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 anatomical features contribute to the basic mechanics of breathing, as well as some highlights of nonrespiratory physiology in the pulmonary system.
ANATOMY OF THE LUNGS
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.
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 histological 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. 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.
FIGURE 34–1 Conducting and respiratory zones in the airway. A) Resin cast of the human airway tree shows dichotomous branching beginning at the trachea. Note the added pulmonary arteries (red) and veins (blue) displayed in the left lung. B) The branching patterns of the airway from the conducting to the transitional and respiratory airway zones are drawn (not all divisions are drawn, and drawings are not to scale). Numbers indicate approximate airway passages following generational branching. C) The total airway cross-sectional area rapidly increases as the airways transition from the conducting to the respiratory zone. (A Reproduced with permission from Fishman AP: Fishman’s Pulmonary Diseases and Disorders, 4th ed. McGraw Hill Medical, 2008; B and C Reproduced with permission from West JB: Respiratory Physiology: The Essentials, 7th ed. Williams & Wilkins, 2005.)
FIGURE 34–2 Cellular transition from conducting airway to the alveolus. The epithelial layer transitions from pseudostratified layer with submucosal glands to a cuboidal and the to a squamous epithelium. The underlying mesynchyme tissue and capillary structure also changes with the airway transition (Reproduced from Fishman AP: Fishman’s Pulmonary Diseases and Disorders, 4th ed. McGraw Hill Medical, 2008).
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).
CLINICAL BOX 34–1
Among Caucasians, cystic fibrosis is one of the most common genetic disorders: greater than 3% of the United States population are carriers for this autosomal recessive disease.
The gene that is abnormal in cystic fibrosis is located on the long arm of chromosome 7 and encodes the cystic fibrosis transmembrane conductance regulator (CFTR), a regulated Cl– channel located on the apical membrane of various secretory and absorptive epithelia. The number of reported mutations in the CFTR gene that cause cystic fibrosis is large (> 1000) and the mutations are now grouped into five classes (I–V) based on their cellular function. Class I mutations do not allow for synthesis of the protein. Class II mutations have protein processing defects. Class III mutations have a block in their channel regulation. Class IV mutations display altered conductance of the ion channel. Class V mutations display reduced synthesis of the protein. The severity of the defect varies with the class and the individual mutation. The most common mutation causing cystic fibrosis is loss of the phenylalanine residue at amino acid position 508 of the protein (ΔF508), a Class II mutation that limits the amount of protein that gets to the plasma membrane.
One outcome of cystic fibrosis is repeated pulmonary infections, particularly with Pseudomonas aeruginosa, and progressive, eventually fatal destruction of the lungs. There is also suppressed chloride secretion across the wall of the airways. One would expect Na+ reabsorption to be depressed as well, and indeed in sweat glands it is. However, in the lungs, it is enhanced, so that the Na+ and water move out of airways, leaving their other secretions inspissated and sticky. This results in a reduced periciliary layer that inhibits function of the mucociliary escalator, and alters the local environment to reduce the effectiveness of antimicrobial secretions.
Traditional treatments of cystic fibrosis address the various symptoms. Chest physiotherapy and mucolytics are used to loosen thick mucus and aid lung clearance. Antibiotics are used to prevent new infections and keep chronic infections in check. Bronchodilators and anti-inflammatory medications are used to help expand and clear air passages. Pancreatic enzymes and nutritive supplements are used to increase nutrient absorption and promote weight gain. Because of the “single gene” mutation of this disease, gene therapy has been closely examined; however, results have not been successful. More recently, drugs that target the molecular defects have been advancing in clinical trials and are showing great promise for better treatments.
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 receptors mediate bronchodilation. They also increase bronchial secretions (eg, mucus), while α1 adrenergic receptors inhibit secretions.
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 34–1a,b). 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 (Figure 34–1c). 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.
