Medical Physiology, 3rd Edition

Organization of the Respiratory System in Humans

Humans optimize each aspect of external respiration—ventilation, circulation, area amplification, gas carriage, local control, and central control

The human respiratory system (Fig. 26-4) has two important characteristics. First, it uses highly efficient convective systems (i.e., ventilatory and circulatory systems) for long-distance transport of O2 and CO2. Second, it reserves diffusion exclusively for short-distance movements of O2 and CO2. The key components of this respiratory system are the following:

1. An air pump. The external convective system consists of the upper respiratory tract and large pulmonary airways, the thoracic cavity and associated skeletal elements, and the muscles of respiration. These components deliver air to and remove air from the alveolar air spaces—alveolar ventilation. Inspiration occurs when muscle contractions increase the volume of the thoracic cavity, thereby lowering intrathoracic pressure; this causes the alveoli to expand passively, which in turn lowers alveolar pressure. Air then flows from the environment to the alveoli, down a pressure gradient. A quiet expiration occurs when the muscles relax. We discuss the mechanics of ventilation in Chapter 27.

2. Mechanisms for carrying O2 and CO2 in the blood. Red blood cells are highly specialized for transporting O2 from the lungs to the peripheral tissues and for transporting CO2 in the opposite direction. They have extremely high levels of hemoglobin and other components that help to rapidly load and unload huge amounts of O2 and CO2. In the pulmonary capillaries, hemoglobin binds O2, thereby enabling the blood to carry ~65-fold more O2 than saline. In the systemic capillaries, hemoglobin plays a key role in the carriage of CO2—produced by the mitochondria—to the lungs. Hemoglobin accomplishes this task by chemically reacting with some of the CO2 and by buffering the H+ formed as carbonic anhydrase converts CO2 to image and H+. Thus, hemoglobin plays a central role in acid-base chemistry, as discussed in Chapter 28, as well as in the carriage of O2 and CO2, treated in Chapter 29.

3. A surface for gas exchange. The gas exchange barrier in humans consists of the alveoli, which provide a huge but extremely thin surface area for passive diffusion of gases between the alveolar air spaces and the pulmonary capillaries. We discuss the anatomy of the alveoli below in this chapter and explore pulmonary gas exchange in Chapter 30. A similar process of gas exchange occurs between the systemic capillaries and mitochondria.

4. A circulatory system. The internal convective system in humans consists of a four-chambered heart and separate systemic and pulmonary circulations. We discuss the flow of blood to the lungs—perfusion—in Chapter 31.

5. A mechanism for locally regulating the distribution of ventilation and perfusion. Efficient gas exchange requires that the ratio of ventilation to perfusion be uniform for all alveoli to the extent possible. However, neither the delivery of fresh air to the entire population of alveoli nor the delivery of mixed-venous blood to the entire population of pulmonary capillaries is uniform throughout the lungs. The lungs attempt to maximize the uniformity of ventilation-perfusion ratios by using sophisticated feedback control mechanisms to regulate local air flow and blood flow, as discussed in Chapter 31.

6. A mechanism for centrally regulating ventilation. Unlike the rhythmicity of the heart, which is intrinsic to that organ, that of the respiratory system is not intrinsic to the lungs or the chest wall. Instead, respiratory control centers in the central nervous system rhythmically stimulate the muscles of inspiration. Moreover, these respiratory centers appropriately modify the pattern of ventilation during exercise or other changes in physical or mental activity. Sensors for arterial imageimage, and pH are part of feedback loops that stabilize these three “blood gas” parameters. We discuss these subjects in Chapter 32.


FIGURE 26-4 Respiratory apparatus in humans.

Respiratory physiologists have agreed on a set of symbols to describe parameters that are important for pulmonary physiology and pulmonary function testing (Table 26-2).

