V1 = C2 x (V1 + FRC ) so that: FRC = (C1 x V1 / C2) - V1 Figure 10 C1 = concentration of helium V1 = volume of air in the tube - helium does not dissolve in air, but rather will equilibrate in the spirometer and the lungs C2 = concentration of helium after diluted in the total volume of lungs (V2) (Reproduced from West: Respiratory Physiology- the essentials). *Note: Think of the lung as a balloon not as a jar. II VENTILATION A. Minute ventilation vs Alveolar ventilation The amount of air inspired into the lungs over some period of time is called ventilation. Usually, it is measured for one minute, and therefore we call it minute ventilation (VE). Therefore, VE is the amount of air inspired (or expired) during one minute: . . VE = VT x f where VT is the tidal volume, and f is the number of breaths per minute. (A dot above a symbol means a change with respect to time). . Figure 11 air that does reach the lungs on inhalation In a normal adult male, VT = 500ml, and f =12 breaths/minute. Therefore, VE = 6000ml/min. However, not all the air inhaled into the lungs reaches the gas exchanging area (the respiratory zone). Some of the air remains in the conducting airways, i.e. in the anatomical dead space (Figure 12). The volume of the anatomical dead space in the adult subject is about 150ml. Thus, the amount of air that reaches the respiratory zone per minute and available for gas exchange, the alveolar ventilation (VA), is: VA= (500-150 ml) x 12= 4200 ml/min. . . . removal of air contributed by anatomic dead space fresh air Figure 12 - not all the air inhaled into the lungs reaches the gas exchanging area. some of the air remains in the conduction airways = anatomical dead space (VD) The volume of the anatomical dead space in the adult subject is about 150mL (anatomical dead space is difficult to measure, but a close approximation is a subject's weight in pounds). for 150lb person Physiological dead-space Physiological dead space = alveolar dead space + anatomical dead space Under some pathological conditions, a certain amount of inspired air, although reaching the respiratory zone, does not take part in gas exchange. In this case, alveoli either receive a decreased blood supply or no blood supply at all. These alveoli represent alveolar dead space. The sum of alveolar and anatomical dead space is called the physiological dead space (VD). Therefore, the difference between minute and alveolar ventilation is the dead space ventilation that is wasted from the gas exchange point of view, i.e. VD=VE VA, or in terms of volume, VD=VT-VA. ... P = total pressure Px = partial pressure of gas x Fx = fractional concentration in dry gas Px = Fx*P FO2 = 21% FCO2 = 0.03% Barometric P = 760mmHg Contribution of water vapour to barometric pressure = 47mmHg Px = (P-47mmHg)*Fx PO2 = (760-47mmHg)*21/100 = 150mmHg PCO2 = (760-47mmHg)*0.03/100 -alveolar dead space can occur under pathological conditions, e.g. blood clot - even if the alveoli have gas flow, there is no blood flow to the area and thus no gas exchange B.Types of Alveolar Ventilation . Normal Alveolar Ventilation: V matches CO2 and keeps PaCO2 at a constant level (figure 13). A - partial pressures on the air when it reaches the lungs decreases on AVERAGE - on first breath, the partial pressure of oxygen will also be 150mmHg - however there is immediate diffusion of oxygen and carbon dioxide (a large pressure gradient is present) - the movement of gasses leads to a decrease in the average pressure Figure 13 Types of Alveolar Ventilation (Conted) ventilation exceeds the body's needs - must be taken w.r.t the body's requirements Alveolar hyperventilation: This occurs when more O2 is supplied and more CO2 removed than the metabolic rate requires (VE exceeds the needs of the body). As a consequence, alveolar and arterial partial pressures of O2 rise and those of CO2 decrease. Note that this is with respect to the metabolism so ventilation during exercise is not hyperventilation. Alveolar hypoventilation: A fall in the overall level of ventilation can reduce alveolar ventilation below that required by the metabolic activity of the body. Under the condition of alveolar hypoventilation, the rate at which O2 is added to alveolar gas, and the rate at which CO2 is eliminated, is lowered, so that the alveolar partial pressure of O2 (PAO2) falls and PACO2 rises. As a result of this, the blood in the pulmonary capillary is less oxygenated, and PaO2 falls below normal values. Similarly, PaCO2 rises above the normal value. Alveolar hypoventilation may occur during severe disorders of the lungs (e.g. chronic obstructive lung disease), or when there is damage to the respiratory muscles. It can also occur when the chest cage is injured and the lungs collapse, or when the central nervous system is depressed. PACO2 (alveolar) is not the same as PaCO2 (arterial) . III GAS DIFFUSION A.Diffusion Rate In order to fulfill the purpose of ventilation, oxygen from the alveolar gas must be transferred across the alveolar-capillary membrane. This process occurs by passive diffusion. Diffusion is governed by Fick's Law, which states that the rate of diffusion of a gas through a tissue is proportional to the tissue area and the difference in gas partial pressure between the 2 sides, and is inversely proportional to the tissue thickness. Thus, Diffusion rate is proportional to: surface area (50-100 m2) partial pressure gradient 1/thickness (~0.2 mm) alveolar capillary membrane can thicken in the case of edema, accumulation of fluid in the ISF Diffusion Rate (Contned) In the venous blood reaching the alveoli, because of the O2 consumption and CO2 production by the metabolic processes, PO2 is lower and PCO2 is higher than in the alveoli. Since the diffusion direction is from higher to lower pressure, O2 diffuses from the alveolar gas to the blood, and CO2 diffuses in the opposite direction. O2 from a gaseous medium diffuses through the alveolar-capillary membrane to a liquid plasma in the pulmonary capillaries (Figure 14). In order for a gas to diffuse through a liquid, the gas must be soluble in the liquid. Since CO2 is considerably more soluble than O2, it diffuses approximately 20 times more rapidly than O2. Figure 14 9 layers to diffuse through (liquid and solid) Ultrastructure of the respiratory membrane as shown in cross-section. (Reproduced from Guyton: Textbook of Medical Physiology). Diffusion Rate (Contned) Let us follow the course of an imaginary volume of blood as it flows through the pulmonary capillaries. At the beginning of the pulmonary capillaries there is a large difference between PO2 on either side of the alveolar-capillary membrane. Thus, the O2 gradient between the blood and the lungs is quite large. This large difference becomes smaller with time as the blood flows through the lungs. By the end of the capillary, as more O2 has moved from the lungs to the blood, the O2 gradient (across the capillary) becomes less. It then follows that as flow continues, the rate of diffusion must decrease (due to a smaller pressure gradient). There is a similar situation occurring with PCO2. Furthermore, at the beginning of the capillaries, PCO2 is 46 mm Hg but 40 mm Hg in alveolar gas. The difference in PCO2 between the 2 sides of the alveolarcapillary membrane is 10 times smaller than that for PO2. It seems as though O2 would diffuse much faster than CO2. This does not happen though, because another factor comes into play. The diffusion rate of CO2 greatly exceeds that of O2, due to CO2 being more soluble in the blood. Therefore, the time required for equilibrium between alveolar air and capillary blood is approximately the same for the two gases. - for diffusion to take place, a gas must be dissolved in the liquid - the amount of gas that dissolves in a liquid is proportional to its partial pressure - carbon dioxide is 20x more soluble in blood than - oxygen has a greater pressure gradient, and carbon dioxide has a larger solubility B. Transit Time Although the transit time of blood through the pulmonary capillaries is only 0.75 seconds at rest, diffusion is so rapid that the PO2 of the air and that of the blood reach equilibrium before the blood has passed even half way along the pulmonary capillary. During the transit time, blood in the capillaries is in contact with the air in the alveoli. Diffusion of the gases occurs along the pressure gradient. In a normal lung, diffusion of both O2 and CO2 is accomplished within 1/3 of the red blood cell transit time (Figure 15). Therefore, in a resting person with an impaired rate of diffusion (e.g. a patient with pulmonary edema) PO2 and PCO2 may be normal (because CO2 and O2 may still be able to diffuse during the transit