Chapter 34: Introduction to Pulmonary Structure & Mechanics

After studying this chapter, you should be able to:

• List the passages through which air passes from the exterior to the alveoli, and describe the cells that line each of them.

• List the major muscles involved in respiration, and state the role of each.

• Define the basic measures of lung volume and give approximate values for each in a normal adult.

• Define lung compliance and airway resistance.

• Compare the pulmonary and systemic circulations, and list some major differences between them.

• Describe basic lung defense and metabolic functions.

• Define partial pressure and calculate the partial pressure of each of the important gases in the atmosphere at sea level.

The structure of the respiratory system is uniquely suited to its primary function, the transport of gases in and out of the body. In addition, the respiratory system provides a large volume of tissue that is constantly exposed to the outside environment, and thus, to potential infection and injury. Finally, the pulmonary system includes a unique circulation that must handle the blood flow. This chapter begins with the basic anatomy and cellular physiology that contribute to the respiratory system and some of their unique features. The chapter also includes discussion of how the anatomic features contribute to the basic mechanics of breathing, as well as some highlights of nonrespiratory physiology in the pulmonary system.

REGIONS OF THE RESPIRATORY TRACT

Airflow through the respiratory system can be broken down into three interconnected regions: the upper airway; the conducting airway; and the alveolar airway (also known as the lung parenchyma or acinar tissue). The upper airway consists of the entry systems, the nose/nasal cavity and mouth that lead into the pharynx. The larynx extends from the lower part of the pharynx to complete the upper airway. The nose is the primary point of entry for inhaled air; therefore, the mucosal epithelium lining the nasopharyngeal airways is exposed to the highest concentration of inhaled allergens, toxicants, and particulate matter. With this in mind, it is easy to understand that in addition to olfaction, the nose and upper airway provides two additional crucial functions in airflow—(1) filtering out large particulates to prevent them from reaching the conducting and alveolar airways and (2) serving to warm and humidify air as it enters the body. Particulates larger than 30–50 μm in size tend to not to be inhaled through the nose whereas particulates on the order of 5–10 μm impact on the nasopharynx and do enter the conducting airway. Most of these latter particles settle on mucous membranes in the nose and pharynx. Because of their momentum, they do not follow the airstream as it curves downward into the lungs, and they impact on or near the tonsils and adenoids, large collections of immunologically active lymphoid tissue in the back of the pharynx.

CONDUCTING AIRWAY

The conducting airway begins at the trachea and branches dichotomously to greatly expand the surface area of the tissue in the lung. The first 16 generations of passages form the conducting zone of the airways that transports gas from and to the upper airway described above (Figure 34–1). These branches are made up of bronchi, bronchioles, and terminal bronchioles. The conducting airway is made up of a variety of specialized cells that provide more than simply a conduit for air to reach the lung (Figure 34–2). The mucosal epithelium is attached to a thin basement membrane, and beneath this, the lamina propria. Collectively these are referred to as the “airway mucosa.” Smooth muscle cells are found beneath the epithelium and an enveloping connective tissue is likewise interspersed with cartilage that is more predominant in the portions of the conducting airway of greater caliber. The epithelium is organized as a pseudostratified epithelium and contains several cell types, including ciliated and secretory cells (eg, goblet cells and glandular acini) that provide key components for airway innate immunity, and basal cells that can serve as progenitor cells during injury. As the conducting airway transitions to terminal and transitional bronchioles, the histologic appearance of the conducting tubes change. Secretory glands are absent from the epithelium of the bronchioles and terminal bronchioles, smooth muscle plays a more prominent role and cartilage is largely absent from the underlying tissue. Club cells (formerly termed “Clara cells”), nonciliated cuboidal epithelial cells that secrete important defense markers and serve as progenitor cells after injury, make up a large portion of the epithelial lining in the latter portions of the conducting airway.

Epithelial cells in the conducting airway can secrete a variety of molecules that aid in lung defense. Secretory immunoglobulins (IgA), collectins (including surfactant protein (SP) -A and SP-D), defensins and other peptides and proteases, reactive oxygen species, and reactive nitrogen species are all generated by airway epithelial cells. These secretions can act directly as antimicrobials to help keep the airway free of infection. Airway epithelial cells also secrete a variety of chemokines and cytokines that recruit traditional immune cells and other immune effector cells to site of infections. The smaller particles that make it through the upper airway, ~2–5 μm in diameter, generally fall on the walls of the bronchi as the airflow slows in the smaller passages. There they can initiate reflex bronchial constriction and coughing. Alternatively, they can be moved away from the lungs by the “mucociliary escalator.” The epithelium of the respiratory passages from the anterior third of the nose to the beginning of the respiratory bronchioles is ciliated (Figure 34–2). The cilia are bathed in a periciliary fluid where they typically beat at rates of 10–15 Hz. On top of the periciliary layer and the beating cilia rests a mucus layer, a complex mixture of proteins and polysaccharides secreted from specialized cells, glands, or both in the conducting airway. This combination allows for the trapping of foreign particles (in the mucus) and their transport out of the airway (powered by ciliary beat). The ciliary mechanism is capable of moving particles away from the lungs at a rate of at least 16 mm/min. When ciliary motility is defective, as can occur in smokers, or as a result of other environmental conditions or genetic deficiencies, mucus transport is virtually absent. This can lead to chronic sinusitis, recurrent lung infections, and bronchiectasis. Some of these symptoms are evident in cystic fibrosis (Clinical Box 34–1).

The walls of the bronchi and bronchioles are innervated by the autonomic nervous system. Nerve cells in the airways sense mechanical stimuli or the presence of unwanted substances in the airways such as inhaled dusts, cold air, noxious gases, and cigarette smoke. These neurons can signal the respiratory centers to contract the respiratory muscles and initiate sneeze or cough reflexes. The receptors show rapid adaptation when they are continuously stimulated to limit sneeze and cough under normal conditions. The β₂-adrenergic receptors help mediate bronchodilation. They also increase bronchial secretions (eg, mucus), while α₁-adrenergic receptors inhibit secretions.