TABLE 26-2

Symbol Conventions in Respiratory Physiology



Main Symbols




Concentration (or content) in a liquid



Diffusion capacity


Respiratory frequency


Respiratory frequency










Flow of blood (perfusion)




Gas exchange ratio



Saturation of hemoglobin


Volume of gas


Volume of gas


Flow of gas



Modifiers (subscripts)



Systemic arterial














Pulmonary capillary









Systemic venous (in any vascular bed)



Mixed systemic venous

From Macklem PT: Symbols and abbreviations. In Fishman AP, Fisher AB (eds): Handbook of Physiology, Section 3: The Respiratory System, vol 1, Circulation and Nonrespiratory Functions. Bethesda, MD, American Physiological Society, 1985.

Conducting airways deliver fresh air to the alveolar spaces

We will discuss lung development on pages 1155–1156. In the embryo, each lung invaginates into a separate pleural sac, which reflects over the surface of the lung.

The parietal pleura, the wall of the sac that is farthest from the lung, contains blood vessels that are believed to produce an ultrafiltrate of the plasma called pleural fluid. About 10 mL of this fluid normally occupies the virtual space between the parietal and the visceral pleura. The visceral pleura lies directly on the lung and contains lymphatics that drain the fluid from the pleural space. When the production of pleural fluid exceeds its removal, the volume of pleural fluid increases (pleural effusion), limiting the expansion of the lung. Under normal circumstances, the pleural fluid probably lubricates the pleural space, facilitating physiological changes in lung size and shape.

The lungs themselves are divided into lobes, three in the right lung (i.e., upper, middle, and lower lobes) and two in the left (i.e., upper and lower lobes). The right lung, which is less encumbered than the left by the presence of the heart, makes up ~55% of total lung mass and function.

We refer to the progressively bifurcating pulmonary airways by their generation number (Fig. 26-5): The zeroth generation is the trachea, the first-generation airways are the right and left mainstem bronchi, and so on. Inasmuch as the right mainstem bronchus has a greater diameter than the left and is more nearly parallel with the trachea, inhaled foreign bodies more commonly lodge in the right lung than in the left. Humans have ~23 generations of airways. As generation number increases (i.e., as airways become smaller), the amount of cilia, the number of mucus-secreting cells, the presence of submucosal glands, and the amount of cartilage in the airway walls all gradually decrease. The mucus is important for trapping small foreign particles. The cilia sweep the carpet of mucus—kept moist by secretions from the submucosal glands—up toward the pharynx, where swallowing eventually disposes of the mucus. The cartilage is important for preventing airway collapse, which is especially a problem during expiration (see Chapter 27). Airways maintain some cartilage to about the 10th generation, up to which point they are referred to as bronchi.


FIGURE 26-5 Generations of airways.

Beginning at about the 11th generation, the now cartilage-free airways are called bronchioles. Because they lack cartilage, bronchioles can maintain a patent lumen only because the pressure surrounding them may be more negative than the pressure inside and because of the outward pull (radial traction or tethering) of surrounding tissues. Thus, bronchioles are especially susceptible to collapse during expiration. Up until generation ~16, no alveoli are present, and the air cannot exchange with the pulmonary-capillary blood. The airways from the nose and lips down to the alveoli-free bronchioles are the conducting airways, which serve only to move air by convection (i.e., like water moving through a pipe) to those regions of the lung that participate in gas exchange. The most distal conducting airways are the terminal bronchioles (generation ~16). The aggregate volume of conducting airways, the anatomical dead space, amounts to ~150 mL in healthy young males and >100 mL in females. The anatomical dead space is only a small fraction of the total lung capacity, which averages 5 to 6 L in adults, depending on the size and health of the individual.

Alveolar air spaces are the site of gas exchange

Alveoli first appear budding off bronchioles at generation ~17. These respiratory bronchioles participate in gas exchange over at least part of their surface. Respiratory bronchioles extend from generation ~17 to generation ~19, the density of alveoli gradually increasing with generation number (see Fig. 26-5). Eventually, alveoli completely line the airways. These alveolar ducts (generations 20 to 22) finally terminate blindly as alveolar sacs (generation 23). The aggregation of all airways arising from a single terminal bronchiole (i.e., the respiratory bronchioles, alveolar ducts, and alveolar sacs), along with their associated blood and lymphatic vessels, is a terminal respiratory unit or primary lobule.