time). However, when blood flow increases in this person and the transit time consequently becomes shorter (e.g. during exercise), arterial PO2 may decrease and arterial PCO2 may increase. Transit time = how much time an RBC spends in the alveolar capillary network pulmonary arteries lung pulmonary veins a RBC takes 0.75 seconds to cross the pulmonary capillaries while it takes 0.33 seconds to saturate it with oxygen a patient with edema who's alveolar membrane has thickened has a more difficult time saturating blood with oxygen and desaturating with carbon dioxide - upon exercise, RBC's will move too quickly and will not saturate with oxygen Figure 15. Diffusion of O2 and CO2 across the alveolar-capillary membrane and transit time of blood through the pulmonary circulation. Saturation time for O2 and desaturation time for CO2 are shown in a normal case (solid line) and in an abnormal case (dotted line). IV Pulmonary blood flow A.Pulmonary Circulation and Blood Pressure In the pulmonary capillaries, blood is spread out in a multitude of thin-walled vessels which have a surface area of approximately 100 m2, or 40 times the body surface area. The pulmonary circulation differs in many ways from the systemic one. Blood pressure in the pulmonary circulation is lower than in the systemic circulation, and the walls of the pulmonary capillaries are thinner than those of similar vessels in the systemic circulation. Normally, the right ventricle develops a pressure of about 25 mmHg during its systole, and this is transmitted to the pulmonary arteries. When systole ends, right ventricle pressure falls to atmospheric (taken to be 0). Since the pulmonary valves are now closed, blood pressure in the pulmonary circulation decreases gradually during diastole to a low of about 8 mmHg as blood flows through the pulmonary capillaries. The mean pulmonary arterial pressure is about 15 mmHg while the left atrial pressure is about 5 mmHg. - pulmonary circulation does not require a high pressure system - high pressure in the pulmonary system can cause leakage of fluid which will lead to edema - low pressure, and high fluid volume movement is ideal - flow and pressure are intimately related to resistance (thickness of the capillary) the pressure drop across the pulmonary capillaries is about 10mmHg --> low pressure compared to the pressure drop of about 100mmHg in the systemic circulatory system Figure 16. Pressures in the pulmonary and systemic circulations. B. Vascular Resistance Blood flow depends on vascular pressure and resistance, i.e. flow=pressure/resistance. There is a total pressure drop from pulmonary artery to left atrium of about 10 mm Hg (Figure 16, compared to ~100mmHg for the systemic artery to right atrium). Therefore, the pulmonary resistance is only 1/10 that of the systemic circulation. The low vascular resistance in the pulmonary circulation relies on the thin walls of the vascular system. The low vascular resistance and high compliance of the pulmonary circulation allows the lung to accept the whole cardiac output at all times. On the other hand, because of their high compliance, the pulmonary vessels are affected by the pressure within and around them (Figure 17). - the low vascular resistance in the pulmonary circulatory system depends on the think walls of the pulmonary capillaries - however they are highly affected by lung volume as well Vascular Resistance (Contned) - high lung volumes + high pulmonary pressures (deep inspiration) alveoli will be compressed together - depending on where the blood vessels are, some are opened while others are squeezed closed When the pressure around them (alveolar pressure) increases above the pressure inside the capillaries, they collapse. Therefore, at large lung volumes and increased alveolar pressure, the pulmonary capillaries collapse. Changes in lung volume affect larger vessels differently. Both the arteries and the veins increase their caliber as the lung expands. They are pulled open by the radial traction of the surrounding lung parenchyma. Moreover, these vessels are exposed to intrapleural and not alveolar pressure. Pulmonary blood flow is therefore affected by lung volume. Figure 17 Extra-alveolar vessels Alveolar vessels C. Accommodation of Pulmonary Blood Vessels The pulmonary circulation has the capacity to accommodate two- to three-fold increases in cardiac output with little change in pulmonary arterial pressure. The increase in blood flow with little changes in driving pressure indicates that as pulmonary blood flow increases, pulmonary resistance falls. This fall in vascular resistance results from an increasing cross-sectional area of the vascular bed. Blood vessels already perfused may increase their caliber (distension), and previously closed vessels may open as the cardiac output rises (recruitment) (figure 18). vessels at the top are not as open as at the bottom Figure 18 - recruitment and distention upon high exertion can increase cardiac output 2-3 times Reproduced from West: Respiratory Physiology-the essentials. Accommodation of Pulmonary Blood Vessels (Contned) Drugs (serotonin, histamine, norepinephrine) which cause the contraction of smooth muscle increase pulmonary resistance in the larger pulmonary arteries. Drugs (acetylcholine, isoproteranol) which can relax smooth muscle may decrease pulmonary vascular resistance. - drugs can relax muscle --> decrease vascular resistance, alter the diameter of the vessels D. Effects of Gravity on pulmonary blood flow Pulmonary blood flow is affected by gravity and it differs with body posture. In the upright position, blood flow increases almost linearly from top to bottom of the lungs (Figure 19). The vessels are more distended toward the bottom of the lungs because gravity increases vascular pressure. Near the top of the lungs, the pulmonary capillaries may be completely compressed if alveolar pressure is greater than blood pressure in the capillaries. greater blood flow at the bottom of the lungs compared to the top - differential blood flow - extra alveolar vessels are not very extended at low volumes --> lower blood flow observed at the bottom of the lungs Figure 19a. Measurement of the distribution of blood flow in the upright human lung using radioactive xenon. The dissolved xenon is evolved into alveolar gas from the pulmonary capillaries. Note that the somewhat lower blood flow observed at the bottom of the lung is due to extra-alveolar vessels being less expanded at low lung volumes. (Reproduced from West: Respiratory Physiology-the essentials). E. Effects of Gravity on Ventilation - at rest top alveoli are more open than those at the bottom - on breathing the alveoli at the bottom will open more than those at the top - the ones at the bottom will be more ventilated because those at the top were already open Gravity also affects the distribution of ventilation. In an upright lung at rest, in normal gravity, the alveoli at the top of the lungs are more opened than the bottom ones (think of a Slinky held in normal gravity). Therefore, during breathing the alveoli from the bottom of the lungs are opened wider than those at the top, i.e. preferential ventilation of the bottom of the lungs. The distribution of ventilation can be measured in a similar way as that of perfusion but with inhaled radioactive Xenon instead of infused in the blood (Figure 19b) . - ventilation is higher in the lower zones than in the higher zones - more fresh air is going into the bottom zones vs. the higher zones Figure 19b. Measurement of regional differences in ventilation with radioactive xenon. When the gas is inhaled, its radiation can be detected by counters outside the chest. Reproduced from West: Respiratory Physiology-the essentials. F. Distribution of ventilation perfusion ratio in the lungs in normal gravity. - the difference in blood flow between the top and bottom of the lungs is larger than the difference in ventilation - the ventilation perfusion ratio represents the gas exchange taking place - at the top of the lungs there is an abnormally high ventilation perfusion ratio and at the bottom is is unusually low Figure 20. Ventilation increases slowly from top to bottom of the lung but blood flow increases more rapidly. Therefore, the ventilation-perfusion ratio is abnormally high at the top and much lower at the bottom. Reproduced from West: Respiratory Physiology-the essentials. . Using Fick's principle G. Measuring Pulmonary Blood Flow (Q) . ) is equal to the O2 taken up by the O2 consumption per minute (VO 2 blood in the lungs in one minute. The [O2] in the blood entering the lungs is CVO2 and that leaving is CaO2. It then follows that: . . 