ALVEOLAR AIRWAY

Between the trachea and the alveolar sacs, the airways divide 23 times. The last seven generations form the transitional and respiratory zones where gas exchange occurs are made up of transitional and respiratory bronchioles, alveolar ducts, and alveoli (Figure 34–1). These multiple divisions greatly increase the total cross-sectional area of the airways, from 2.5 cm² in the trachea to 11,800 cm² in the alveoli. Consequently, the velocity of airflow in the small airways declines to very low values. The transition from the conducting to the respiratory region that ends in the alveoli also includes a change in cellular arrangements (Figure 34–2; and Figure 34–3). Humans have 300 million alveoli, and the total area of the alveolar walls in contact with capillaries in both lungs is about 70 m².

The alveoli are lined by two types of epithelial cells. Type I cells are flat cells with large cytoplasmic extensions and are the primary lining cells of the alveoli, covering approximately 95% of the alveolar epithelial surface area. Type II cells (granular pneumocytes) are thicker and contain numerous lamellar inclusion bodies. Although these cells make up only 5% of the surface area, they represent approximately 60% of the epithelial cells in the alveoli. Type II cells are important in alveolar repair as well as other cellular physiology. One prime function of the type II cell is the production of surfactant (Figure 34–3D). Typical lamellar bodies, membrane-bound organelles containing whorls of phospholipid, are formed in these cells and secreted into the alveolar lumen by exocytosis. Tubes of lipid called tubular myelin form from the extruded bodies, and the tubular myelin in turn forms a phospholipid film. Following secretion, the phospholipids of surfactant line up in the alveoli with their hydrophobic fatty acid tails facing the alveolar lumen. This surfactant layer plays an important role in maintaining alveolar structure by reducing surface tension (see below). Surface tension is inversely proportional to the surfactant concentration per unit area. The surfactant molecules move further apart as the alveoli enlarge during inspiration, and surface tension increases, whereas it decreases when they move closer together during expiration. Some of the protein-lipid complexes in surfactant are taken up by endocytosis in type II alveolar cells and recycled.

The alveoli are surrounded by pulmonary capillaries. In most areas, air and blood are separated only by the alveolar epithelium and the capillary endothelium, so they are about 0.5 μm apart (Figure 34–3). The alveoli also contain other specialized cells, including pulmonary alveolar macrophages (PAMs, or AMs), lymphocytes, plasma cells, neuroendocrine cells, and mast cells. PAMs are an important component of the pulmonary defense system. Like other macrophages, these cells come originally from the bone marrow. PAMs are actively phagocytic and ingest small particles that evade the mucociliary escalator and reach the alveoli. They also help process inhaled antigens for immunologic attack, and they secrete substances that attract granulocytes to the lungs as well as substances that stimulate granulocyte and monocyte formation in the bone marrow. PAM function can also be detrimental—when they ingest large amounts of the substances in cigarette smoke or other irritants, they may release lysosomal products into the extracellular space to cause inflammation.

RESPIRATORY MUSCLES

The lungs are positioned within the thoracic cavity, which is defined by the rib cage and the spinal column. The lungs are surrounded by a variety of muscles that contribute to breathing (Figure 34–4). Movement of the diaphragm accounts for 75% of the change in intrathoracic volume during quiet inspiration. Attached around the bottom of the thoracic cage, this muscle arches over the liver and moves downward like a piston when it contracts. The distance it moves ranges from 1.5 cm to as much as 7 cm with deep inspiration.

The diaphragm has three parts: the costal portion, made up of muscle fibers that are attached to the ribs around the bottom of the thoracic cage; the crural portion, made up of fibers that are attached to the ligaments along the vertebrae; and the central tendon, into which the costal and the crural fibers insert. The central tendon is also the inferior part of the pericardium. The crural fibers pass on either side of the esophagus and can compress it when they contract. The costal and crural portions are innervated by different parts of the phrenic nerve and can contract separately. For example, during vomiting and eructation, intra-abdominal pressure is increased by contraction of the costal fibers but the crural fibers remain relaxed, allowing material to pass from the stomach into the esophagus.

The other important inspiratory muscles are the external intercostal muscles, which run obliquely downward and forward from rib to rib. The ribs pivot as if hinged at the back, so that when the external intercostals contract they elevate the lower ribs. This pushes the sternum outward and increases the anteroposterior diameter of the chest. The transverse diameter also increases but to a lesser degree. Either the diaphragm or the external intercostal muscles alone can maintain adequate ventilation at rest. Transection of the spinal cord above the third cervical segment is fatal without artificial respiration, but transection below the fifth cervical segment is not because it leaves the phrenic nerves that innervate the diaphragm intact; the phrenic nerves arise from cervical segments 3–5. Conversely, in patients with bilateral phrenic nerve palsy but intact innervation of their intercostal muscles, respiration is somewhat labored but adequate to maintain life. The scalene and sternocleidomastoid muscles in the neck are accessory inspiratory muscles that help elevate the thoracic cage during deep labored respiration.

A decrease in intrathoracic volume and forced expiration result when the expiratory muscles contract. The internal intercostals have this action because they pass obliquely downward and posteriorly from rib to rib and therefore pull the rib cage downward when they contract. Contractions of the muscles of the anterior abdominal wall also aid expiration by pulling the rib cage downward and inward and by increasing the intra-abdominal pressure, which pushes the diaphragm upward.

