Placental Structure and Function

Survival of the embryo and then fetus requires an effective circulatory interface with the circulation of the mother, which is provided by the placenta.²¹ Within 1 week of uterine implantation, vascular projections called chorionic villi arise from the aorta of the embryo and penetrate the uterine endometrium. As gestation proceeds, the villi increase in number and complexity; erode the endometrium; and create irregular pockets called intervillous spaces in the placenta, which fill with maternal blood. The maternal blood flowing through the intervillous spaces bathes the embryonic villi and creates an O₂-rich and nutrient-rich blood environment. As gestation progresses, the villi decrease in size but increase in number and complexity, resulting in an increased surface area that is essential for adequate maternal-fetal gas, nutrient, and waste exchange.

The maternal uterine tissues and blood vessels of the fetal chorionic villi make up the bulk of the placenta. Figure 8-5 shows a cross section of a well-developed placenta. Maternal blood flows into the intervillous space through the spiral arteries, whereas fetal blood is supplied to the villi from two umbilical arteries. Maternal and fetal blood come into close proximity but remain separated by an embryonic membrane that permits the exchange of O₂, CO₂, water, ions, various metabolic molecules, and hormones. Some maternal cells do move into fetal blood, and some fetal cells move into maternal blood and have been found in various maternal organs.

Various chemicals, hormones, bacteria, and viruses can also cross the intervillous space and cause a variety of fetal developmental problems. After exchange occurs with maternal blood, maternal blood exits through venous channels and returns to the maternal circulation. Oxygenated fetal blood leaves the chorionic villi capillaries through placental venules and returns to the fetus through a single umbilical vein. Abnormal implantation of the placenta, tearing of the placenta from the uterine wall, or decreased placental blood flow can retard intrauterine growth and in severe cases can cause fetal asphyxia and increases the risk for brain damage and respiratory distress in the immediate postnatal period.

Various factors enhance the delivery of O₂ to fetal tissues. The partial pressure gradient for O₂ between maternal blood and fetal blood drives the diffusion of O₂ into fetal blood within the chorionic villi capillaries.22,23 The maternal arterial blood has a partial pressure of O₂ (PaO₂) of approximately 100 mm Hg, which mixes with the blood in the intervillous space to produce a mean PO₂ of approximately 50 mm Hg. Fetal blood that enters the villi has a PO₂ of approximately 19 mm Hg, and the pressure gradient between maternal and fetal blood PO₂ (50 − 19 = 31 mm Hg) causes O₂ to diffuse into fetal blood. Blood leaving the villi and entering the umbilical vein has a PO₂ of approximately 30 mm Hg. Table 8-3 summarizes the normal gas and acid-base values in normal fetal umbilical arteries and veins and maternal intervillous blood. Assessment of umbilical vein blood gas data shortly after birth is a method of determining the degree of fetal asphyxiation during the birth process.

The O₂ content and delivery by fetal blood are almost the same as adult blood despite the much lower PO₂; this is due to several factors, including relatively higher content of hemoglobin (18 g/dl) and hematocrit (54%) in fetal blood and the presence of fetal hemoglobin (HbF), which has an increased affinity for O₂ and a more pronounced Bohr effect (reduced oxyhemoglobin affinity with acidosis) to enhance O₂ release.²³ Figure 8-6 illustrates how the increased O₂ affinity is manifested by a leftward shift of the fetal oxyhemoglobin dissociation curve. The P₅₀ (PO₂ that saturates 50% of the hemoglobin) is 6 to 8 mm Hg less than the P₅₀ for adult hemoglobin (HbA), which indicates the degree of the shift toward higher affinity. At birth, approximately 70% of circulating hemoglobin is HbF. HbA gradually replaces HbF during the first 6 months of extrauterine life as HbA genes in bone marrow switch on and HbF genes in the liver (major site of fetal erythrocyte development) are switched off.

Fetal Circulation

Fetal circulation is different than the circulation of the neonate after birth.²⁴ Three important bypass pathways function in the developing fetus to enhance the flow of blood to the developing organs: ductus venosus, ductus arteriosus, and foramen ovale. Oxygenated blood from the placenta is carried in the umbilical vein back to the fetal circulation via the hepatic circulatory system (Figure 8-7). Approximately one-third of this blood flows to the lower trunk and extremities. The other two-thirds flows through the ductus venosus, which bypasses the liver’s circulation and flows to the inferior vena cava. This better oxygenated blood in the inferior vena cava mixes with the venous blood returning from the lower trunk and extremities and enters the right atrium. Approximately 50% of this blood is shunted from the right atrium into the left atrium through an opening in the interatrial septum called the foramen ovale. Left atrial blood flows to the left ventricle and then to the ascending aorta, where it continues on to the brain, brachiocephalic trunk, and descending aorta. Venous blood from the superior vena cava is directed downward through the right atrium into the right ventricle and then into the main pulmonary artery.