The cross-sectional area of the trachea is ~2.5 cm2. Unlike the situation in systemic arteries (see p. 447), in which the aggregate cross-sectional area of the branches always exceeds the cross-sectional area of the parent vessel, the aggregate cross-sectional area falls from the trachea through the first four generations of airways (Fig. 26-6). Because all of the air that passes through the trachea also passes through the two mainstem bronchi and so on, the product of aggregate cross-sectional area and linear velocity is the same for each generation of conducting airways. Thus, the linear velocity of air in the first four generations is higher than that in the trachea, which may be important during coughing (see p. 719). In succeeding generations, the aggregate cross-sectional area rises, at first slowly and then very steeply. As a result, the linear velocity falls to very low values. For example the terminal bronchioles (generation 16) have an aggregate cross-sectional area of ~180 cm2, so that the average linear velocity of the air is only (2.5 cm2)/(180 cm2) = 1.4% of the value in the trachea.


FIGURE 26-6 Dependence of aggregate cross-sectional area and of linear velocity on generation number. At generation 3, the aggregate cross-sectional area has a minimum (not visible) where velocity has its maximum. (Data from Bouhuys A: The Physiology of Breathing. New York, Grune & Stratton, 1977.)

As air moves into the respiratory bronchioles and further into the terminal respiratory unit, where linear velocity is minuscule, convection becomes less and less important for the movement of gas molecules, and diffusion dominates. Notice that the long-distance movement of gases from the nose and lips to the end of the generation-16 airways occurs by convection. However, the short-distance movement of gases from generation-17 airways to the farthest reaches of the alveolar ducts occurs by diffusion, as does the movement of gases across the gas exchange barrier (~0.6 µm).

The alveolus is the fundamental unit of gas exchange. Alveoli are hemispheric structures with diameters that range from 75 to 300 µm. The ~300 million alveoli have a combined surface area of 50 to 100 m2 and an aggregate maximal volume of 5 to 6 L in the two lungs. Both the diameter and the surface area depend on the degree of lung inflation. The lungs have a relatively modest total volume (i.e., ~5.5 L), very little of which is invested in conducting airways (i.e., ~0.15 L). However, the alveolar area is tremendously amplified. For example, a sphere with a volume of 5.5 L would have a surface area of only 0.16 m2, which is far less than 1% of the alveolar surface area.

The alveolar lining consists of two types of epithelial cells, type I and type II alveolar pneumocytes. The cuboidal type II cells exist in clusters and are responsible for elaborating pulmonary surfactant, which substantially eases the expansion of the lungs (see pp. 613–614). The type I cells are much thinner than the type II cells. Thus, even though the two cell types are present in about equal numbers, the type I cells cover 90% to 95% of the alveolar surface and represent the shortest route for gas diffusion. After an injury, type I cells slough and degenerate, whereas type II cells proliferate and line the alveolar space, re-establishing a continuous epithelial layer. Thus, the type II cells appear to serve as repair cells.

The pulmonary capillaries are usually sandwiched between two alveolar air spaces. In fact, the blood forms an almost uninterrupted sheet that flows like a twisted ribbon between abutting alveoli. At the type I cells, the alveolar wall (i.e., pneumocyte plus endothelial cell) is typically 0.15 to 0.30 µm thick. Small holes (pores of Kohn)imageN26-10 perforate the septum separating two abutting alveoli. The function of these pores, which are surrounded by capillaries, is unknown.


Pores of Kohn

Contributed by Emile Boulpaep, Walter Boron

The so-called pores of Kohn are named after H.N. Kohn, who in 1893 described pores through the alveolar wall in lungs from patients with pneumonia. He thought that these pores were pathological. However, nearly a half-century earlier, others had described alveolar pores in normal lungs. Kohn's mentor later named the pores after his student, and the name stuck.