In order for air to get into the conducting airway it must pass through the glottis, defined as the area including and between the vocal folds within the larynx. The abductor muscles in the larynx contract early in inspiration, pulling the vocal cords apart and opening the glottis. During swallowing or gagging, a reflex contraction of the adductor muscles closes the glottis and prevents aspiration of food, fluid, or vomitus into the lungs. In unconscious or anesthetized patients, glottic closure may be incomplete and vomitus may enter the trachea, causing an inflammatory reaction in the lung (aspiration pneumonia).

LUNG PLEURA

The pleural cavity and its infoldings serve as a lubricating fluid/area that allows for lung movement within the thoracic cavity (Figure 34–5A). There are two layers that contribute to the pleural cavity: the parietal pleura and the visceral pleura. The parietal pleura is a membrane that lines the chest cavity containing the lungs. The visceral pleura is a membrane that lines the lung surface. The pleural fluid (~15–20 mL) forms a thin layer between the pleural membranes and prevents friction between surfaces during inspiration and expiration.

The lung itself contains a vast amount of free space—it is ~80% air. Although this maximizes surface area for gas exchange, it also requires an extensive support network to maintain lung shape and function. The connective tissue within the visceral pleura contains three layers that help support the lung. Elastic fibers that follow the mesothelium effectively wrap the three lobes of the right lung and the two lobes of the left lung (Figure 34–5B). A deep sheet of fine fibers that follow the outline of the alveoli provide support to individual air sacks. Between these two separate sheets lies connective tissue that is interspersed with individual cells for support and lung maintenance/function.

Blood & Lymph in the Lung

Both the pulmonary circulation and the bronchial circulation contribute to blood flow in the lung. In the pulmonary circulation (Figure 34–6), almost all the blood in the body passes via the pulmonary artery to the pulmonary capillary bed, where it is oxygenated and returned to the left atrium via the pulmonary veins. The pulmonary arteries strictly follow the branching of the bronchi down to the respiratory bronchioles. The pulmonary veins, however, are spaced between the bronchi on their return to the heart. The separate and much smaller bronchial circulation includes the bronchial arteries that come from systemic arteries. They form capillaries, which drain into bronchial veins or anastomose with pulmonary capillaries or veins. The bronchial veins drain into the azygos vein. The bronchial circulation nourishes the trachea down to the terminal bronchioles and also supplies the pleura and hilar lymph nodes. It should be noted that lymphatic channels are more abundant in the lungs than in any other organ. Lymph nodes are arranged along the bronchial tree and extend down until the bronchi are ~5 mm in diameter. Lymph node sizes can range from 1 mm at the bronchial periphery to 10 mm along the trachea. The nodes are connected by lymph vessels and allow for unidirectional flow of lymph to the subclavian veins.

INSPIRATION & EXPIRATION

The lungs and the chest wall are elastic structures. Normally, no more than a thin layer of fluid is present between the lungs and the chest wall (intrapleural space). The lungs slide easily on the chest wall, but resist being pulled away from it in the same way that two moist pieces of glass slide on each other but resist separation. The pressure in the “space” between the lungs and chest wall (intrapleural pressure) is subatmospheric (Figure 34–7). The lungs are stretched when they expand at birth, and at the end of quiet expiration their tendency to recoil from the chest wall is just balanced by the tendency of the chest wall to recoil in the opposite direction. If the chest wall is opened, the lungs collapse; and if the lungs lose their elasticity, the chest expands and becomes barrel-shaped.

Inspiration is an active process. The contraction of the inspiratory muscles increases intrathoracic volume. The intrapleural pressure at the base of the lungs, which is normally about –2.5 mm Hg (relative to atmospheric) at the start of inspiration, decreases to about –6 mm Hg. The lungs are pulled into a more expanded position. The pressure in the airway becomes slightly negative, and air flows into the lungs. At the end of inspiration, the lung recoil begins to pull the chest back to the expiratory position, where the recoil pressures of the lungs and chest wall balance (see below). The pressure in the airway becomes slightly positive, and air flows out of the lungs. Expiration during quiet breathing is passive in the sense that no muscles that decrease intrathoracic volume contract. However, some contraction of the inspiratory muscles occurs in the early part of expiration. This contraction exerts a braking action on the recoil forces and slows expiration. Strong inspiratory efforts reduce intrapleural pressure to values as low as –30 mm Hg, producing correspondingly greater degrees of lung inflation. When ventilation is increased, the extent of lung deflation is also increased by active contraction of expiratory muscles that decrease intrathoracic volume.

QUANTITATING RESPIRATORY PHENOMENA

Modern spirometers permit direct measurement of gas intake and output. Since gas volumes vary with temperature and pressure and since the amount of water vapor in them varies, these devices have the ability to correct respiratory measurements involving volume to a stated set of standard conditions. It should be noted that correct measurements are highly dependent on the ability for the practitioner to properly encourage the patient to fully utilize the device. Modern techniques for gas analysis make possible rapid, reliable measurements of the composition of gas mixtures and the gas content of body fluids. For example, O₂ and CO₂ electrodes, small probes sensitive to O₂ or CO₂, can be inserted into the airway or into blood vessels or tissues and the Po₂ and Pco₂ recorded continuously. Chronic assessment of oxygenation is carried out noninvasively with a pulse oximeter, which can be easily placed on a fingertip.

Lung Volumes & Capacities

Important quantitation of lung function can be gleaned from the displacement of air volume during inspiration and/or expiration. Lung capacities refer to subdivisions that contain two or more volumes. Volumes and capacities recorded on a spirometer from a healthy individual are shown in Figure 34–8. Diagnostic spirometry is used to assess a patient’s lung function for purposes of comparison with a normal population, or with previous measures from the same patient. The amount of air that moves into the lungs with each inspiration (or the amount that moves out with each expiration) during quiet breathing is called the tidal volume (TV). Typical values for TV are on the order of 500–750 mL. The air inspired with a maximal inspiratory effort in excess of the TV is the inspiratory reserve volume (IRV; typically ~2 L). The volume expelled by an active expiratory effort after passive expiration is the expiratory reserve volume (ERV; ~1 L), and the air left in the lungs after a maximal expiratory effort is the residual volume (RV; ~1.3 L). When all four of the above components are taken together, they make up the total lung capacity (~5 L). The total lung capacity can be broken down into alternative capacities that help define functioning lungs. The vital lung capacity (~3.5 L) refers to the maximum amount of air expired from the fully inflated lung, or maximum inspiratory level (this represents TV + IRV + ERV). The inspiratory capacity (~2.5 L) is the maximum amount of air inspired from the end-expiratory level (IRV + TV). The functional residual capacity (FRC; ~2.5 L) represents the volume of the air remaining in the lungs after expiration of a normal breath (RV + ERV).