2= Q(CaO2 - CVO2) VO .. or where: Q= VO2/ (CaO2 CVO2) VO2: measured by comparing [O2] in the expired gas collected in a large spirometer and [O2] in inspired gas; CaO2: measured from an artery; CVO2: measured via a catheter from the pulmonary artery. . V TRANSPORT OF O2 and CO2 A.O2 Physically Dissolved in Plasma The amount of dissolved gas carried by the blood is directly proportional to the partial pressure of the gas, according to Henrys Law (Henry's Law states that the number of gas molecules dissolved in a liquid is proportional to the partial pressure of the gas above the liquid). Because O2 is relatively insoluble in H2O, the amount of O2 dissolved in blood is very small, and linearly proportional to PO2. In 100 ml of plasma, there is 0.3 ml of O2 (i.e. 0.3 volume %) when equilibrated with . PO2 of 100 mm Hg. O2 consumption (VO2) by the body cells, even at rest, is much greater than what can be supplied from the amount dissolved in blood. At rest, O2 is about 300 ml O2/min. Therefore, if O2 were only found in plasma, the tissue demand for O2 would never be met. B. O2 Bound to Hemoglobin Hemoglobin, Hb, is found in red blood cells, and permits whole blood to take up to 65 times as much O2 as plasma, at a PO2 of 100 mm Hg. Hb constitutes 1/3 of the total weight of red blood cells; there are 147g of Hb in each liter of blood. Each molecule of Hb consists of a heme (iron porphyrin) joined to a globin (protein) (Figure 21). Hb consists of 4 polypeptide chains, each containing an Fe++ ion that can bind to 1 molecule of O2. Hb is essential for the transport of O2 by blood because it combines rapidly and reversibly with O2: Hb + O2 HbO2 At PO2 of 100 mm Hg, the total amount of O2 physically dissolved in the blood is 0.3 vol.%, and the total amount of O2 bound to Hb is 19.5 vol. %. This means that the total amount of O2 in arterial blood is about 20 vol. %. One can see from this that Hb plays an important role in determining the total amount of O2 carried by the blood. Note that the O2 that is bound to Hb does not contribute to the PO2 of the blood. Only molecules physically dissolved in the blood plasma are responsible for PO2. However, the PO2 of the plasma does determine the amount of O2 that combines with Hb. - hemoglobin provides an immediate switch mechanism for loading and releasing oxygen - small changes in O2 levels in the blood/tissue cause hemoglobin to load/ release - four protein chains, two alpha two beta - four Fe3+ ions - at maximum, one molecule of hemoglobin can bind four molecules of O2 Figure 21 C. The O2 dissociation curve Hb unloads O2 in working muscles The HbO2 dissociation curve (Figure 22) determines the amount of O2 carried by Hb for a given partial pressure of O2. The curve is flat at high values of PO2 (at alveolar level of PO2) and steep at low values of PO2 (at peripheral tissue levels of PO2). The implications of this are as follows: at high values of PO2, the amount of O2 bound to Hb, or HbO2, stays roughly constant, when alveolar PO2 drops by 20 mmHg, from 100 mmHg to 80 mmHg. PO2 has to drop to 60 mmHg in order for HbO2 to drop significantly. At low PO2, Hb unloads O2 very quickly compared to at high PO2 Figure 22 The O2 dissociation curve (Conted) At low values of PO2, as seen in the peripheral tissues, a small drop in PO2 unloads the O2 from Hb to the tissue. The fact that HbO2 dissociates into Hb and O2 more readily at lower PO2 values is of crucial importance: at the tissue level, PO2 may get as low as 1-3 mmHg. A drop in PO2, for example, from 40 to 20 mmHg results in a decrease in %HbO2 from about 75% to 35%. (Compare this to a drop in PO2 from 100 to 80 mmHg, where % HbO2 changes by less than 3 %!) This takes place at the tissue level, where metabolic processes need O2. This is an important mechanism that operates automatically in matching tissue O2 supply to tissue O2 need. The O2 dissociation curve (Conted) As blood enters the tissue capillaries, plasma PO2 is greater than interstitial fluid PO2 (Figure 23). O2 readily diffuses across the capillary membrane into the interstitial fluid. This lowers plasma PO2, and O2 diffuses out of the erythrocytes into the plasma. The lowering of erythrocyte PO2 causes the dissociation of HbO2 into Hb and O2. The O2 which diffused into the interstitial fluid moves into the cells. The net result is the transfer of large quantities of O2 from HbO2 into the cells purely by passive diffusion. Under resting conditions, Hb is still 75% saturated at the end of the tissue capillaries. This underlies an important automatic mechanism by which cells can obtain more oxygen whenever they need it, like during exercise. In the muscle cell, a similar substance to hemoglobin has been found- myoglobin. Its major function is to act as an intracellular carrier which facilitates the diffusion of oxygen throughout the muscle cell. Figure 23 Shape of Hemoglobin dissociation curve The quaternary structure of Hb determines its affinity for O2; cooperative binding The combination of the first heme in Hb with O2 increases the affinity of the second heme for O2, etc. (cooperative binding). Myoglobin, found in skeletal muscle, resembles Hb but binds only one O2 molecule. The O2-myoglobin curve is hyperbolic in shape. It follows that myoglobin will release its O2 only at very low PO2 The O2 dissociation curve (Conted) The total amount of O2 in the blood depends mostly on Hb concentration (figure 24). Under conditions of decreased Hb concentration (anaemia) even when O2 saturation is 97.5%, less O2 can be carried in the blood by Hb. Figure 24 D. The Bohr Effect The Bohr Effect is the shift of the HbO2 dissociation curve to the right when blood CO2 or temperature increases, or blood pH decreases (Figure 25). Here is the logic behind the Bohr effect: when we exercise, we increase our CO2 and acid production and generate heat. The curve shifting to the right means that for a given drop in PO2, an additional amount of O2 is released from Hb to the working tissues. The same effect is seen when 2,3-diphosphoglycerate (2,3DPG), an end product of red blood cell metabolism, increases. 2,3-DPG levels may increase during chronic hypoxia (due to high altitude or lung disease). A decrease in temperature, an increase in pH, and a decrease in CO2 have the opposite effect on the dissociation curve, shifting it to the left. Keep in mind that all of these factors, however, have little effect on the total amount of O2 combined with Hb above 80 mm Hg. - bohr effect - match O2 release to O2 need; automatic mechanism of Hb - increase temp, CO2, acidity --> curve shift right - exercise - increase acidity of blood, CO2 levels - such a high PO2 is no longer needed to cause the release of O2 from Hb and vice versa Figure 25 Reproduced from West: Respiratory Physiology- the essentials). DPG - degradation product of RBC's E. Carbon monoxide poisoining CO has an extremely high affinity for the O2 binding sites in hemoglobin (210-fold). Therefore it reduces the amount of O2 bound to hemoglobin. It also shifts the O2-hemoglobin curve to the left, thus decreasing the unloading of O2 to the tissue. In CO poisoning, there is little stimulation to increase ventilation because PaO2 remains normal. F. Transport of CO2 CO2 is the primary product of the oxidative processes taking place in the body cells, and it is removed from the tissues by the blood. On average, a person uses about 300 ml/min of O2 and produces about 250 ml/min of CO2 at rest. These numbers can go up twenty times during heavy exercise. CO2 is carried in three forms in the blood (figures 26 & 27): 1) Physically dissolved in blood (10%): According to Henrys Law, CO2 from the tissues diffuses into the plasma where it is physically dissolved. 