Modern ultrastructural findings are consistent with the hypothesis that the pores of Kohn are fixation artifacts. If lungs are fixed by instilling the fixative into the trachea, one can observe small holes in the alveolar wall (Cordingley, 1972). However, if the lungs are fixed by perfusing the pulmonary blood vessels, the alveolar wall is continuous (i.e., no pores are to be seen).

Whether the pores are fixation artifacts or not, they are so small (about half the diameter of a pulmonary capillary) that it is unlikely that they play an important role in collateral ventilation; that is, the movement of air between adjacent alveoli.

For an excellent review, consult Mitzner's chapter in The Lung.


Cordingley JL. Pores of Kohn. Thorax. 1972;27:433–441.

Gil J, Weibel ER. Improvements in demonstration of lining layer of lung alveoli by electron microscopy. Respir Physiol. 1969;70:13–36.

Mitzner W. Collateral ventilation. Crystal RG, West JB. The Lung: Scientific Foundations. Raven Press: New York; 1991.

Parra SC, Gaddy LR, Takaro T. Ultrastructural studies of canine interalveolar pores (of Kohn). Lab Invest. 1978;38:8–13.

The lung receives two blood supplies: the pulmonary arteries and the bronchial arteries (Fig. 26-7). The pulmonary arteries, by far the major blood supply to the lung, carry the relatively deoxygenated mixed-venous blood. After arising from the right ventricle, they bifurcate as they follow the bronchial tree, and their divisions ultimately form a dense, richly anastomosing, hexagonal array of capillary segments that supply the alveoli of the terminal respiratory unit. The pulmonary capillaries have an average internal diameter of ~8 µm, and each segment of the capillary network is ~10 µm in length. The average erythrocyte spends ~0.75 second in the pulmonary capillaries as it traverses up to three alveoli. After gas exchange in the alveoli, the blood eventually collects in the pulmonary veins.


FIGURE 26-7 Blood supply to the airways.

The bronchial arteries are branches of the aorta and thus carry freshly oxygenated blood. They supply the conducting airways. At the level of the respiratory bronchioles, capillaries derived from bronchial arteries anastomose with those derived from pulmonary arteries. Because capillaries of the bronchial circulation drain partially into pulmonary veins, there is some venous admixture of the partially deoxygenated blood from the bronchial circulation and the newly oxygenated blood (see p. 891). This mixing represents part of a small physiological shunt. A small amount of the bronchial blood drains into the azygos and accessory hemiazygos veins.

The lungs play important nonrespiratory roles, including filtering the blood, serving as a reservoir for the left ventricle, and performing several biochemical conversions

Although their main function is to exchange O2 and CO2 between the atmosphere and the blood, the lungs also play important roles that are not directly related to external respiration.


Ventilation is essential for delivery of odorants to the olfactory epithelium (see pp. 354–356). Sniffing behavior, especially important for some animals, allows one to sample the chemicals in the air without the risk of bringing potentially noxious agents deep into the lungs.

Processing of Inhaled Air Before It Reaches the Alveoli

Strictly speaking, the warming, moisturizing, and filtering of inhaled air in the conducting airways is a respiratory function. It is part of the cost of doing the business of ventilation. Warming of cool, inhaled air is important so that gas exchange in the alveoli takes place at body temperature. If the alveoli and the associated blood were substantially cooler than body temperature, the solubility of these alveolar gases in the cool pulmonary-capillary blood would be relatively high. As the blood later warmed, the solubility of these gases would decrease, resulting in air bubbles (i.e., emboli) that could lodge in small systemic vessels and cause infarction. Moisturizing is important to prevent the alveoli from becoming desiccated. Finally, filtering of large particles is important to prevent small airways from being clogged with debris that may also be toxic.