The relatively low PO₂ and various prostaglandins in fetal blood cause the ductus arteriosus, a muscular vessel attached to the trunk of the pulmonary artery and the aorta, to dilate and the pulmonary arteries to constrict; this leads to increased pulmonary vascular resistance and higher pulmonary artery pressure than aortic blood pressure. As a result, 90% of the blood flow entering the pulmonary artery takes the path of least resistance by shunting through the ductus arteriosus and flows to the aorta. Only 10% flows into the lungs. Blood flowing through the ductus arteriosus mixes with the blood flowing through the aorta routed into the systemic circulation. Some of this blood flows to the gut, lower extremities, and placenta. Two umbilical arteries carry blood from the fetal aorta to the placenta to carry out fetal-maternal gas and nutrient exchange.

Cardiopulmonary Events at Birth

Various mechanisms work together to reduce and clear the amount of lung fluid at birth in preparation for air inflation.²⁵ Days before birth, the epithelia of the lung stop the production of lung fluid. The lung fluid is actively absorbed back into the fetal circulation. Most of the active lung water absorption is facilitated by active sodium channel activity that is stimulated by fetal and maternal thyroid hormones, glucocorticoids, and epinephrine and increasing fetal lung and blood O₂ content. In addition, some evidence suggests that the water channel aquaporin is also active in this process.²⁶ During normal vaginal delivery, approximately one-third of the lung fluid is cleared through compression of the thorax in the birth canal. The pulmonary capillaries and lymphatics clear the remaining fluid.

A newborn must develop very high transpulmonary pressure gradients during the first few breaths to open and replace the remaining lung fluid with air and establish a stable lung volume for gas exchange. These large pressure gradients overcome the opposing forces of fluid viscosity in the airways and surface tension in the alveoli. The stimulus for these initial respiratory efforts is apparently sent via peripheral and central chemoreceptors and augmented further by skin thermoreceptors.

The newborn infant is stimulated by new tactile and thermal stimuli, all of which stimulate breathing. In addition, as placental gas transfer is suddenly interrupted, the newborn quickly becomes hypoxemic, hypercapnic, and acidotic. This situation triggers strong inspiratory efforts (Figure 8-8). At first, no air enters the newborn lung until the transpulmonary pressure gradient exceeds 40 cm H₂O. As lung volume increases in a stepwise fashion with each breath, increasingly less pressure is needed to overcome the opposing forces. The volume trapped in the lung stabilizes quickly and is crucial to adequate gas exchange.

Figure 8-9 summarizes the major cardiopulmonary changes that occur during the transition from a fluid-filled lung to an air-filled lung. As the lung expands with air, and gas exchange starts within the lung, pulmonary blood PO₂ increases, PCO₂ decreases, and pH increases; this results in pulmonary vasodilation, lower pulmonary vascular resistance, and constriction of the ductus arteriosus, which facilitates greater blood flow through the pulmonary circulation. Ductus arteriosus closure is stimulated further by the loss of maternal prostaglandins. The combination of increasing alveolar air content and constriction of the ductus arteriosus promotes progressive improvement in the matching of ventilation and blood flow, which increases the PO₂ and decreases the PCO₂ of blood leaving the lungs. After the clamping of the umbilical cord, cessation of umbilical and placental blood flow causes closure of the ductus venosus and a rapid increase in systemic vascular resistance. As systemic vascular resistance increases, left-sided heart pressures increase. Left atrial pressures also increase as a result of increased pulmonary blood flow that returns from the lungs. With left-sided heart pressures now higher than right-sided pressures, the foramen ovale closes.

When this last right-to-left shunt closes, the transition between fetal and extrauterine circulations is functionally complete. Full transition occurs later as the ductus arteriosus and foramen ovale close anatomically through the formation of fibrosis. Anatomic closure of the ductus normally occurs within 3 weeks of birth. Permanent closure of the tissue flap covering the foramen ovale may take several months.

All of these changes normally occur during the first few minutes after birth and allow the newborn to achieve normal gas exchange. Many abnormal conditions can interfere with these transition events and can lead to persistence of the fetal circulation and cardiorespiratory failure.