2) Combined with Hb to form HbCO2 (11%): Contrary to O2 that combines with the heme portion of Hb, CO2 combines with the globin portion; hence there is no competition for binding on Hb. 3) As bicarbonate (79%): CO2 combines with H2O to produce carbonic acid (H2CO3). This reaction is very slow in plasma, but as CO2 diffuses into the erythrocytes, the reaction is aided by the enzyme carbonic anhydrase (CA), according to: high concentration of carbonic anhydrase in RBC's (1) CO2 + H2O H2CO3 H2CO3 then ionizes into bicarbonate (HCO3-) and H+ ions as: H2CO3 HCO3- + H+ (2) CA chloride shift maintain neutrality of the cell Figure 26 - red blood cell membrane is permeable to bicarbonate - carbon dioxide diffuses into/out of the cell from the plasma Figure 27 Transport of CO2 All these reactions are reversible, so they can proceed in either direction, depending upon the prevailing conditions. If CO2 production increases, the production of HbCO2, HCO3-, and H+ increases, as in equations 1 and 2. Lowering of blood PCO2 results in HCO3- going to H2CO3 and further into CO2 and H2O, and HbCO2 generating Hb and CO2. This situation occurs when venous blood flows through the lung capillaries, as in equations 3 and 4: H+ + HCO3 H2CO3 H2O + CO2, CA (3) (4) HbCO2 Hb + CO2 Because the blood PCO2 is higher than alveolar PCO2, a net diffusion from the blood into the alveoli lowers the blood PCO2. Normally, as fast as CO2 is generated from HCO3- and HbCO2, it diffuses into the alveoli. G. The Haldane Effect In the tissue capillaries, Hb free of O2 (the O2 has diffused to the tissues) may combine with H+, in the reaction: H+ + HbO2 HHb + O2 This occurs because reduced Hb is less acidic than HbO2. Hb acts as a buffer. Consequently, the presence of reduced Hb in the tissue capillaries helps with the blood loading of CO2, by pushing equations 1 and 2 to the right. This is known as the Haldane effect (Figure 28). As a result, for a given PCO2, more CO2 is carried in deoxygenated blood than in oxygenated blood. The O2 saturation of blood influences the CO2 dissociation curve by shifting it to the right; as Hb unloads O2 into the tissues, it is able to take up increased amounts of CO2 from the tissues. The Haldane effect, in short, is the fact that mixed venous blood can carry more CO2 than can arterial blood. - haldane effect - due to the buffering of H+ ions by Fe2+ - occurs because once Hb has released its oxygen at peripheral tissues, the iron of Hb is reduced to Fe2 + from Fe3+ - thus it can now bind H+ ions --> more carbon dioxide will be consumed to produce H+ and bicarbonate to maintain equilibrium --> deoxygenated blood can carry more carbon dioxide than arterial blood - shift right in carbon dioxide xontent The Haldane Effect (Conted) Because all these reactions are reversible, they can proceed in either direction, depending upon the prevailing conditions. If the production CO2 of increases, as is the case at the tissue level, the production of HbCO2, HCO3-, and H+ increases, as in equations 1 and 2. A sudden lowering of blood PCO2 results in HCO3- going to H2CO3 and further into CO2 and H2O, and HbCO2 generating Hb and CO2. This second situation is precisely the case when venous blood flows through the lung capillaries, as in equations 3 and 4: H+ + HCO3- H2CO3 H2O + CO2, HbCO2 Hb + CO2 (3) (4) Because the blood PCO2 is higher than alveolar PCO2, a net diffusion from the blood into the alveoli lowers the blood PCO2. Normally, as fast as CO2 is generated from HCO3- and HbCO2, it diffuses into the alveoli. The Haldane Effect (Conted) Unlike the HbO2 curve, the CO2 dissociation curve (Figure 28) has no steep or flat portions; the relationship between CO2 content and PCO2 is almost linear. This means that if we hypoventilate and alveolar PCO2 rises, then arterial, capillary, tissue and venous CO2 also rise. Doubling alveolar ventilation halves alveolar PCO2; it therefore follows that an increase in alveolar ventilation proportionally increases CO2 removal. Figure 28 shift right/up in carbon dioxide content - hyperventilation - will not increase the amount of O2 in the blood, RBC's are saturated (vol% vs. PO2 plateaus) - but you can certainly decrease the amount of CO2 in the blood (linear relationship) H. Respiratory Failure Respiratory failure occurs when the respiratory system is unable to do its job properly, due to failure of: 1) 2) 3) the gas exchanging capabilities of the lungs; the neural control of ventilation (i.e. the drive to breathe); the neuromuscular breathing apparatus (i.e. the respiratory muscles and their innervation). I. Arterial Hypoxia (Hypoxemia) Blood hypoxia refers to deficient blood oxygenation, i.e. low PaO2 and low % Hb saturation. In hypoxic conditions, if PaO2 decreases below 60 mm Hg, O2 content in arterial and venous blood becomes lower than the normal values at sea level. - hypoxia - low air concentration of O2 There are 5 general causes of hypoxia: - hypoxemia - low blood concentration of O2 1) Inhahlation of low PO2 (e.g. at high altitude). 2) Hypoventilation: PaO2 decreases and PaCO2 increases. It means that alveolar ventilation in relation to the metabolic CO2 production is reduced. Hypoventilation occurs due to: diseases affecting the central nervous system, neuromuscular diseases, barbiturates, other drugs and narcotics. 3) Ventilation/perfusion imbalance in the lungs: this occurs when the amount of fresh gas reaching an alveolar region per breath is either too little or too much for the blood flow through the capillaries of that region. Arterial Hypoxia (Hypoxemia) (Conted) 4) Shunts of blood across the lungs: venous blood bypasses the gas exchanging region of the lungs and returns to systemic circulation, deoxygenated. - some babies are born with a heart perforation that was important for shunting blood from the right heart to the left heart in utero to maximize blood flow to the brain --> example of hypoxemia due to shunting, blood flow to pulmonary circulation is decreased 5) O2 diffusion impairment (e.g. thickening of the alveolar-capillary membrane, or pulmonary edema). VI Control of Breathing A.Voluntary vs Automatic Breathing When we think of respiration, we think of an automatic, involuntary activity that brings enough air into the pulmonary alveoli to maintain the O2 and CO2 tensions of alveolar gas or arterial blood at optimal levels in different conditions, e.g. sleep, rest, or exercise. The central nervous system controls gas exchange by integrating all the information coming from the periphery which in turn, gives an adequate depth and frequency of breathing (minute ventilation). In fact, breathing is under both voluntary (e.g. voluntary hyperventilation) and involuntary (e.g. while asleep) control. Anatomically, there are separate neurological structures for automatic and voluntary control, although the two systems interact. The cerebral hemispheres control voluntary breathing that can be effective even when automatic control no longer functions while the brainstem controls involuntary breathing. If you stop ventilation voluntarily, you will find that in spite of your efforts to prevent it, breathing will eventually start again. This occurs because the arterial PCO2 has reached about 50 mm Hg and arterial PO2 has reached about 70 mm Hg, at which point voluntary control is over-ridden. This is called the breaking point. The over-riding of the voluntary control by the automatic control depends upon the information from the receptors sensitive to CO2 and O2 levels (in arterial blood and/or cerebro-spinal fluid). B. Structures Involved in the Control of Breathing The neuronal structures involved in involuntary control of breathing are located in the brain stem (pons and medulla). Like in other physiological systems, there are 3 basic elements in the respiratory control system (figure 29): - voluntary --> cerebral hemispheres - involuntary --> pons and medulla - the two systems interact e.g. breaking point 1) sensors: these gather information about lung volume (pulmonary receptors) and O2 and CO2 content (chemoreceptors). 2) controllers: information from the sensors is sent to the controller, in the pons and medulla, via afferent neural fibers. Once it has reached the pons and medulla, the peripheral information and inputs from the higher structures of the central nervous system are integrated. 3) effectors: as a result of the integration, neuronal impulses are generated and sent via spinal motoneurons to the effectors, i.e. the respiratory muscles. This results in ventilation being adjusted to the person's metabolic needs. Since the main function of the lungs is to exchange O2 and CO2 between alveolar gas and blood, whenever the demand for O2 and the production of CO2 increase (as during exercise), ventilation must increase too, to satisfy this requirement. Figure 29 sense O2, CO2 concentration volume of lungs --> provide appropriate tidal volume and breathing frequency C. Respiratory Neurons 1. Respiratory neurons in the medulla generate the basic respiratory rhythmicity. Cutting the pneumotaxic centers in the rostral (upper) pons causes breathing to become deep and slow (this is the same effect as cutting the vagus nerve which brings afferent information). - pons fine tunes breathing patterns - cutting no information would arrive from the periphery the pons slows breathing pattern - usually there is only inspiratory neural activity - expiratory is usually passive - deep and slow inspiration 2. 