Dynamic measurements of lung volumes and capacities have been used to help determine lung dysfunction. The forced vital capacity (FVC), the largest amount of air that can be expired after a maximal inspiratory effort, is frequently measured clinically as an index of pulmonary function. It gives useful information about the strength of the respiratory muscles and other aspects of pulmonary function. The fraction of the vital capacity expired during the first second of a forced expiration is referred to as FEV₁ (forced expiratory volume in the first second; Figure 34–9). The FEV₁ to FVC ratio (FEV₁/FVC) is a useful tool in the recognizing classes of airway disease (Clinical Box 34–2). Other dynamic measurements include the respiratory minute volume (RMV) and the maximal voluntary ventilation (MVV). RMV is normally ~6 L (500 mL/ breath × 12 breaths/min). The MVV is the largest volume of gas that can be moved into and out of the lungs in 1 min by voluntary effort. Typically this is measured over a 15 sec period and prorated to a minute; normal values range from 140 L/min to 180 L/min for healthy adult men. Changes in RMV and MVV in a patient can be indicative of lung dysfunction.

COMPLIANCE OF THE LUNGS & CHEST WALL

Compliance is developed due to the tendency for tissue to resume its original position after an applied force has been removed. After an expiration during quiet breathing (eg, at the FRC), the lungs have a tendency to collapse and the chest wall has a tendency to expand. The interaction between the recoil of the lungs and recoil of the chest can be measured through a spirometer that has a valve just beyond the mouthpiece. The mouthpiece contains a pressure-measuring device. After the person inhales a given amount, the valve is shut, closing off the airway. The respiratory muscles are then relaxed while the pressure in the airway is recorded. The procedure is repeated after inhaling or actively exhaling various volumes. The curve of airway pressure obtained in this way, plotted against volume, is the pressure-volume curve of the total respiratory system (P_TR in Figure 34–10). The pressure is zero at a lung volume that corresponds to the volume of gas in the lungs at FRC (relaxation volume). As can be noted from Figure 34–10, this relaxation pressure is the sum of slightly negative pressure component from the chest wall (P_w) and a slightly positive pressure from the lungs (P_L). P_TR is positive at greater volumes and negative at smaller volumes. Compliance of the lung and chest wall is measured as the slope of the P_TR curve, or, as a change in lung volume per unit change in airway pressure (ΔV/ΔP). It is normally measured in the pressure range where the relaxation pressure curve is steepest, and normal values are ~0.2 L/cm H₂O in a healthy adult man. However, compliance depends on lung volume and thus can vary. In an extreme example, an individual with only one lung has approximately half the ΔV for a given ΔP. Compliance is also slightly greater when measured during deflation than when measured during inflation. Consequently, it is more informative to examine the whole pressure-volume curve. The curve is shifted downward and to the right (compliance is decreased) by pulmonary edema and interstitial pulmonary fibrosis (Figure 34–11). Pulmonary fibrosis is a progressive restrictive airway disease in which there is stiffening and scarring of the lung. The curve is shifted upward and to the left (compliance is increased) in emphysema.

Airway Resistance

Airway resistance is defined as the change of pressure (ΔP) from the alveoli to the mouth divided by the change in flow rate . Because of the structure of the bronchial tree, and thus the pathway for air that contributes to its resistance, it is difficult to apply mathematical estimates of the movement through the bronchial tree. However, measurements where alveolar and intrapleural pressure can be compared to actual pressure (eg, Figure 34–7 middle panel) show the contribution of airway resistance. Airway resistance is significantly increased as lung volume is reduced. Also, bronchi and bronchioles significantly contribute to airway resistance. Thus, contraction of the smooth muscle that lines the bronchial airways will increase airway resistance, and make breathing more difficult.

Role of Surfactant in Alveolar Surface Tension

An important factor affecting the compliance of the lungs is the surface tension of the film of fluid that lines the alveoli. The magnitude of this component at various lung volumes can be measured by removing the lungs from the body of an experimental animal and distending them alternately with saline and with air while measuring the intrapulmonary pressure. Because saline reduces the surface tension to nearly zero, the pressure-volume curve obtained with saline measures only the tissue elasticity (Figure 34–12), whereas the curve obtained with air measures both tissue elasticity and surface tension. The difference between the saline and air curves is much smaller when lung volumes are small. Differences are also obvious in the curves generated during inflation and deflation. This difference is termed hysteresis, and notably is not present in the saline generated curves. The alveolar environment, and specifically the secreted factors that help reduce surface tension and keep alveoli from collapsing, contribute to hysteresis.

The low surface tension when the alveoli are small is due to the presence of surfactant in the fluid lining the alveoli. Surfactant is a mixture of dipalmitoylphosphatidylcholine (DPPC), other lipids, and proteins. If the surface tension is not kept low when the alveoli become smaller during expiration, they collapse in accordance with the law of Laplace. In spherical structures like an alveolus, the distending pressure (P) equals two times the tension (T) divided by the radius (r; P = 2T/r); if T is not reduced as r is reduced, the tension overcomes the distending pressure. Surfactant also helps prevent pulmonary edema. It has been calculated that if it were not present, the unopposed surface tension in the alveoli would produce a 20 mm Hg force; such a force would greatly favor transudation of fluid from the blood into the alveoli.