Lower Airway and Alveoli

The human lung continues to develop alveoli for years until it reaches a stable stage, at which the total number has increased to approximately 480 million alveoli.³² All development is generally complete by 10 years of age with most occurring in the first postnatal years.³³ This development largely occurs by the formation of increasing numbers of septa in the terminal airspaces that continue to subdivide the airspace into shallow immature alveoli. These immature alveoli enlarge in size and undergo further refinement of pulmonary capillaries over the ensuing months and years.³⁴ By adulthood, the alveolar-capillary membrane has a gas exchange surface area of approximately 140 m².³⁵

It was previously thought that the above-described alveolar development process ended several years after birth. However, numerous studies in various mammals have shown that compensatory lung growth can rapidly occur in the lung when part or all of the other lung is removed.36–38 Stem cell activation in the lungs, in response to gene and mechanical stretch, appears to be responsible for alveolar development well into adulthood after loss of lung tissue.³⁹

Development of Vascular, Lymphatic, and Nervous Systems

The basic architecture of the pulmonary circulation is complete at birth. The main pulmonary trunk arises from the right ventricle and divides into left and right pulmonary arteries that supply each lung. These arteries divide further to form direct or conventional arteries and supernumerary arteries. Conventional arteries follow the airway branching, whereas supernumerary arteries follow an irregular pattern that allows substantial collateralization of flow between different regions of lung. Both types of pulmonary arteries come together to supply blood to large clusters of alveoli that are supplied by a single bronchiole. Most of the growth in the vascular system that occurs after birth includes further smooth muscle growth within the walls of arteries and arterioles and greater density and refinement of the arterioles and capillaries in the distal airway region.33,34

The respiratory system is a unique organ in that it receives a double blood supply: one from the left ventricle and one from the right ventricle. The right heart supplies the bulk of the flow to the pulmonary circulation. The left heart supplies a smaller amount of flow (approximately 1% to 2% of cardiac output) to the bronchial arteries, which arise from the aorta and supply oxygenated blood to the tracheobronchial tree. The bronchial arteries supply O₂ to the airway tissue, blood vessels, nerves, lymphatics, and visceral pleura. In addition, O₂ is directly absorbed across the airway lumen. Although the pulmonary and bronchial circulations have entirely different origins and purposes, they mix and supply blood flow to the microcirculation of the alveoli; this provides some collateral circulation and allows the shunting of blood. The lung’s double circulation benefits the entire lung in health and helps compensate for deficiencies or disease processes that can affect either circulation.

Paralleling the development of the pulmonary vascular circulation is a network of lymphatic vessels and blind lymphatic capillaries. The lymphatic vessels are located in the connective tissue tracts of the lung that surround the bronchi, bronchioles, blood vessels, nerves, and pleural membrane. They play a central role in the control of fluid and protein balance within the lung and house various defensive cells. Fluid collected from the pleural space and interstitium is carried by the pleural capillaries and vessels through the lymphatic system back to the root of the lung (hilum) where numerous lymph nodes are located.

Before birth, neuronal centers in the brainstem (medulla oblongata and pons) form for the automatic control of breathing, and various afferent and efferent nerves form to sense and control different aspects of the respiratory system. The phrenic nerves and intercostal nerves are formed long before birth and are the primary components of the somatic (motor) nervous system that carry nervous signals from the brainstem to the respiratory muscles. They innervate the diaphragm (phrenic nerves) and intercostal muscles (intercostal nerves). These muscles are primarily responsible for enlarging the thorax during inspiration and allow exhalation by relaxing and allowing the thorax and lungs to recoil back to their preinspiratory position.

Visceral control of the smooth muscle of the respiratory system is carried out by branches of the sympathetic and parasympathetic nervous systems and mediators transported to the lungs via the pulmonary circulation. Nerve fibers from the brainstem and spinal cord enter the lungs and grow in the same connective tissue tracts that surround the airways and house the blood and lymphatic vessels long before birth. Their development parallels airway and vessel development. These nervous fibers innervate the smooth muscles of the bronchioles to cause bronchodilation (sympathetic fibers), the mucous glands to produce mucus (parasympathetic), and the blood vessels to cause vasoconstriction (sympathetic). Cranial nerve X (vagus nerve) carries motor and sensory signals of the parasympathetic system. Branches from each thoracic spinal nerve carry sympathetic motor and sensory signals to and from the lungs.

Chest Wall Development, Diaphragm, and Lung Volume

The thoracic wall in infants is more compliant, and their muscles are less developed than the muscles of adults and provide little structural support. The infant thoracic cage is also more boxlike, with the ribs being horizontally oriented or elevated (Figure 8-12). In addition, the diaphragm inserts into the thoracic cage in a horizontal plane, which decreases the effective ability to enlarge the thorax.