3. Removing influence of both vagus nerves and the rostral pons causes apneuses (tonic inspiratory activity interrupted by short expirations). - inspiratory activity from the medulla - similar pattern to if one was holding their breath D. Chemoreceptors PO2, PCO2, and pH in arterial blood are detected by chemoreceptors. If these pressures or pH are changed, ventilation will also change in attempt to return the gas pressures to their normal values. Information from the chemoreceptors is carried to the respiratory neurons. In turn, the activity of respiratory neurons will increase if PaO2 is too low (less than 60 mm Hg) or PaCO2 is higher than 40 mm Hg. The activity of the respiratory neurons will decrease if PaO2 is higher than 100 mm Hg or PaCO2 is lower than 40 mm Hg. There are 2 types of chemoreceptors: central and peripheral. 1) Central Chemoreceptors: Central chemoreceptors are located on the ventral surface of the medulla. They detect the pH of the cerebrospinal fluid (CSF) surrounding them (PCO2 and pH of the CSF are influenced by those of arterial blood) (figure 30). The central chemoreceptors give rise to the main drive to breathe under normal conditions. The sensitivity of these receptors may be easily assessed by a CO2 rebreathing test (figure 31). We can have a subject breathe different CO2 mixtures, or rebreathe expired air from a bag filled with O2 so that with each expiration, the inspired PCO2 gradually increases. Stimulation of the chemoreceptors increases minute ventilation, and the resulting hyperventilation reduces PCO2 in the blood, and therefore in the CSF. - CO2 blood levels increase (hypoventilation) - cells in the brain are permeable to CO2 but not to H+ and bicarbonate - CO2 enters the CSF, binds to water and generates bicarbonate, consuming H+, lowering pH and stimulating chemoreceptors --> main control of breathing Figure 30. Environment of the central chemoreceptors. They are bathed in brain extracellular fluid (ECF), through which CO2 easily diffuses from the blood vessels to cerebrospinal fluid (CSF). The CO2 reduces the CSF pH, thus stimulating the chemoreceptor. H+ and HCO3- cannot easily cross the bloodbrain barrier. (Reproduced from West: Respiratory Physiology- the essentials) - subject breathes in a bag full of oxygen - oxygen levels are not a problem - carbon dioxide levels increase as subject breathes - direct relationship between minute ventilation and PCO2 - increasing breathing frequency and tidal volumes --> chemoreceptors are very sensitive to CO2 levels Figure 31. Ventilatory response to hypercapnia (elevated CO2 in blood): Small increases in PCO2, increase minute ventilation (left) due to an increase in respiratory rate (center) and tidal volume (right). 2) Peripheral Chemoreceptors: Peripheral chemoreceptors are mainly sensitive to changes in PO2, but are also stimulated by increased PCO2 and decreased pH. They are located in the carotid bodies (i.e. the bifurcation of the common carotid arteries) and in the aortic bodies (next to the ascending aorta) (Figure 32). The carotid and aortic bodies are made up of blood vessels, structural supporting tissue, and numerous nerve endings of sensory neurons of the glossopharyngeal (in carotid bodies, IX nerve) and vagus nerves (in aortic bodies, X nerve). The afferent fibers of these receptors project to the dorsal group of respiratory neurons in the medulla. Figure 32. Peripheral chemoreceptors. stimulated mostly by decreases in PO2 carotid bodies send information via the glossopharyngeal nerve (9th cranial nerve) to the medulla aortic bodies send information to the medulla via the vagus nerves E. Ventilatory response to decreased PO2 The effects of hypoxia on ventilation can be studied by having a subject breathe gas mixtures with decreased concentrations of O2. During normocapnia (normal levels of CO2 in blood), the alveolar PO2 can be reduced to about 60 mm Hg before appreciable changes in minute ventilation occur. However, at increased PCO2, a decrease of PO2 below 100 mmHg can already cause an increase in minute ventilation. Thus, an increase in PCO2 and a decrease in PO2 interact giving an augmented ventilatory response (Figure 33). Figure 33 - it takes quite a bit of time before ventilation increases with respect to PAO2 - there is not an immediate change in ventilation with changes in PO2 - high levels of CO2 will increase ventilation immediately even if levels of O2 are not low - combining the effect of PO2 and PCO2 the jump in ventilation is more immediate and pronounced (Reproduced from West: Respiratory Physiology- the essentials) F. Pulmonary Vagal Receptors There are 3 types of receptors in the lung that respond to mechanical stimuli: 1) Pulmonary Stretch Receptors; 2) Irritant Receptors; 3) Juxta-capillary or J receptors (C-fibres); Afferent fibres from all of these receptors travel in the vagus nerves. If the vagus nerve is sectioned, the result is slow, deep breathing. 1) Pulmonary Stretch Receptors: - fire in response to lung distention - tell the brain about lung volume - not very active in day to day breathing - more active in babies, animals, during exercise Pulmonary stretch receptors are located in smooth muscles of the trachea down to the terminal bronchioles. They are innervated by large, myelinated fibres, and they discharge in response to distension of the lung. Their activity is sustained as long as the lung is distended. Activity of these receptors phasically increases as lung volume increases during each inspiration. The main reflex effect of stimulating these receptors, the Hering-Breuer Inflation Reflex, is a decrease in respiratory frequency due to a prolongation of expiratory time. In other words, an increase in lung volume tends to inhibit the beginning of the next inspiratory effort (negative feedback mechanism). The opposite response is also seen, i.e. the deflation reflex. The Hering-Breuer reflex is weak in adults unless the tidal volume exceeds 1 L as in exercise, but is noticeable in infants and animals. 2) Irritant Receptors: - respond to noxious gases - mast cells release histamine --> bronchoconstrictor that decreases the diameter of the airways - flow of air is impeded - involved in asthmatic attack The irritant receptors are located between airway epithelial cells in the trachea down to the respiratory bronchioles. They are stimulated by noxious gases, cigarette smoke, histamine, cold air, and dust. They are innervated by myelinated fibers, and their stimulation leads to bronchoconstriction and hyperpnea (rapid breathing). The irritant receptors may be important in the reflex bronchoconstriction triggered by histamine release during an allergic asthmatic attack. 3) Juxta-Capillary Receptors: The name of these fibres originates from their location in the alveolar walls close to the capillaries. They are innervated by non-myelinated fibres and have short lasting bursts of activity. They are stimulated by an increase in pulmonary interstitial fluid, like what may occur in pulmonary congestion and edema. The reflex effects caused by these receptors include rapid and shallow respiration, although intense stimulation causes apnea. These receptors may play a role in dyspnea (sensation of difficulty in breathing) associated with left heart failure and lung edema or congestion. VII. MECHANICS OF THE VENTILATORY APPARATUS A.Pleural Space The ventilatory apparatus consists of the lungs and the surrounding chest wall. The chest wall includes not only the rib cage, but also the diaphragm and the abdominal wall. The lungs fill the chest so that the visceral pleura (on lungs) are in contact with the parietal pleura (on chest wall) of the chest cage (Figure 34). Consequently, the lungs and the chest wall act in unison. Mechanically, the lung and chest wall operate in series with one another. However, the lungs are not directly attached to the chest wall. some lungs that inflate/deflate more easily than others - associated with disease - different stiffness, distend more easily/difficultly Figure 34 attached to inside of chest Pleural Space (Conted) The visceral and parietal pleura are coupled together by a thin layer of liquid that fills the intrapleural space (figure35). The liquid allows the lungs to slide against the internal wall of the chest during breathing and to follow the change in thoracic configuration. Pleural pressure (Ppl) is the pressure that can be measured in the liquid-filled space between lung and chest. At rest, the pressure in the pleural space, the pleural pressure (Ppl), is negative. This is due to the opposing forces acting on the lung and chest wall. Indeed, if a hole is punctured through the chest wall (pneumothorax), the lungs collapse and the chest springs outwards (figure 35). - if a hole is made in the lungs Figure 35 air will move along its pressure gradient - pressure difference will disappear - lungs will collapse and chest will expand Reproduced from