FIGURE 34–3 Prominent cells in the adult human alveolus. A) A cross-section of the respiratory zone shows the relationship between capillaries and the airway epithelium. Only 4 of the 18 alveoli are labeled. B) Enlargement of the boxed area from (A) displaying intimate relationship between capillaries, the interstitium, and the alveolar epithelium. C) Electron micrograph displaying a typical area depicted in (B). The pulmonary capillary (cap) in the septum contains plasma with red blood cells. Note the closely apposed endothelial and pulmonary epithelial cell membranes separated at places by additional connective tissue fibers (cf); en, nucleus of endothelial cell; epl, nucleus of type I alveolar epithelial cell; a, alveolar space; ma, alveolar macrophage. D) Type II cell formation and metabolism of surfactant. Lamellar bodies (LB) are formed in type II alveolar epithelial cells and secreted by exocytosis into the fluid lining the alveoli. The released lamellar body material is converted to tubular myelin (TM), and the TM is the source of the phospholipid surface film (SF). Surfactant is taken up by endocytosis into alveolar macrophages and type II epithelial cells. N, nucleus; RER, rough endoplasmic reticulum; CB, composite body. (For (A) From Greep RO, Weiss L: Histology, 3rd ed. New York: McGraw-Hill, 1973; (B) Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology: The Mechanisms of Body Function, 11th ed. McGraw-Hill, 2008; (C) Burri PA: Development and growth of the human lung. In: Handbook of Physiology, Section 3, The Respiratory System. Fishman AP, Fisher AB [editors]. American Physiological Society, 1985; and (D) Wright JR: Metabolism and turnover of lung surfactant. Am Rev Respir Dis 136:426, 1987.)
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.
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.
FIGURE 34–4 Muscles and movement in respiration. A) An idealized diagram of respiratory muscles surrounding the rib cage. The diaphragm and intercostals play prominent roles in respiration. B) and C) X-ray of chest in full expiration (B) and full inspiration (C). The dashed white line on in C is an outline of the lungs in full expiration. Note the difference in intrathoracic volume. (Reproduced with permission A) from Fishman AP: Fishman’s Pulmonary Diseases and Disorders, 4th ed. McGraw Hill Medical, 2008; B, C from Comroe JH Jr: Physiology of Respiration, 2nd ed., Year Book, 1974.)
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 to 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).
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 which lines the chest cavity containing the lungs. The visceral pleura is a membrane which 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.
FIGURE 34–5 Pleural space and connective fibers. A) Front sectional drawing of lung within the rib cage. Note the parietal and visceral pleura and the infoldings around the lung lobes that include pleural space. B) Connective fiber tracts of the lung are highlighted. Note the axial fibers along the airways, the peripheral fibers in the pleura, and the septal fibers. (Reproduced with permission from Fishman AP: Fishman’s Pulmonary Diseases and Disorders,4th ed. McGraw Hill Medical, 2008)
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 to 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 and 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.
FIGURE 34–6 Pulmonary circulation. A, B) Schematic diagrams of the relation of the main branches of pulmonary arteries (A) and pulmonary veins (B) to the bronchial tree. LA = left atrium; RV = right ventricle. C) Representative areas of blood flow are labeled with corresponding blood pressure (mm Hg). (A, B Reproduced with permission from Fishman AP: Fishman’s Pulmonary Diseases and Disorders, 4th ed. McGraw Hill Medical, 2008; C Modified from Comroe JH Jr: Physiology of Respiration, 2nd ed. Year Book, 1974.)
MECHANICS OF RESPIRATION
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.
FIGURE 34–7 Pressure in the alveoli and the pleural space relative to atmospheric pressure during inspiration and expiration. The dashed line indicates what the intrapleural pressure would be in the absence of airway and tissue resistance; the actual curve (solid line) is skewed to the left by the resistance. Volume of breath during inspiration/expiration is graphed for comparison.
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 or earlobe.
Lung Volumes and 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. Diagnositic 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 to 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).
FIGURE 34–8 Lung volumes and capacity measurements. Lung volumes recorded by a spirometer. Lung capacities are determined from volume recordings. See text for definitions. (Reproduced with permission from Fishman AP: Fishman’s Pulmonary Diseases and Disorders, 4th ed. McGraw Hill Medical, 2008).
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 1 sec; 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 s period and prorated to a minute; normal values range from 140 to 180 L/min for healthy adult males. Changes in RMV and MVV in a patient can be indicative of lung dysfunction.
CLINICAL BOX 34–2
Altered Airflow in Disease:
Representative spirograms measuring volume over time (sec) for subjects displaying normal (A), obstructive (B) or restrictive (C) patterns. Note the differences in the FEV1, FVC and FEV1/FVC (shown at bottom). Fishman’s Pulmonary Diseases and Disorders, Chapter 34, Figure 34–16.