As an infant inhales, the diaphragm moves down, but the flexible chest wall moves very little in the anteroposterior dimension as the chest wall muscles attempt to pull it upward and outward. Compounding this situation is a proportionately larger abdominal visceral content that restricts the vertical motion of the diaphragm. The ribs take on a progressively downward slope as a child grows, and by 10 years of age, the rib cage has the configuration seen in adults. Ossification of the ribs and sternum is normally complete by 25 years of age, and this, combined with muscular development, results in a stiffer chest wall that moves more in the anteroposterior dimension with inspiratory effort.

With a more compliant thorax, the resultant balance of these static forces in an infant favors a reduced lung volume. Proportionately lower lung volumes in an infant can lead to early airway closure, widespread alveolar collapse (atelectasis), ventilation/perfusion () mismatch, and resultant hypoxemia. The combination of a reduced lung volume and high O₂ consumption in an infant renders the infant more susceptible to profound hypoxemia in situations that disturb ventilation, lung volume, or matching further. Infants possess a remarkable ability to elevate their lung volume dynamically. Infants, especially infants in distress, can actively increase lung volume by trapping gas, which improves matching and gas exchange. Infants accomplish gas trapping actively by using the diaphragm during exhalation to slow expiration and to adduct (close) the vocal cords and narrow the glottis. The combination of these two maneuvers effectively regulates volume in the lung and dynamically elevates lung volume. The narrowing of the glottis or larynx during exhalation is referred to as “laryngeal braking.” Infants in respiratory distress commonly grunt, a manifestation of laryngeal braking. A more compliant chest wall contributes to suprasternal, substernal, intercostal, and subcostal retractions in distressed infants and young children (see Mini Clini).

Components of the Thoracic Wall

The thoracic cavity is formed by the tissues of the chest, upper back, and diaphragm.⁴¹ It is a cone-shaped cavity that houses the lungs and the contents of the mediastinum (Figure 8-16). It functions to protect the vital organs within and is capable of changing shape to enable air to be moved into and out of the lungs. The thoracic cavity is formed from epithelial, connective, and muscle tissues.

The various parts of the thoracic wall are shown in Figure 8-17. The outer covering of the thorax is formed by the integumentary system, which includes skin, hair, subcutaneous fat, and breast tissues. Skin is a composite of an outer epidermis and an inner connective tissue layer called the dermis. Below the dermis is a layer of subcutaneous fat. Skeletal muscle, encased in a layer of connective tissue called fascia, is found under the subcutaneous fat. Skeletal muscle tissue forms the various muscles of the chest and back and lies over and between the ribs. The ribs of the rib cage lie in the inner portion of the thoracic wall. The inner layer of the thoracic wall is lined with a serous membrane called the parietal pleura. It is apposed by another serous membrane called the visceral pleura, which covers the lung. A thin, fluid-filled pleural space forms between the parietal and visceral pleural membranes.

The rigidity of the thorax is provided by the bone tissue of the rib cage. The bony parts of the rib cage include the sternum, ribs, thoracic vertebral bones, scapula, and clavicle (Figure 8-18). The sternum is a long, vertical flat bone found on the anterior side that is composed of three bones: the manubrium, the body (or gladiolus), and the xiphoid process. The superior edge of the manubrium forms a shallow depression that is known as the suprasternal (or jugular) notch. The fused connection between the manubrium and the body is known as the sternal angle; it is also known as the angle of Louis. The sternal angle is an external marker of the point where the trachea divides into the left and right main stem bronchi. A cartilaginous joint called the costal cartilage is on the lateral edges of the manubrium and sternal body and forms the attachment between the ribs and sternum. This joint allows the rib cage to bend and permits the thorax to increase and decrease in size.

The rib cage is formed by 12 pairs of ribs.⁴¹ Rib pairs 1 through 7 are known as the true ribs because they are attached directly to the sternum. The first ribs and the upper sternum form the opening into the thorax that is called the thoracic inlet, or operculum. Ribs 8 through 12 are called false ribs because they are either indirectly attached to the sternum or not attached at all. The vertebrochondral ribs include rib pairs 8, 9, and 10, which are indirectly attached to the sternum through a common cartilaginous strap. Rib pairs 11 and 12 are called floating ribs because they are not attached to the sternum. Each rib has a sternal end; a long, curved, and relatively flat body; and a head that articulates with the thoracic vertebrae (Figure 8-19). Intercostal muscles lie between the ribs and hold them together. Just below each rib is a thoracic artery, vein, and nerve that supply blood flow and nerve communications to that region of the chest wall (see Figure 8-17).