West: Respiratory Physiology- the essentials. B. Static Properties: Elastic propeties of the lungs and chest wall To evaluate the elastic properties of the respiratory system (chest wall and lungs), we measure changes in the recoil pressure of each separate structure (Figure 36) for a given change in lung volume. Lung volumes can be measured by means of the spirometry (see section 1-I). For the respiratory system, pressures are measured using manometers or pressure transducers, as referenced to atmospheric pressure. "Negative pressure" indicates a pressure below atmospheric, and "positive pressure" indicates a pressure above atmospheric pressure. The recoil pressure of a structure is defined as the pressure difference between the inside and outside of the structure (transmural pressure). The recoil pressure of the chest wall, trans-chest-wall pressure (Pw) is the difference between Ppl and the pressure at the body surface. Ppl can be measured using a flexible balloon introduced into the esophagus. Because the esophagus is located between the two pleural spaces, esophageal pressure provides a close approximation of pleural pressure. The body surface is under atmospheric pressure (bs). Thus, Pw = Ppl Pbs Elastic propeties of the lungs and chest wall (Conted) The recoil pressure of the lungs, transpulmonary pressure (Pl) is measured from the difference between Palv and Ppl. When there is no air flow, closed nose and mouth, Palv and the pressure measured at the mouth are the same. Thus, Pl = Palv - Ppl The recoil pressure of the total respiratory system, the transrespiratory system pressure (Prs), is measured as the difference between Palv and Pbs: Prs = Palv Pbs (where Palv=Pl-Ppl and Pbs=Ppl-Pw; by rearranging the 2 equations above) Hence, Prs is the sum of the pressures generated by its two components, lung and chest: Prs = Pl + Pw Elastic properties of the lungs and chest wall - the recoil pressure of a structure: the pressure difference between the inside and outside of the structure (transmural pressure) - the esophageal pressure provides a good approximation for the pleural pressure - Ppl can be measure using a flexible balloon introduced into the esophagus - the body surface pressure is under atmospheric pressure trans pulmonary pressure = recoil pressure = pressure different across the lungs = the difference between alveoli and pleural pressure Figure 36 Reproduced from "The Normal Lung, Murray, 2nd ed. Saunders Company" Note that in this static example, Pao= Pbs = Patm C. Compliance Compliance of the lungs: - easy to distend - highly compliant - compliance = 1/elastance The compliance of the lungs, or chest wall, or total respiratory system, is a parameter which refers to the ease with which each of these structures can be distended. The standard procedure for measuring the respiratory system compliance in humans is to determine the static pressure-volume relationship while lung volume is decreased step by step from TLC (figure 37). Compliance is expressed as the volume change in the lungs for a unitary change in pressure, i.e. the slope of the pressure-volume curve in figure 37. The pressure required to maintain a given volume of gas inside the lungs increases as the volume increases, i.e. the slope decreases with increases in lung volume in figure 37. Compliance of the lungs is also altered in diseases such emphysema and fibrosis (figure 37). Compliance of the lungs (Conted): The pressure difference between the alveoli (Palv) and the pleural space (Ppl) equals the pressure drop across the lung tissues. This is the pressure required to maintain the lungs at a given inflation volume against their tendency to recoil elastically. Thus, - difference between inside and Cl = V / (Palv - Ppl) outside - must take this difference for a living subject - otherwise the pressure outside is just 0 where CL is called the compliance of the lungs or its inverse elastance (EL=1/CL) so that El = (Palv - Ppl) / V The elastic recoil of the lungs is produced in part by the elastic lung tissue. However, a large part of the recoil forces arises from the properties of the liquid film lining the inside of the lungs. The surface tension in this film generates a substantial force because the surface area of the film is so large (see section VII-F). compliance changes with lung volume - the slope gets more shallow, becomes more difficult to inhale Figure 37 - slope = compliance = change in volume/change in pressure - at high lung volumes it becomes harder and harder to stretch the lungs - in emphysema there is an obstruction of the alveolar walls --> lungs are extremely compliant - easy to inflate for a given pressure - fibrosis lungs are much less compliant - they will stretch less for a given pressure Reproduced from "The Normal Lung, Murray, 2nd ed. Saunders Company" Compliance of the chest wall The tissues of the thorax (i.e. the chest wall) also have elastic properties that cause it to recoil either inward or outward, depending on its volume. Figure 38 shows the theoretical experiment of measuring the pressure-volume relationship of a thorax without lungs. The compliance of the thorax is defined in terms of a change in thoracic volume V (the change in volume of the thorax is the same as the change in volume of the lungs) and a change in pressure across the chest wall, Ppl. Thus, Cw = V/ Ppl Note that the pressure reported when measuring the compliance of the lungs were always positive (figure 37) because the lungs always tended to collapse. On the contrary, the chest wall tends to collapse only after reaching a volume of 60% vital capacity whereas it wants to spring out below that value (figure 38); therefore the pressure reported for the chest wall in figure 38 are sometimes positive sometimes negative. Figure 38 theoretical experiment - chest is connected to the manometer without the lungs - at 60% vital capacity no difference in pressure is observed - the chest is at equilibrium - differs from the lungs which always wanted to collapse, there is always a positive pressure - negative pressure results, the chest wants to expand - pneumothorax, chest wants to expand due to the negative pressure with the collapse of the lungs - chest is inflated with positive pressure with a known volume of air to total lunch capacity - the chest generates a positive pressure, it wants to collapse Reproduced from "The Normal Lung, Murray, 2nd ed. Saunders Company" Compliance of the respiratory system: The pressure drop across the respiratory system, Prs, is the sum of the pressure drop across the lung and that across the chest wall. Therefore, the compliance of the respiratory system, Crs, is related to the compliances of the lung and chest wall by Crs = V / Prs Crs = V / (Pl+Pw) 1/Crs = 1/Cl +1/Cw At FRC, Prs is zero because the system is at rest. This stable condition is caused by the inward recoil of the lungs (Pl is about +5 cmH2O) which is balanced by the outward recoil of the chest wall (Pcw is about -5 cmH2O) (figure 39). This means that, at FRC, the lungs are above their resting volume and the chest is below its resting volume (recall the concept of the pneumothorax). - lung - always on the positive side of pressure axis - chest wall is at equilibrium at about 60% tidal volume the pressure across the entire respiratory system is the sum of the pressure across the chest wall and the pressure across the lungs FRC - volume of the lung where the whole system is at equilibrium - the volume at which the positive pressure generated by the lungs is equal and opposite to the negative pressure generated by the chest Figure 39. Volume-pressure relationships of chest wall and lung combined (solid line). Reproduced from "The Normal Lung, Murray, 2nd ed. Saunders Company" Pneumothorax The elastic properties of the respiratory system are best illustrated by what happens when the chest is opened during thoracic surgery, i.e. a pneumothorax (refer back to figure 35). Air enters the pleural space because Ppl is less than atmospheric pressure. The lungs collapse to its resting position below RV, and the chest wall expands towards its resting position, at about 75% of total lung capacity. A traumatic or spontaneous pneumothorax may be a lifethreatening emergency since the lungs are uncoupled from the chest wall. D. Dynamics of a breath From a mechanical point of view, the respiratory system may be regarded as a pump with elastic, flow-resistive and inertial properties (figure 40). At rest, the lungs are at FRC and Ppl is negative due to the opposite forces acting on the lungs and chest wall. During inspiration, the diaphragm contracts and the chest wall is pulled open. This creates a more negative Ppl that causes