Airflow Measurements of Obstructive & Restrictive Disease
In the example above, a healthy FVC is ∼4.0 L and a healthy FEV1 is ∼3.3 L. The calculated FEV1/FVC is ∼80%. Patients with obstructive or restrictive diseases can display reduced FVC, on the order of 2.0 L in the example above. Measurement of FEV1, however, tends to vary significantly between the two diseases. In obstructive disorders, patients tend to show a slow, steady slope to the FVC, resulting in a small FEV1, on the order of 1.0 L in the example. However, in the restrictive disorder patients, airflow tends to be fast at first, and then quickly level out to approach FVC. The resultant FEV1 is much greater, on the order of 1.8 L in the example, even though FVC is equivalent (compare B, C above). A quick calculation of FEV1/FVC for obstructive (50%) versus restrictive (90%) patients defines the hallmark measurements in evaluating these two diseases. Obstructive disorders result in a marked decrease in both FVC and FEV1/FVC, whereas restrictive disorders result in a loss of FVC without loss in FEV1/FVC. It should be noted that these examples are idealized and several disorders can show mixed readings.
Asthma is characterized by episodic or chronic wheezing, cough, and a feeling of tightness in the chest as a result of bronchoconstriction. Although the disease is not fully understood, three airway abnormalities are present: airway obstruction that is at least partially reversible, airway inflammation, and airway hyperresponsiveness to a variety of stimuli. A link to allergy has long been recognized, and plasma IgE levels are often elevated. Proteins released from eosinophils in the inflammatory reaction may damage the airway epithelium and contribute to the hyperresponsiveness. Leukotrienes are released from eosinophils and mast cells, and can enhance bronchoconstriction. Numerous other amines, neuropeptides, chemokines, and interleukins have effects on bronchial smooth muscle or produce inflammation, and they may be involved in asthma.
Because β2-adrenergic receptors mediate bronchodilation, β2-adrenergic agonists have long been the mainstay of treatment for mild to moderate asthma attacks. Inhaled and systemic steroids are used even in mild to moderate cases to reduce inflammation; they are very effective, but their side effects can be a problem. Agents that block synthesis of leukotrienes or their CysLT1 receptor have also proved useful in some cases.
FIGURE 34–9 Volume of gas expired by a normal adult man during a forced expiration, demonstrating the FEV1 and the forced vital capacity (FVC). From the graph the forced expiratory volume in 1 s (FEV1) to FVC ration (FEV1/FVC) can be calculated (4L/5L = 80%). (Reproduced, with permission, from Crapo RO: Pulmonary-function testing. N Engl J Med 1994; 331:25. Copyright © 1994, Massachusetts Medical Society.)
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 inspiration 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 demonstrated in living subjects through a spirometer that has a valve just beyond the mouthpiece. The mouthpiece contains a pressure-measuring device. After the subject 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 (PTR 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 (Pw) and a slightly positive pressure from the lungs (PL). PTR is positive at greater volumes and negative at smaller volumes. Compliance of the lung and chest wall is measured as the slope of the PTR 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 male. 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.
FIGURE 34–10 Pressure–volume curves in the lung. The pressure–volume curves of the total respiratory system (PTR), the lungs (PL), and the chest (PW) are plotted together with standard volumes for functional residual capacity and tidal volume. The transmural pressure is intrapulmonary pressure minus intrapleural pressure in the case of the lungs, intrapleural pressure minus outside (barometric) pressure in the case of the chest wall, and intrapulmonary pressure minus barometric pressure in the case of the total respiratory system. From these curves, the total and actual elastic work associated with breathing can be derived (see text). (Modified from Mines AH: Respiratory Physiology, 3rd ed. Raven Press, 1993.)
FIGURE 34–11 Static expiratory pressure–volume curves of lungs in normal subjects and subjects with severe emphysema and pulmonary fibrosis. (Modified and reproduced with permission from Pride NB, Macklem PT: Lung mechanics in disease. In: Handbook of Physiology. Section 3, The Respiratory System. Vol III, part 2. Fishman AP [editor]. American Physiological Society, 1986.)
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 to reduce surface tension and keep alveoli from collapsing, contribute to hysteresis.