Formation of the phospholipid film is greatly facilitated by the proteins in surfactant. This material contains four unique proteins: surfactant protein (SP)-A, SP-B, SP-C, and SP-D. SP-A is a large glycoprotein and has a collagen-like domain within its structure. It has multiple functions, including regulation of the feedback uptake of surfactant by the type II alveolar epithelial cells that secrete it. SP-B and SP-C are smaller proteins, which are the key protein members of the monomolecular film of surfactant. Like SP-A, SP-D is a glycoprotein. Its full function is uncertain, however it plays an important role in the organization of SP-B and SP-C into the surfactant layer. Both SP-A and SP-D are members of the collectin family of proteins that are involved in innate immunity in the conducting airway as well as in the alveoli. Some clinical aspects of surfactant are discussed in Clinical Box 34–3.

WORK OF BREATHING

Work is performed by the respiratory muscles in stretching the elastic tissues of the chest wall and lungs (elastic work; approximately 65% of the total work), moving inelastic tissues (viscous resistance; 7% of total), and moving air through the respiratory passages (airway resistance; 28% of total). Because the dimensions of pressure × volume (g/cm² × cm³ = g × cm) has the same dimensions as work (force × distance; g × cm), the work of breathing can be calculated from the previously presented pressure-volume curve (Figure 34–10). Note that the relaxation pressure curve of the total respiratory system (P_TR) differs from that of the lungs alone (P_L). The amount of elastic work required to inflate the whole respiratory system is less than the amount required to inflate the lungs alone because part of the work comes from elastic energy stored in the thorax.

Estimates of the total work of quiet breathing range from 0.3 up to 0.8 kg-m/min. The value rises markedly during exercise, but the energy cost of breathing in normal individuals represents less than 3% of the total energy expenditure during exercise. The work of breathing is greatly increased in diseases such as emphysema, asthma, and heart failure with dyspnea and orthopnea. The respiratory muscles have length-tension relations like those of other skeletal and cardiac muscles, and when they are severely stretched, they contract with less strength. They can also become fatigued and fail (pump failure), leading to inadequate ventilation.

DIFFERENCES IN VENTILATION & BLOOD FLOW IN DIFFERENT PARTS OF THE LUNG

In the upright position, ventilation per unit lung volume is greater at the base of the lung than at the apex. The reason for this is that at the start of inspiration, intrapleural pressure is less negative at the base than at the apex, and since the intrapulmonary intrapleural pressure difference is less than at the apex, the lung is less expanded. Conversely, at the apex, the lung is more expanded; that is, the percentage of maximum lung volume is greater. Because of the stiffness of the lung, the increase in lung volume per unit increase in pressure is smaller when the lung is initially more expanded, and ventilation is consequently greater at the base. Blood flow is also greater at the base than the apex. The relative change in blood flow from the apex to the base is greater than the relative change in ventilation, so the ventilation/perfusion ratio is low at the base and high at the apex.

The ventilation and perfusion differences from the apex to the base of the lung have usually been attributed to gravity: they tend to disappear in the supine position, and the weight of the lung would be expected to create pressure at the base in the upright position. However, the inequalities of ventilation and blood flow in humans were found to persist to a remarkable degree in the weightlessness of space. Therefore, other factors also play a role in producing the inequalities.

DEAD SPACE & UNEVEN VENTILATION

Because gaseous exchange in the respiratory system occurs only in the terminal portions of the airways, the gas that occupies the rest of the respiratory system is not available for gas exchange with pulmonary capillary blood. Normally, the volume (in mL) of this anatomic dead space is approximately equal to the body weight in pounds. As an example, in a man who weighs 150 lb (68 kg), only the first 350 mL of the 500 mL inspired with each breath at rest mixes with the air in the alveoli. Conversely, with each expiration, the first 150 mL expired is gas that occupied the dead space, and only the last 350 mL is gas from the alveoli. Consequently, the alveolar ventilation, ie, the amount of air reaching the alveoli per minute, is less than the RMV. Note that because of the dead space, rapid shallow breathing produces much less alveolar ventilation than slow deep breathing at the same RMV (Table 34–1).

It is important to distinguish between the anatomic dead space (respiratory system volume exclusive of alveoli) and the total (physiologic) dead space (volume of gas not equilibrating with blood; ie, wasted ventilation). In healthy individuals, the two dead spaces are identical and can be estimated by body weight. However, in disease states, no exchange may take place between the gas in some of the alveoli and the blood, and some of the alveoli may be overventilated. The volume of gas in nonperfused alveoli and any volume of air in the alveoli in excess of that necessary to arterialize the blood in the alveolar capillaries is part of the dead space (nonequilibrating) gas volume. The anatomic dead space can be measured by analysis of the single-breath N₂ curves (Figure 34–13). From mid-inspiration, the patient takes as deep a breath as possible of pure O₂, then exhales steadily while the N₂ content of the expired gas is continuously measured. The initial gas exhaled (phase I) is the gas that filled the dead space and that consequently contains no N₂. This is followed by a mixture of dead space and alveolar gas (phase II) and then by alveolar gas (phase III). The volume of the dead space is the volume of the gas expired from peak inspiration to the midportion of phase II.

Phase III of the single-breath N₂ curve terminates at the closing volume (CV) and is followed by phase IV, during which the N₂ content of the expired gas is increased. The CV is the lung volume above RV at which airways in the lower, dependent parts of the lungs begin to close off because of the lesser transmural pressure in these areas. The gas in the upper portions of the lungs is richer in N₂ than the gas in the lower, dependent portions because the alveoli in the upper portions are more distended at the start of the inspiration of O₂ and, consequently, the N₂ in them is less diluted with O₂. It is also worth noting that in most normal individuals, phase III has a slight positive slope even before phase IV is reached. This indicates that even during phase III there is a gradual increase in the proportion of the expired gas coming from the relatively N₂-rich upper portions of the lungs.