expansion of the lungs (figure 41). Figure 40 - syringe(=diaphragm) with a balloon at the end - pulling on the syringe reduces the pressure around the balloon and thus the balloon increases in size, the pressure gradient will decrease and an inflow of air results - pushing the syringe in increases the pressure in space analogous the intrapleural space, the balloon will decrease in size, and the pressure gradient is increased - air will flow out to reestablish the equilibrium pressure gradient Dynamics of a breath airway Figure 41 - contraction of the muscles in the chest increases the size of the chest (and lungs) and decreases the pleural pressure - alveolar pressure is lowered relative to atmospheric pressure - air flows along the pressure gradient into the lungs - on expiration the chest muscles stop contracting - the pleural pressure increases - lungs recoil, creating a positive pressure on the air in the alveoli - air flows out of the lungs F=flow the constriction of the airway makes increases the resistance of the airway Dynamics of a breath As the lungs are pulled further away from their resting position (which is below RV), Ppl becomes even more subatmospheric (figure 42). As the volume of the lungs is increased, gas in the lungs is decompressed. The pressure in the alveoli (Palv) drops below atmospheric pressure. The created negative pressure gradient between the alveoli and atmosphere generates air flow to the lungs. As inspiration proceeds, the lungs are filling up with air, and the pressure gradient and the air flow gradually decrease. At the end of inspiration air flow stops because Palv 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, and Palv increases. The positive pressure gradient between the atmosphere and the lungs 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, air flow=0 ml/s and Palv=0 cmH2O, and Ppl is about -5 cmH20 (figure 42). Dynamics of a breath cross hatched region: - due to airway resistance - creates a delay - the air cannot immediately enter the alveoli upon increasing the volume of the lungs lung volume increases lungs at max volume, pressure gradient is not as large, negative flow decreases lung volume decreases decrease in pleural pressure chest recoils Figure 42 - on inspiration the volume of the lungs increase - negative flow - air goes inside the lungs increasing the size of the lungs - decreases the pressure in the lungs - on expiration the volume of the lungs decrease - creates a positive flow of air out of the lungs due to the increase of pressure inflow of air negative flow inward alveolar pressure decreases becomes sub atmospheric positive flow out of lungs alveolar pressure increases until chest recoils at which point it begins to decrease again (Reproduced from West: Respiratory Physiology- the essentials). Dynamics of a breath The time course of changes in pleural pressure during inspiration and expiration depends on contraction of the diaphragm and airway resistance. The dotted area in the graph shows the amount of pleural pressure necessary to overcome airway (and tissue) resistance. E. Airway Resistance In order to have gas flow through the airways, the pressure at the airway opening (Pao) must be different to that in the alveoli (Palv). The resistance of the airways to gas flow (Raw) is the ratio of this pressure difference and the flow. Raw = (Palv Pao)/Flow - in diseases like asthma, smooth muscles contract making the lumen smaller - mucus secretion also constricts the lumen --> increase in airway resistance where flow is equal to a change in volume per unit of time. A large diameter airway can carry a large flow for a given pressure difference and so has a smaller resistance than a small diameter airway. Airway resistance is therefore related to airway caliber and is an important determinant of lung function. In certain diseases (such as asthma) airway resistance can become very high making breathing difficult. Dynamic compression of airways - curve A is the same as the expiration curve of alveolar pressure graph - no matter how a subject breathes out the descending curve is independent of the effort made in exhalation as fast and hard as possible Figure 43. When a subject inspires to TLC and exhales to RV, during expiration, flow rises very rapidly to a high value and then declines over the rest of expiration. The descending portion of the flow-volume curve is independent of effort because of the compression of the airways by intrathoracic pressure (see figure 44a). (Reproduced from West: Respiratory Physiology- the essentials). Forced expiration pleural space there is a resistance that opposes forced exhalation - there is a pressure drop along the airways - pressure decreases along the airway due to the resistance of the tubes - there is no chance in pressure in the pleural space because the fluid is not changing -->the descending portion of flow volume curve is independent of the effort upon exhalation at rest, not breathing pleural pressure becomes more negative, alveoli expand, pressure in alveoli becomes negative, negative flow transmural pressure more negative pressure in the pleural space pleural fluid is compressed by contraction of chest muscle, pleural pressure becomes positive, pressure drop along the airway --> airway collapses Figure 44a. Before inspiration (A), airway pressure is zero and intrapleural pressure is -5cm H2O. During inspiration (B), pleural and airway pressures fall. At the end of inspiration (C), airway pressure is zero and the airway transmural pressure is 8cm H2O. During forced expiration (D), intra-pleural and alveolar pressures are increased. Because of the pressure drop along the airways as flow begins, there is a point at which there is a positive pressure tending to close the airways. (Reproduced from West: Respiratory Physiology- the essentials). emphysema - lungs are highly compliance, easy to inflate - lungs to not recoil - breathing out is more difficult - lungs inflate to higher lung volume - air gets 'trapped' - for a give lung volume there is lower flow in an obstructive subject fibrosis - low compliance - lung volume is very small (TLC to RV) for a given lung volume there is a greater flow in a restrictive subject - chest wants to collapse, it is so stiff Figure 44b. In restrictive diseases (e.g. pulmonary fibrosis), the maximum flow rate and maximum volume exhaled are reduced. In obstructive diseases (e.g. emphysema), the flow rate is very low and a scooped out appearance is often seen. (Reproduced from West: Respiratory Physiology- the essentials). F. Surface Tension The surface tension of the liquid film lining the lungs is an important contributor to the mechanical properties of the respiratory system. This tension arises because the molecules in the surface of the film tend to arrange themselves in the configuration involving the lowest energy. Being more attracted to themselves than to air, they like to hold hands rather than freely associate with air molecules. This causes a tension to be generated across the film surface (figure 45A). If the surface is curved, such as on the inside of an alveolus or airway, this tension can produce a pressure (figure 45B). Alveoli can be modeled to some degree of approximation as being like a collection of soap bubbles (figure 45C). The pressure, P, inside the soap bubble of radius R, resulting from a surface tension T, is given by LaPlaces Law: P=4T/R. - all the alveoli in the lungs have different pressure - the pressure in smaller alveoli is greater than in larger alveoli --> small alveoli should collapse and form larger ones This equation shows that the pressure inside a small bubble is greater than that inside a large bubble (Figure 45C). Surface Tension - surface tension is a problem in the lungs because the alveoli are spherical and the surface tension vectors in a spherical environment will create an inward pressure, a force towards the middle - the pressure is governed by LaPlace's law Figure 45 A: Surface tension is the force acting across an imaginary line 1 cm long in a liquid surface. B: Surface forces in a soap bubble tend to reduce the area of the surface and thereby generate a pressure within the bubble. C: Because the smaller bubble generates a larger pressure, it blows up the large bubble. (Reproduced from West: Respiratory Physiology- the essentials). G. Pulmonary Surfactant - surfactant locate themselves between water molecules and decrease surface tension - acts as a detergent - you cannot breathe without surfactant The soap bubble analogy suggests that small alveoli should collapse into large ones (Figure 45c). This means that the gas exchanging regions of the lung is unstable. However, alveolar collapse is prevented from happening by a substance called pulmonary surfactant, secreted by alveolar type II cells. Pulmonary surfactant has 2 principal roles: 1) Making the surface tension inside the alveoli change with the lung volume in a way that prevents the pressure inside the small alveoli from exceeding that of the large alveoli. (Surfactant has biophysical properties that allow it to decrease the surface tension to a greater extent in the smaller than in the larger alveoli, thereby stabilizing the lungs). 