Warming, moisturizing, and filtering are all more efficient with nose breathing than with mouth breathing. The nose, including the nasal turbinates, has a huge surface area and a rich blood supply. Nasal hairs tend to filter out large particles (greater than ~15 µm in diameter). The turbulence set up by these hairs—as well as the highly irregular surface topography of the nasal passages—increases the likelihood that particles larger than ~10 µm in diameter will impact and embed themselves in the mucus that coats the nasal mucosa. Moreover, air inspired through the nose makes a right-angle turn as it heads toward the trachea. The inertia of larger particles causes them to strike the posterior wall of the nasopharynx, which coincidentally is endowed with large amounts of lymphatic tissue that can mount an immunological attack on inspired microbes. Of the larger particles that manage to escape filtration in the upper airways, almost all will impact the mucus of the trachea and the bronchi.

Smaller particles (2 to 10 µm in diameter) also may impact a mucus layer. In addition, gravity may cause them to sediment from the slowly moving air in small airways and to become embedded in mucus. Particles with diameters below ~0.5 µm tend to reach the alveoli suspended in the air as aerosols. The airways do not trap most (~80%) of these aerosols but expel them in the exhaled air.

The lung has a variety of strategies for dealing with particles that remain on the surface of the alveoli or penetrate into the interstitial space. Alveolar macrophages (on the surface) or interstitial macrophages may phagocytose these particles, enzymes may degrade them, or lymphatics may carry them away. In addition, particles suspended in the fluid covering the alveolar surface may flow with this fluid up to terminal bronchioles, where they meet a layer of mucus that the cilia propel up to progressively larger airways. There, they join larger particles—which entered the mucus by impaction or sedimentation—on their journey to the oropharynx. Coughing and sneezing (see Box 32-4), reflexes triggered by airway irritation, accelerate the movement of particulates up the conducting airways.

Left Ventricular Reservoir

The highly compliant pulmonary vessels of the prototypic 70-kg human contain ~440 mL of blood (see Table 19-2), which is an important buffer for filling of the left ventricle. For example, if one clamps the pulmonary artery of an experimental animal so that no blood may enter the lungs, the left side of the heart can suck enough blood from the pulmonary circulation to sustain cardiac output for about two beats.

Filtering Small Emboli from the Blood

The mixed-venous blood contains microscopic emboli, small particles (e.g., blood clots, fat, air bubbles) capable of occluding blood vessels. If these emboli were to reach the systemic circulation and lodge in small vessels that feed tissues with no collateral circulation, the consequences—over time—could be catastrophic. Fortunately, the pulmonary vasculature can trap these emboli before they have a chance to reach the left side of the heart. If the emboli are sufficiently few and small, the affected alveoli can recover their function. Keep in mind that alveolar cells do not need the circulation to provide them with O2 or to remove their CO2. In addition, after a small pulmonary embolism, alveolar cells may obtain nutrients from anastomoses with the bronchial circulation. However, if pulmonary emboli are sufficiently large or frequent, they can cause serious symptoms or even death. A liability of the blood filtration function is that emboli made up of cancer cells may find the perfect breeding ground for support of metastatic disease.

Biochemical Reactions

The entire cardiac output passes through the lungs, exposing the blood to the tremendous surface area of the pulmonary-capillary endothelium. It is apparently these cells that are responsible for executing biochemical reactions that selectively remove many agents from the circulation while leaving others unaffected (Table 26-3). Thus, the lung can be instrumental in determining which signaling molecules in the mixed-venous blood reach the systemic arterial blood. The pulmonary endothelium also plays an important role in converting angiotensin I (a decapeptide) to angiotensin II (an octapeptide), a reaction that is catalyzed by angiotensin-converting enzyme (see p. 841).

TABLE 26-3

Handling of Agents by the Pulmonary Circulation




PGE1, PGE2, PGF, leukotrienes

Histamine, epinephrine, dopamine

Serotonin, bradykinin

Angiotensin II, arginine vasopressin, gastrin, oxytocin

Angiotensin I (converted to angiotensin II)

PG, prostaglandin.

From Levitzky MG: Pulmonary Physiology, 4th ed. New York, McGraw-Hill, 1999.