FIGURE 34–12 Pressure–volume curves in the lungs of a cat after removal from the body. Saline: lungs inflated and deflated with saline to reduce surface tension, resulting in a measurement of tissue elasticity. Air: lungs inflated (Inf) and deflated (Def) with air results in a measure of both tissue elasticity and surface tension. (Reproduced with permission from Morgan TE: Pulmonary surfactant. N Engl J Med 1971;284:1185.)
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 equals two times the tension divided by the radius (P = 2T/r); if T is not reduced as r is reduced, the tension overcomes the distending pressure. Surfactant also helps to 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 favoring 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.
CLINICAL BOX 34–3
Surfactant is important at birth. The fetus makes respiratory movements in utero, but the lungs remain collapsed until birth. After birth, the infant makes several strong inspiratory movements and the lungs expand. Surfactant keeps them from collapsing again. Surfactant deficiency is an important cause of infant respiratory distress syndrome (IRDS, also known as hyaline membrane disease), the serious pulmonary disease that develops in infants born before their surfactant system is functional. Surface tension in the lungs of these infants is high, and the alveoli are collapsed in many areas (atelectasis). An additional factor in IRDS is retention of fluid in the lungs. During fetal life, Cl– is secreted with fluid by the pulmonary epithelial cells. At birth, there is a shift to Na+ absorption by these cells via the epithelial Na+ channels (ENaCs), and fluid is absorbed with the Na+. Prolonged immaturity of the ENaCs contributes to the pulmonary abnormalities in IRDS.
Overproduction/dysregulation of surfactant proteins can also lead to respiratory distress and is the cause of Pulmonary Alveolar Proteinosis (PAP).
Treatment of IRDS is commonly done with surfactant replacement therapy. Interestingly, such surfactant replacement therapy has not been as successful in clinical trials for adults experiencing respiratory distress due to surfactant dysfunction.
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 pressure times volume (g/cm2 × cm3 = g × cm) has the same dimensions as work (force × distance), the work of breathing can be calculated from the previously presented pressure–volume curve (Figure 34–10). The total elastic work required for inspiration is represented by the area ABCA. Note that the relaxation pressure curve of the total respiratory system differs from that of the lungs alone. The actual elastic work required to increase the volume of the lungs alone is area ABDEA. 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. The elastic energy lost from the thorax (area AFGBA) is equal to that gained by the lungs (area AEDCA).
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 congestive 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 (Figure 34–13), 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.
FIGURE 34–13 Intrapleural pressures in the upright position and their effect on ventilation. Note that because intrapulmonary pressure is atmospheric, the more negative intrapleural pressure at the apex holds the lung in a more expanded position at the start of inspiration. Further increases in volume per unit increase in intrapleural pressure are smaller than at the base because the expanded lung is stiffer. (Reproduced with permission from West JB: Ventilation/Blood Flow and Gas Exchange, 5th ed. Blackwell, 1990.)
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).
TABLE 34–1 Effect of variations in respiratory rate and depth on alveolar ventilation.
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 34–14). From mid-inspiration, the subject 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.
FIGURE 34–14 Single-breath N2 curve. From mid-inspiration, the subject takes a deep breath of pure O2 then exhales steadily. The changes in the N2 concentration of expired gas during expiration are shown, with the various phases of the curve indicated by roman numerals. Notably, region I is representative of the dead space (DS); from I–II is a mixture of DS and alveolar gas; the transition form III–IV is the closing volume (CV), and the end of IV is the residual volume (RV).
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 (VT) times the PCO2 of the expired gas (PECO2) equals the arterial PCO2 (PaCO2) times the difference between the TV and the dead space (VD) plus the PCO2 of inspired air (PICO2) times VD(Bohr’s equation):
The term PICO2 × VD is so small that it can be ignored and the equation solved for VD, where
If, for example: Hg; and , then
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 under-perfused alveoli, is greater than PCO2.
GAS EXCHANGE IN THE LUNGS
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.
TABLE 34–2 Properties of Gases.
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 (PB) at sea level is 760 mm Hg (1 atmosphere). The partial pressure (indicated by the symbol P) of O2 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 34–14). 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 34–15.
FIGURE 34–15 Partial pressures of gases (mm Hg) in various parts of the respiratory system. Typical partial pressures for inspired air, alveolar air, and expired air are given. See text for additional details.