The upper and lateral regions of the thorax house the bones of the pectoral girdles. The pectoral girdle on each side is formed by the clavicle and scapula.⁴¹ The scapula forms the socket for the shoulder joint and is stabilized or moved by skeletal muscles of the upper back. The clavicle supports and stabilizes the shoulder joint through a flexible attachment to the manubrium of the sternum.

Rib Movement

The various ribs move in different ways, and some may move more than others at different times. The first rib moves slightly, raising and lowering the sternum. Its slight motion increases the anteroposterior diameter of the chest. This action is not used during quiet breathing and becomes active only under conditions that require increased ventilation or deep breathing. Ribs 2 through 7 move simultaneously about two axes (Figure 8-20). As each rib rotates about the axis of its neck, its sternal end rises and falls. This movement increases the anteroposterior thoracic diameter in what is commonly referred to as a “pump handle”–like motion. At the same time, the rib moves about its long axis from its angle at the sternum. This motion causes the middle part of the rib to move up and down in what is commonly described as a “bucket handle.” The compound action of ribs 2 through 7 changes both the anteroposterior and the transverse dimensions in an upward and outward motion. Ribs 8 through 10 rotate in a pattern similar to that of ribs 2 through 7. However, elevation of the anterior ends of these ribs produces a small backward movement of the lower sternum that slightly reduces the thoracic anteroposterior diameter. Outward rotation of the middle section of these ribs increases the transverse diameter of the thorax. Ribs 11 and 12 participate in changing the contour of the chest in a minor way as they are pulled upward and outward in a “caliper”-like motion.

Respiratory Muscles

Changes in thoracic cavity dimension during breathing are the product of tension developed by various skeletal muscles.⁴² Collectively, these muscles are known as the respiratory muscles; their origins, insertions, somatic nervous supply, and actions are summarized in Tables 8-4 and 8-5. The diaphragm and intercostal muscles are the primary muscles of ventilation. They are active both while at rest and when the individual exhibits stress-induced increases in breathing. The accessory muscles of ventilation assist the diaphragm and intercostal muscles when ventilatory demand increases. The scalene, sternocleidomastoid, pectoral, and abdominal wall muscles are the predominant accessory muscles. Other abdominal and chest wall muscles may also function as accessory muscles.

The diaphragm is a thin, musculotendinous, dome-shaped structure that separates the thoracic and abdominal cavities (Figure 8-21).⁴³ It originates from the chest and abdominal wall and converges in a central tendon at the top of its dome. The posterior portion arises from the first three lumbar vertebrae. The lateral costal portions arise from the inner surface of ribs 7 through 12 and transverse abdominal muscles on each side. The anterior portion arises from the inner surface of the xiphoid process of the sternum. The best estimates of muscle fiber composition in the adult human diaphragm indicate that there are about 55% slow oxidative–type, 21% fast oxidative–type, and 24% fast glycolytic–type muscle fibers.⁴⁴ These findings coupled with an abundant blood supply throughout the breathing cycle help to explain in part why the diaphragm is so highly aerobic and fatigue-resistant compared with other skeletal muscles and more capable of long-term rhythmic contraction.

In an upright position and with the diaphragm relaxed, the liver forces the dome of the right hemidiaphragm upward approximately 1 cm higher than the left hemidiaphragm at the end of a quiet exhalation. The highest portion of the right dome sits at the eighth or ninth thoracic vertebra posteriorly and at the fifth rib anteriorly. The left diaphragmatic dome sits at the ninth or tenth thoracic vertebra posteriorly and the sixth rib anteriorly. Movements of the hemidiaphragms are synchronous in healthy subjects. When lying down in a supine position, the weight of the abdominal contents forces the diaphragm farther up into the thoracic cavity. During quiet breathing, the diaphragm is responsible for approximately 75% of the change in thoracic volume.⁴⁵ When the muscle fibers of the diaphragm are tensed during inspiration, the dome of the diaphragm is pulled down 1 to 2 cm; this results in enlargement of the thoracic cavity and compression of the abdominal contents. During maximal inspiration, the diaphragm can be pulled down approximately 10 cm. Exhalation results when diaphragmatic tension decreases, and the diaphragm returns to its relaxed position.