The total dead space can be calculated from the Pco₂ of expired air, the Pco₂ of arterial blood, and the TV. The tidal volume (V_T) times the Pco₂ of the expired gas (Peco₂) equals the arterial Pco₂ (Paco₂) times the difference between the TV and the dead space (V_D) plus the Pco₂ of inspired air (Pico₂) times V_D (Bohr equation):

The term Pico₂ × V_D is so small that it can be ignored and the equation solved for V_D, where V_D = V_T – (Peco₂ × V_T)/(Paco₂)

If, for example: Peco₂ = 28 mm Hg; Paco₂ = 40 mm Hg and V_T = 500 mL, then V_D = 150 mL

The equation can also be used to measure the anatomic dead space if one replaces Paco₂ with alveolar Pco₂ (Paco₂), which is the Pco₂ of the last 10 mL of expired gas. Pco₂ is an average of gas from different alveoli in proportion to their ventilation regardless of whether they are perfused. This is in contrast to Paco₂, which is gas equilibrated only with perfused alveoli, and consequently, in individuals with underperfused alveoli, is greater than Pco₂.

PARTIAL PRESSURES

Unlike liquids, gases expand to fill the volume available to them, and the volume occupied by a given number of gas molecules at a given temperature and pressure is (ideally) the same regardless of the composition of the gas. Partial pressures are frequently used to describe gases in respiration. The pressure of a gas is proportional to its temperature and number of moles occupying a certain volume (Table 34–2). The pressure exerted by any one gas in a mixture of gases (its partial pressure) is equal to the total pressure times the fraction of the total amount of gas it represents.

The composition of dry air is 20.98% O₂, 0.04% CO₂, 78.06% N₂, and 0.92% other inert constituents such as argon and helium. The barometric pressure (P_B) at sea level is 760 mm Hg (1 atmosphere). The partial pressure (indicated by the symbol P) of O₂ (ie, Po₂) in dry air is therefore 0.21 × 760, or 160 mm Hg at sea level. The Pn₂ and the other inert gases is 0.79 × 760, or 600 mm Hg; and the Pco₂ is 0.0004 × 760, or 0.3 mm Hg. The water vapor in the air in most climates reduces these percentages, and therefore the partial pressures, to a slight degree. Air equilibrated with water is saturated with water vapor, and inspired air is saturated by the time it reaches the lungs. The Ph₂o at body temperature (37°C) is 47 mm Hg. Therefore, the partial pressures at sea level of the other gases in the air reaching the lungs are Po₂, 150 mm Hg; Pco₂, 0.3 mm Hg; and Pn₂ (including the other inert gases), 563 mm Hg.

Gas diffuses from areas of high pressure to areas of low pressure, with the rate of diffusion depending on the concentration gradient and the nature of the barrier between the two areas. When a mixture of gases is in contact with, and permitted to, equilibrate with a liquid, each gas in the mixture dissolves in the liquid to an extent determined by its partial pressure and its solubility in the fluid. The partial pressure of a gas in a liquid is the pressure that, in the gaseous phase in equilibrium with the liquid, would produce the concentration of gas molecules found in the liquid.

SAMPLING ALVEOLAR AIR

Theoretically, all but the first 150 mL expired from a healthy 150 lb man (ie, the dead space) with each expiration is the gas that was in the alveoli (alveolar air), but some mixing always occurs at the interface between the dead-space gas and the alveolar air (Figure 34–13). A later portion of expired air is therefore the portion taken for analysis. Using modern apparatus with a suitable automatic valve, it is possible to collect the last 10 mL expired during quiet breathing. The composition of alveolar gas is compared with that of inspired and expired air in Figure 34–14.

Pao₂ can also be calculated from the alveolar gas equation:

where Fio₂ is the fraction of O₂ molecules in the dry gas, Pio₂ is the inspired Po₂, and R is the respiratory exchange ratio; that is, the flow of CO₂ molecules across the alveolar membrane per minute divided by the flow of O₂ molecules across the membrane per minute.

COMPOSITION OF ALVEOLAR AIR

Oxygen continuously diffuses out of the gas in the alveoli into the bloodstream, and CO₂ continuously diffuses into the alveoli from the blood. In the steady state, inspired air mixes with the alveolar gas, replacing the O₂ that has entered the blood and diluting the CO₂ that has entered the alveoli. Part of this mixture is expired. The O₂ content of the alveolar gas then falls and its CO₂ content rises until the next inspiration. Because the volume of gas in the alveoli is about 2 L at the end of expiration (FRC), each 350 mL increment of inspired and expired air has relatively little effect on Po₂ and Pco₂. Indeed, the composition of alveolar gas remains remarkably constant, not only at rest but also under a variety of other conditions.

DIFFUSION ACROSS THE ALVEOLOCAPILLARY MEMBRANE

Gases diffuse from the alveoli to the blood in the pulmonary capillaries or vice versa across the thin alveolocapillary membrane made up of the pulmonary epithelium, the capillary endothelium, and their fused basement membranes (Figure 34–3). Whether or not substances passing from the alveoli to the capillary blood reach equilibrium in the 0.75 s that blood takes to traverse the pulmonary capillaries at rest depends on their reaction with substances in the blood. Thus, for example, the anesthetic gas nitrous oxide (N₂O) does not react and reaches equilibrium in about 0.1 s (Figure 34–15). In this situation, the amount of N₂O taken up is not limited by diffusion but by the amount of blood flowing through the pulmonary capillaries; that is, it is flow-limited. On the other hand, carbon monoxide (CO) is taken up by hemoglobin in the red blood cells at such a high rate that the partial pressure of CO in the capillaries stays very low and equilibrium is not reached in the 0.75 s the blood is in the pulmonary capillaries. Therefore, the transfer of CO is not limited by perfusion at rest and instead is diffusion-limited. O₂ is intermediate between N₂O and CO; it is taken up by hemoglobin, but much less avidly than CO, and it reaches equilibrium with capillary blood in about 0.3 s. Thus, its uptake is perfusion-limited.