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 O2molecules 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 34–16). 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.
FIGURE 34–16 Uptake of various substances during the 0.75 s they are in transit through a pulmonary capillary. N2O is not bound in blood, so its partial pressure in blood rises rapidly to its partial pressure in the alveoli. Conversely, CO is avidly taken up by red blood cells, so its partial pressure reaches only a fraction of its partial pressure in the alveoli. O2 is intermediate between the two.
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 (VCO) 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 biological 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 34–17). 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.
FIGURE 34–17 Diagram of normal differences in ventilation and perfusion of the lung in the upright position. Outlined areas are representative of changes in alveolar size (not actual size). Note the gradual change in alveolar size from top (apex) to bottom. Characteristic differences of alveoli at the apex of the lung are stated. (Modified from Levitzky MG: Pulmonary Physiology, 6th ed. McGraw-Hill, 2003).
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.
CLINICAL BOX 34–4
Diseases Affecting the Pulmonary Circulation
Sustained idiopathic pulmonary hypertension can occur at any age. Like systemic arterial hypertension, it is a syndrome with multiple causes. However, the causes are different from those causing systemic hypertension. They include hypoxia, inhalation of cocaine, treatment with dexfenfluramine and related appetite-suppressing drugs that increase extracellular serotonin, and systemic lupus erythematosus. Some cases are familial and appear to be related to mutations that increase the sensitivity of pulmonary vessels to growth factors or cause deformations in the pulmonary vascular system.
All these conditions lead to increased pulmonary vascular resistance. If appropriate therapy is not initiated, the increased right ventricular afterload can lead eventually to right heart failure and death. Treatment with vasodilators such as prostacyclin and prostacyclin analogs is effective. Until recently, these had to be administered by continuous intravenous infusion, but aerosolized preparations that appear to be effective are now available.
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 O2enters the blood. These effects are summarized in Figure 34–18.
FIGURE 34–18 Effects of decreasing or increasing the ventilation/perfusion ratio on the PCO2 and PO2 in an alveolus. The drawings above the curve represent an alveolus and a pulmonary capillary, and the dark red areas indicate sites of blockage. With complete obstruction of the airway to the alveolus, PCO2 and PO2 approximate the values in mixed venous blood. With complete block of perfusion, PCO2 and PO2 approximate the values in inspired air. (Reproduced with permission from West JB: Ventilation/Blood Flow and Gas Exchange, 5th ed. Blackwell, 1990.)
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).
TABLE 34–3 Receptors affecting smooth muscle in pulmonary arteries and veins.
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.
TABLE 34–4 Biologically active substances metabolized by the lungs.
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 to 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 one 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 (ΔP/Δ).
Surfactant decreases surface tension in the alveoli and helps to 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 anatomical dead space. Increased dead space can occur in response to disease that affects air exchange in the respiratory zone (physiological 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).
For all questions, select the single best answer unless otherwise directed.
1. On the summit of Mt. Everest, where the barometric pressure is about 250 mm Hg, the partial pressure of O2 in mm Hg is about
2. The forced vital capacity is
A. the amount of air that normally moves into (or out of) the lung with each respiration.
B. the amount of air that enters the lung but does not participate in gas exchange.
C. the amount of air expired after maximal expiratory effort.
D. the largest amount of gas that can be moved into and out of the lungs in 1 min.
3. The tidal volume is
A. the amount of air that normally moves into (or out of) the lung with each respiration.
B. the amount of air that enters the lung but does not participate in gas exchange.
C. the amount of air expired after maximal expiratory effort.
D. the amount of gas that can be moved into and out of the lungs in 1 min.
4. Which of the following is responsible for the movement of O2 from the alveoli into the blood in the pulmonary capillaries?
A. Active transport
C. Secondary active transport
D. Facilitated diffusion
E. Passive diffusion
5. Airway resistance
A. is increased if the lungs are removed and inflated with saline.
B. does not affect the work of breathing.
C. is increased in paraplegic patients.
D. is increased in following bronchial smooth muscle contraction.
E. makes up 80% of the work of breathing.
6. Surfactant lining the alveoli
A. helps prevent alveolar collapse.
B. is produced in alveolar type I cells and secreted into the alveolus.
C. is increased in the lungs of heavy smokers.
D. is a glycolipid complex.
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