Increased lung volume causes the diaphragm to flatten out. Contraction of a flattened diaphragm can result in tension on the lower ribs that causes them to be pulled inward, resulting in compression of the thoracic cavity. This condition can occur in individuals with severe gas trapping as a result of emphysema or asthma. To compensate, these individuals must recruit other muscles to enlarge the thorax. Less efficient breathing and excessive muscle work result. Nonpulmonary diseases can also affect diaphragm function. Abdominal wall muscle tensioning (splinting) owing to pain, abdominal distention with fluid (ascites), or other causes of rigidity of the abdominal wall can interfere with diaphragmatic descent during inspiration.

Functionally, the diaphragm is divided into a right and a left hemidiaphragm. Each hemidiaphragm is innervated by a phrenic nerve that arises from branches of spinal nerves C3, C4, and C5.⁴³ Spinal cord injuries at or above the level of the third cervical vertebrae result in diaphragmatic paralysis. In this situation, the individual has lost all nervous control of the respiratory muscles and is unable to breathe. Unilateral phrenic nerve injury or disease to one side can spare the other nerve and permit unilateral ventilation.

Although the diaphragm is the primary ventilatory muscle, it is not essential for survival. Limited, short-term ventilation is possible using accessory muscles, even if the diaphragm is paralyzed. If either or both of the hemidiaphragms are paralyzed, the affected component or components remain in a resting position. During deep inspiration, the paralyzed diaphragm rises as other ventilatory muscles reduce the intrathoracic pressure. During quiet breathing, the paralyzed diaphragm may remain immobile or may move in either direction. The pressures above and below a paralyzed diaphragm tend to make it rise during inspiration.

The diaphragm normally does not actively participate in exhalation. During exhalation, it returns to its resting position during the passive recoil of the lungs and thorax. During forced exhalation, abdominal wall muscles compress the abdominal cavity and increase pressure in the abdominal cavity. The diaphragm is forced upward, and the lungs compress, forcing gas from them. The diaphragm performs important functions other than ventilation; it aids in generating high intraabdominal pressures by remaining fixed while the abdominal muscles contract, facilitating vomiting, coughing, sneezing, defecation, and parturition.

During quiet breathing, the diaphragm does most of the work. Other muscles are slightly active during quiet breathing and become more active with forceful breathing. These other muscles are generally known as the accessory muscles of breathing.

The accessory muscles of inspiration include various muscles in the neck, chest, and upper back. Eleven pairs of intercostal muscles are found between the ribs.⁴⁶ The external intercostal muscles (Figure 8-22) originate on the upper ribs and attach to the lower ribs. The fibers of these muscles run at an oblique angle between the ribs. When they generate tension, they lift the ribs upward and cause the thoracic cavity to enlarge the thorax (Hamberger mechanism). They receive nerve signals from the intercostal nerves that arise from thoracic spinal nerves (T1-12). They are more active during the inspiratory phase of forceful breathing and are thought to play a role in stabilizing excessive rib motion during forceful breathing.⁴⁷

Three pairs of scalene muscles (scalenus anterior, scalenus medius, and scalenus posterior) arise from the lower five or six cervical vertebrae and insert on the clavicle and first two ribs (Figure 8-23). They lift the upper chest when active. The scalene muscles are slightly active during resting inhalation and become more active with forceful inspiration, especially when ventilatory demands increase.⁴⁸ Such instances may occur in healthy subjects during exercise or in patients who have pulmonary disease. In healthy subjects, inspiratory efforts against a closed glottis or obstructed airway activate the scalene muscles. When alveolar pressure decreases to −10 cm H₂O, scalene muscles are active in all subjects. The scalene muscles are largely inactive during expiratory efforts but can become active to fixate the ribs as abdominal muscles contract during forceful exhalation such as coughing.

Sternocleidomastoid muscles (Figure 8-24) originate from the manubrium and clavicle and insert on the mastoid process of the temporal bone. Normally, this muscle flexes and rotates the head and is active during shoulder shrugging. When the head is held in an upright position by tensing the trapezius muscle of the upper back and neck, the sternocleidomastoid muscles can function to lift the upper chest. They receive nerve impulses from branches of the accessory nerves (cranial nerve XI) and cervical nerves C1 and C2. These muscles are active during forceful inspiration and become visible as thick bands on either side of the neck during the inspiratory phase in an individual who is in respiratory distress. This motion increases the anteroposterior diameter of the chest.⁴⁹

The major and minor pectoralis muscles are broad fan-shaped muscles of the upper anterior chest (Figure 8-25). The pectoralis major originates on the humerus and inserts onto the clavicle and sternum. The pectoralis minor originates from the anterior region of the ribs 3 through 5 and inserts onto the scapula. When these muscles receive impulses from the pectoral nerves, they normally function to adduct the arms in a hugging motion. They are also capable of generating some anterior thoracic lift when the arms are braced on a surface in front of a subject. Individuals who have chronic shortness of breath often use these muscles by sitting in a “tripod” position. This position is generated by sitting upright and leaning forward with both arms braced on a table or other stationary object.