The diffusing capacity of the lung for a given gas is directly proportional to the surface area of the alveolocapillary membrane and inversely proportional to its thickness. The diffusing capacity for CO (Dlco) is measured as an index of diffusing capacity because its uptake is diffusion-limited. Dlco is proportional to the amount of CO entering the blood divided by the partial pressure of CO in the alveoli minus the partial pressure of CO in the blood entering the pulmonary capillaries. Except in habitual cigarette smokers, this latter term is close to zero, so it can be ignored and the equation becomes:

The normal value of Dlco at rest is about 25 mL/min/mm Hg. It increases up to threefold during exercise because of capillary dilation and an increase in the number of active capillaries. The Po₂ of alveolar air is normally 100 mm Hg, and the Po₂ of the blood entering the pulmonary capillaries is 40 mm Hg. The diffusing capacity for O₂, like that for CO at rest, is about 25 mL/min/mm Hg, and the Po₂ of blood is raised to 97 mm Hg, a value just under the alveolar Po₂.

The Pco₂ of venous blood is 46 mm Hg, whereas that of alveolar air is 40 mm Hg, and CO₂ diffuses from the blood into the alveoli along this gradient. The Pco₂ of blood leaving the lungs is 40 mm Hg. CO₂ passes through all biologic membranes with ease, and the diffusing capacity of the lung for CO₂ is much greater than the capacity for O₂. It is for this reason that CO₂ retention is rarely a problem in patients with alveolar fibrosis even when the reduction in diffusing capacity for O₂ is severe.

PULMONARY BLOOD VESSELS

The pulmonary vascular bed resembles the systemic one, except that the walls of the pulmonary artery and its large branches are about 30% as thick as the wall of the aorta, and the small arterial vessels, unlike the systemic arterioles, are endothelial tubes with relatively little muscle in their walls. The walls of the postcapillary vessels also contain some smooth muscle. The pulmonary capillaries are large, and there are multiple anastomoses, so that each alveolus sits in a capillary basket.

PRESSURE, VOLUME, & FLOW

With two quantitatively minor exceptions, the blood put out by the left ventricle returns to the right atrium and is ejected by the right ventricle, making the pulmonary vasculature unique in that it accommodates a blood flow that is almost equal to that of all the other organs in the body. One of the exceptions is part of the bronchial blood flow. There are anastomoses between the bronchial capillaries and the pulmonary capillaries and veins, and although some of the bronchial blood enters the bronchial veins, some enters the pulmonary capillaries and veins, bypassing the right ventricle. The other exception is blood that flows from the coronary arteries into the chambers of the left side of the heart. Because of the small physiologic shunt created by those two exceptions, the blood in systemic arteries has a Po₂ about 2 mm Hg lower than that of blood that has equilibrated with alveolar air, and the saturation of hemoglobin is 0.5% less.

The pressure in the various parts of the pulmonary portion of the pulmonary circulation is shown in Figure 34–6C. The pressure gradient in the pulmonary system is about 7 mm Hg, compared with a gradient of about 90 mm Hg in the systemic circulation. Pulmonary capillary pressure is about 10 mm Hg, whereas the oncotic pressure is 25 mm Hg, so that an inward-directed pressure gradient of about 15 mm Hg keeps the alveoli free of all but a thin film of fluid. When the pulmonary capillary pressure is more than 25 mm Hg, pulmonary congestion and edema result.

The volume of blood in the pulmonary vessels at any one time is about 1 L, of which less than 100 mL is in the capillaries. The mean velocity of the blood in the root of the pulmonary artery is the same as that in the aorta (about 40 cm/s). It falls off rapidly, then rises slightly again in the larger pulmonary veins. It takes a red cell about 0.75 s to traverse the pulmonary capillaries at rest and 0.3 s or less during exercise.

EFFECT OF GRAVITY

Gravity has a relatively marked effect on the pulmonary circulation. In the upright position, the upper portions of the lungs are well above the level of the heart, and the bases are at or below it. Consequently, in the upper part of the lungs, the blood flow is less, the alveoli are larger, and ventilation is less than at the base (Figure 34–16). The pressure in the capillaries at the top of the lungs is close to the atmospheric pressure in the alveoli. Pulmonary arterial pressure is normally just sufficient to maintain perfusion, but if it is reduced or if alveolar pressure is increased, some of the capillaries collapse. Under these circumstances, no gas exchange takes place in the affected alveoli and they become part of the physiologic dead space.

In the middle portions of the lungs, the pulmonary arterial and capillary pressure exceeds alveolar pressure, but the pressure in the pulmonary venules may be lower than alveolar pressure during normal expiration, so they are collapsed. Under these circumstances, blood flow is determined by the pulmonary artery–alveolar pressure difference rather than the pulmonary artery–pulmonary vein difference. Beyond the constriction, blood “falls” into the pulmonary veins, which are compliant and take whatever amount of blood the constriction lets flow into them. This has been called the waterfall effect. Obviously, the compression of vessels produced by alveolar pressure decreases and pulmonary blood flow increases as the arterial pressure increases toward the base of the lung. In the lower portions of the lungs, alveolar pressure is lower than the pressure in all parts of the pulmonary circulation and blood flow is determined by the arterial-venous pressure difference. Examples of diseases affecting the pulmonary circulation are given in Clinical Box 34–4.