2) Reducing overall surface tension so that we are able to breathe. If the surface tension in the liquid lining layer was equal to that of water, we simply would not be able to inflate our lungs. - surfactant will stack itself such that it will decrease the surface tension in smaller alveoli more than larger ones - equilibrate pressure around the lungs VIII VENTILATION DURING EXERCISE A. Tidal Volume and Breathing Frequency during Exercise .) Comparisons of the components determining pulmonary minute ventilation (V E during progressive exercise up to maximum: When exercise starts, both tidal volume (VT) and breathing frequency (f) increase proportionally (Figure 46 a & b). However, VT plateaus; therefore, high ventilatory rates during hard exercise are due to incremental increases in f. Because of the increased breathing frequency, inspiratory and expiratory times decrease during progressive exercise but expiratory times fall relatively more than inspiratory time (Figure 46 c & d). Consequently, peak expiratory flow rate increases more than peak inspiratory flow rate. expiratory time decreases more than inspiratory time Figure 46 a & b - remember that lung compliance decreases at very high lung volumes - thus, high ventilatory rates during hard exercise are due to incremental increases in f Brooks, G.A., et al., Exercise Physiology,Human Bioenergetics and its applications, 3rd edition, California: Mayfield, 1999. Figure 46 b & c - there is a greater decrease in expiratory time - the peak expiratory flow rates increase more than inspiratory flow rate - there must be a faster flow of air on exhalation a measure of exercise Brooks, G.A., et al., Exercise Physiology,Human Bioenergetics and its applications, 3rd edition, California: Mayfield, 1999. B. Minute ventilation and metabolic rate during exercise In both untrained and trained subjects, minute ventilation (VE) increases linearly with metabolic rate (VO2) up to about 50% to 65% of VO2 max (Figure 47). Thereafter, VE increases at a rate disproportionately greater than the change in VO2. Note that an effect of endurance training is to delay the ventilatory inflection point (Tvent). . . . . . - there is no hyperventilation during exercise because metabolism is increased proportionally Figure 47 - it is unknown why there is an increase in ventilation suddenly - it was once thought that it was because of the aerobic threshold - it corresponds to the change in metabolism to glycolysis - corresponds to the buildup of lactic acid in the blood - later studies have shown that this is not entirely true - they don't seem to be related ventilatory inflection point training retards the point at which there is an increase in ventilation ventilation increases linearly with the body's metabolism increased oxygen consumption with increased activity .. Is Ventilation a limiting factor in aerobic performance at sea level? (VE/Q) . -Resting values of VE can increase 35 folds during exercise (from 5L/min to 190 L/min, in a fit individual). -Resting values of cardiac output (CO) can increase 5-6 folds during exercise (from 5L/min to 25-30 L/min, in a fit individual). . . .. -The VE/Q 1 at rest. Because VE can increase more than Q during exercise, .. there is an increase in VE/Q. The increase in this ratio is one reason why ventilation is not believed to limit aerobic performance. . . -In a less fit individual, the absolute values of VE and Q will be less but the ratio will increase to a similar extent. Is Ventilation a limiting factor in aerobic performance at sea level? (alveolar surface area) -The alveolar surface area is 50m2 (1/2 of a single tennis court). -The average blood volume is 5L. -4% of this 5L is in the pulmonary system at any one time during maximal exercise. -Therefore, there is a large capacity for gas exchange. C. Control of Ventilation during Exercise The Central Chemoreceptors During Exercise During exercise, there is an alkalotic (pH) response in the medullary ECF. This decreases the ventilatory response. Therefore, the role of the central chemoreceptors is important at rest but not so much during exercise. Control of Ventilation during Exercise (Conted) Peripheral Chemoreceptors: it is unknown exactly how ventilation is controlled during exercise, but it is thought to be regulated through many different controls we do not know exactly which receptors are responsible Peripheral chemoreceptors are mainly sensitive to changes in PO2, but are also stimulated by increased PCO2 and decreased pH. but during exercise, PCO2 remains constant or goes down, so they could not stimulate the chemoreceptors Control of Ventilation during Exercise (Conted) Peripheral Chemoreceptors (Conted): -PaO2 remains rather constant during exercise (Figure 48). Therefore the increase in ventilation cannot come from the stimulation of the peripheral chemoreceptors by changes in O2. -PaCO2 is often seen to decrease during exercise (Figure 48). Therefore the increase in ventilation cannot come from the stimulation of the peripheral chemoreceptors by CO2. -However, during exercise, arterial pH does decrease (Figure 48) and PaO2 fluctuates subtly with arterial pulse waves. Therefore, it is possible that during exercise, these fluctuations in PaO2 increase the sensitivity of the peripheral chemoreceptors to CO2 and H+. Figure 48 arterial PO2 remains constant --> could not stimulate chemoreceptors - it may decrease slightly in elite athletes PCO2 goes down because of hyperventilation with respect to the body's metabolism - PCO2 remains constant or decreases --> could not stimulate chemoreceptors (they are responsive to high levels of CO2) there is an increase in protons in the blood because of lactic acid formation --> may be responsible for the increase in ventilation =exercise intensity Control of Ventilation during Exercise (Conted) Peripheral Mechanoreceptors during Exercise -The pulmonary mechanoreceptors, the muscle spindles, the Golgi tendons, and the skeletal joint receptors were thought to play a role in the increase in VE during exercise. E . . , but it is -Stimulation of these mechanoreceptors does produce an increase in V small compared to the large and abrupt increases observed during exercise. - this is not well known however Control of Breathing during Exercise Conted) Onset and Recovery from Exercise -VE is known to start increasing even before the exercise has started. This control is thought to be neural. A similar control is thought to operate at the end of exercise because a very rapid decrease in VE is observed (Figure 49). . . -Humoral control is believed to be responsible for the ventilatory response during the exercise event. Figure 49 - ventilation increases rapidly at the beginning of exercise and stops increasing very quickly - it is believed that the increase is ventilation and recovery time is neurally controlled --> very quick change - during exercise it is believed that the control is humoral --> slower changes APPENDIX 1 Pressures: P = total pressure Px = partial pressure of gas x Fx = fractional concentration in dry gas Px = PFx Examples: Barometric P = 760mmHg FO2 = 21% * FCO2 = 0.03% * Px = (P-47mmHg)Fx (in a gas with a water vapor pressure of 47mmHg) PO2 = (760mmHg 47mmHg)21/100 = 150mmHg PCO2 = (760mmHg 47mmHg)0.03/100 = 0.2mmHg * Fractional concentrations are generally given as the fraction of dry gas volume that is occupied by the gas in question. Because of that convention, barometric pressure has to be corrected for the contribution from water vapor. APPENDIX 2 Asthma: Chronic inflammatory disease of the airways, clinically characterized by airway obstruction, and enhanced airway responsiveness to contractile agonists and/or allergens. Emphysema: Enlargement of the air spaces due to the destruction of the walls of the alveoli. The lungs actually self-destruct, attacked by proteolytic enzymes secreted by leukocytes in response to a variety of factors. The airways tend to collapse because of the loss of radial traction. Fibrosis: Progressive distortion of the alveolar architecture with inflammation and accumulation of fibrotic tissue. ... View Full Document

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