The trapezius muscles are flat triangular muscles that are located on the upper back and neck (Figure 8-26). They arise from the occipital bone, seventh cervical vertebra, and all of the thoracic vertebrae. They insert onto the scapulae and lateral third of the clavicles. Their action is to rotate the scapulae, lift the shoulders, and flex the head up and back. They become active during forceful inspiration by helping to brace the head and allowing the sternocleidomastoid muscles to lift the thorax.

The accessory muscles of exhalation become active during forceful breathing (see Table 8-5). Generally, these muscles act to compress the thoracic cavity and facilitate exhalation. The internal intercostal muscles (see Figure 8-22) lie between the ribs and just behind the external intercostal muscles. They originate along the inferior border of the upper ribs and insert into the superior border of the lower ribs. The muscle fibers of the internal intercostal muscles run downward and less obliquely than the external intercostal muscle fibers. This orientation causes these muscles to pull the ribs together, which results in compression of the thoracic cavity. They are stimulated by branches of the intercostal nerves and are most active during forceful exhalation. They also become active toward the end of deep inhalation and act to antagonize the lifting effect of the external intercostal muscles, which effectively stabilizes rib motion during forceful exhalation.⁴⁹

When the abdominal wall muscles contract, they compress the abdominal cavity. This compression forces the diaphragm upward, compressing the thoracic cavity. The abdominal muscles include pairs of external oblique, internal oblique, transverse abdominis, and rectus abdominis muscles (Figure 8-27).⁵⁰ The external oblique muscles are the outermost layer of abdominal wall muscle and lie over the lateral aspects of the abdominal cavity. They originate on the anterior surface of the lower eight ribs and abdominal aponeurosis and insert into the linea alba (a connective tissue band on the midanterior surface of the abdomen), iliac crest, and inguinal ligament. The internal oblique muscles lie just underneath the external oblique muscles. They originate on the lumbar vertebrae, iliac crest, and inguinal ligaments and insert into the pubis and costal region of the lower ribs; this results in a fiber orientation that is at right angles to the external oblique muscles. The transverse abdominis muscles lie below the internal oblique muscles. Muscle fibers of the transverse abdominis run around the lateral wall of the abdomen by originating on the lower six ribs, iliac crest, and inguinal ligaments and inserting into the linea alba. The rectus abdominis muscles are a pair of muscular bands that run vertically on the anterior surface of the abdomen. These muscular bands arise from the pubis, travel upward over the abdominal cavity, and insert into the costal region of ribs 5, 6, and 7 and the xiphoid process of the sternum.

The abdominal wall muscles receive nerve impulses from branches of the lower intercostal and iliohypogastric nerves. When forceful contraction of the abdominal wall muscle group occurs, it results in increasing intraabdominal pressure, which forces the diaphragm upward and compresses the thorax.

Myographic analysis of each of the different abdominal wall muscles reveals that they are active during resting and forceful exhalation.⁵¹ They become more active when the elastic recoil of the lung and thorax cannot provide the needed expiratory flow during forceful exhalation, such as coughing, sneezing, talking loudly, and playing wind-powered musical instruments.⁵² The most active muscle of the group during resting and forceful exhalation in most body positions is the transverse abdominis, and the least active muscles are the rectus abdominis muscles. The abdominal muscles can also contribute to inspiration by contracting at end-exhalation. This contraction reduces end-expiratory lung volume so that the chest wall can recoil outward, assisting the next inspiratory effort.⁵³ Elevating abdominal pressure increases both the length and the radius of curvature of the diaphragm. Both of these effects result in greater transdiaphragmatic pressure for a given contractile tension. In patients with chronic obstructive pulmonary disease, any increase in ventilatory demand significantly increases the use of the abdominal muscles. Loss of effective use of the abdominal wall muscles results in a marked inability to exhale forcefully and to cough effectively.

Pleural Membranes, Space, and Fluid

The thoracic cavity is subdivided into the mediastinum and the left and right pleural cavities. The centrally located mediastinum contains the trachea, esophagus, heart, great vessels, and other organs.⁵⁴ The left and right pleural cavities contain the lungs. The surfaces of the inner thoracic wall, mediastinum, and lungs are covered with serous membranes called the pleural membranes (see Figure 8-17). The parietal pleural membrane lines the chest wall and mediastinum, whereas the lungs are covered by the visceral pleura. Both membranes are constructed from a thin surface layer of mesothelial cells, and below the layer of mesothelial cells is a layer of connective tissue that houses blood vessels, lymphatic vessels, and nerve fibers.⁵⁵ Numerous microscopic openings, called stomata, are found in the surface of the pleura and are surrounded by mesothelial cells. The stomata open into the lymphatic drainage system of the pleural membrane. The parietal pleura contains sensory fibers that are responsible for the painful sensation that is associated with inflammation of the pleura—a condition called pleurisy.