VENTILATION/PERFUSION RATIOS

The ratio of pulmonary ventilation to pulmonary blood flow for the whole lung at rest is about 0.8 (4.2 L/min ventilation divided by 5.5 L/min blood flow). However, relatively marked differences occur in this ventilation/perfusion ratio in various parts of the normal lung as a result of the effect of gravity, and local changes in the ventilation/perfusion ratio are common in disease. If the ventilation to an alveolus is reduced relative to its perfusion, the Po₂ in the alveolus falls because less O₂ is delivered to it and the Pco₂ rises because less CO₂ is expired. Conversely, if perfusion is reduced relative to ventilation, the Pco₂ falls because less CO₂ is delivered and the Po₂ rises because less O₂ enters the blood.

As noted above, ventilation, as well as perfusion in the upright position, declines in a linear fashion from the bases to the apices of the lungs. However, the ventilation/perfusion ratios are high in the upper portions of the lungs. When widespread, nonuniformity of ventilation and perfusion in the lungs can cause CO₂ retention and lowers systemic arterial Po₂.

REGULATION OF PULMONARY BLOOD FLOW

It is unsettled whether pulmonary veins and pulmonary arteries are regulated separately, although constriction of the veins increases pulmonary capillary pressure and constriction of pulmonary arteries increases the load on the right side of the heart.

Pulmonary blood flow is affected by both active and passive factors. There is an extensive autonomic innervation of the pulmonary vessels, and stimulation of the cervical sympathetic ganglia reduces pulmonary blood flow by as much as 30%. The vessels also respond to circulating humoral agents. A diversity of some the receptors involved and their effect on pulmonary smooth muscle are summarized in Table 34–3. Many of the dilator responses are endothelium-dependent and presumably operate via release of nitric oxide (NO).

Passive factors such as cardiac output and gravitational forces also have significant effects on pulmonary blood flow. Local adjustments of perfusion to ventilation occur with local changes in O₂. With exercise, cardiac output increases and pulmonary arterial pressure rises. More red cells move through the lungs without any reduction in the O₂ saturation of the hemoglobin in them, and consequently, the total amount of O₂ delivered to the systemic circulation is increased. Capillaries dilate, and previously underperfused capillaries are “recruited” to carry blood. The net effect is a marked increase in pulmonary blood flow with few, if any, alterations in autonomic outflow to the pulmonary vessels.

When a bronchus or a bronchiole is obstructed, hypoxia develops in the underventilated alveoli beyond the obstruction. The O₂ deficiency apparently acts directly on vascular smooth muscle in the area to produce constriction, shunting blood away from the hypoxic area. Accumulation of CO₂ leads to a drop in pH in the area, and a decline in pH also produces vasoconstriction in the lungs, as opposed to the vasodilation it produces in other tissues. Conversely, reduction of the blood flow to a portion of the lung lowers the alveolar Pco₂ in that area, and this leads to constriction of the bronchi supplying it, shifting ventilation away from the poorly perfused area. Systemic hypoxia also causes the pulmonary arterioles to constrict, with a resultant increase in pulmonary arterial pressure.

METABOLIC & ENDOCRINE FUNCTIONS OF THE LUNGS

In addition to their functions in gas exchange, the lungs have a number of metabolic functions. They manufacture surfactant for local use, as noted above. They also contain a fibrinolytic system that lyses clots in the pulmonary vessels. They release a variety of substances that enter the systemic arterial blood (Table 34–4), and they remove other substances from the systemic venous blood that reach them via the pulmonary artery. Prostaglandins are removed from the circulation, but they are also synthesized in the lungs and released into the blood when lung tissue is stretched.

The lungs play an important role in activating angiotensin. The physiologically inactive decapeptide angiotensin I is converted to the pressor, aldosterone-stimulating octapeptide angiotensin II in the pulmonary circulation. The reaction occurs in other tissues as well, but it is particularly prominent in the lungs. Large amounts of the angiotensin-converting enzyme responsible for this activation are located on the surface of the endothelial cells of the pulmonary capillaries. The converting enzyme also inactivates bradykinin. Circulation time through the pulmonary capillaries is less than 1 s, yet 70% of the angiotensin I reaching the lungs is converted to angiotensin II in a single trip through the capillaries. Four other peptidases have been identified on the surface of the pulmonary endothelial cells, but their full physiologic role is unsettled.

Removal of serotonin and norepinephrine reduces the amounts of these vasoactive substances reaching the systemic circulation. However, many other vasoactive hormones pass through the lungs without being metabolized. These include epinephrine, dopamine, oxytocin, vasopressin, and angiotensin II. In addition, various amines and polypeptides are secreted by neuroendocrine cells in the lungs.

• Air enters the respiratory system in the upper airway, proceeds to the conducting airway and then on to the respiratory airway that ends in the alveoli. The cross-sectional area of the airway gradually increases through the conducting zone, and then rapidly increases during the transition from conducting to respiratory zones.

• The mucociliary escalator in the conducting airway helps keep particulates out of the respiratory zone.

• There are several important measures of lung volume, including tidal volume, inspiratory volume, expiratory reserve volume, forced vital capacity (FVC), the forced expiratory volume in 1 second (FEV₁), respiratory minute volume, and maximal voluntary ventilation.

• Net “driving pressure” for air movement into the lung includes the force of muscle contraction, lung compliance (ΔP/ΔV), and airway resistance .

• Surfactant decreases surface tension in the alveoli and helps keep them from deflating.

• Not all air that enters the airway is available for gas exchange. The regions where gas is not exchanged in the airway are termed “dead space.” The conducting airway represents anatomic dead space. Increased dead space can occur in response to disease that affects air exchange in the respiratory zone (physiologic dead space).

• The pressure gradient in the pulmonary circulation system is much less than that in the systemic circulation.

• There are a variety of biologically activated substances that are metabolized in the lung. These include substances that are made and function in the lung (eg, surfactant), substances that are released or removed from the blood (eg, prostaglandins), and substances that are activated as they pass through the lung (eg, angiotensin II).