The space between the membranes is called the pleural space and is filled with approximately 0.26 ml/kg, or about 18 ml in a 70-kg adult, of pleural fluid.⁵⁶ Pleural fluid is a clear fluid with a pH of 7.60 to 7.65 that has few cells, a small amount of protein (about 1 g/dl), and glucose and electrolytes in concentrations that approximate those of plasma. The small volume of pleural fluid is spread out over the entire surface of both lungs and functions as a lubricant to reduce friction as the lungs move within the thorax and as an airtight seal that adheres together the two pleural membranes. Pleural fluid is secreted and reabsorbed by the two pleural membranes. A little more than half of the pleural fluid is thought to be produced by the parietal pleura according to Starling forces of filtration. Pleural fluid is formed from the systemic blood flow to each pleura. Blood pressure–driven filtration is supplied to the parietal pleura by blood flow from the intercostal arteries, and the bronchial circulation of the lung supplies most of the blood flow to the visceral pleura.

It is estimated that the pleurae produce 150 to 250 ml of pleural fluid per day.⁵⁷ Most of the fluid is thought to be absorbed by the visceral pleura capillaries (according to Starling forces), and the rest is cleared by drainage through the lymphatic stomata of parietal pleura, by solute-coupled liquid absorption, and through some transcytosis. Fluid and solutes or cells cleared by lymphatic drainage are carried by the pulmonary lymphatics to the hilar region, where they enter the major lymphatic vessels that drain back to the subclavian veins and right heart.

The angle where the costal parietal pleura joins the diaphragmatic parietal pleura is known as the costophrenic angle. It is located in the right and left lateral and inferior regions of the thoracic cavities. This angle is clearly visible and is an important landmark in the normal chest radiograph. Normally, it is a sharp angle of about 30 to 45 degrees. Excess fluids between the visceral and parietal pleura tend to pool here in an upright individual. This pooling of fluid causes the angle to appear blunted or flattened to 90 degrees when viewed in the chest radiograph.

Mediastinum

The mediastinum lies between the left and right pleural cavities that contain the lungs (see Figure 8-16). The mediastinum is bounded on either side by the pleural cavities, anteriorly by the sternum, posteriorly by the thoracic vertebrae, inferiorly by the diaphragm, and superiorly by the thoracic inlet. The mediastinum can be subdivided into three subcompartments.⁵⁴ Between the sternum and pericardium is an anterior compartment, which contains the thymus gland and lymph nodes. The middle compartment contains the pericardium, heart, great vessels, phrenic and upper portions of the vagus nerves, trachea, portions of the right and left main stem bronchi, and lymph nodes. The posterior compartment contains the thoracic aorta, esophagus, and thoracic duct. Also found in the posterior mediastinum are the sympathetic nervous system ganglionic chains and lower portions of the vagus nerve and lymph nodes.

Lungs

The lungs are multilobed, cone-shaped, spongelike organs that lie within the pleural cavities (Figure 8-28). They are pink at birth and develop a gray coloration with age. Average adult lungs are hollow low-density organs that occupy a volume of approximately 3.5 L and weigh approximately 900 g.⁵⁵ The organs within the mediastinum bulge into the left hemithorax, resulting in a narrower and slightly smaller left lung. The liver below the right lung elevates the right diaphragm and results in a slightly shorter right lung.

The lungs extend from the diaphragm to a point 1 to 2 cm above the medial third of the clavicles. The uppermost regions are called the apices. At end-expiration, the anterior lower lung borders extend to approximately the sixth rib at the midclavicular line. Laterally, the lower lung border is at the eighth rib at the midaxillary line. The top of the lungs, viewed posteriorly, extends upward from the eighth or ninth thoracic vertebra to the first thoracic vertebra. The diaphragm rises and falls with resting breathing between the ninth and twelfth thoracic vertebrae.

The anterior, lateral, and posterior lung surfaces lie and move against the thoracic inner wall. The medial surfaces of the lungs lie in close contact to the mediastinal surfaces. Figure 8-29 shows the medial surfaces of the lungs and the opening in this region, which is called the hilum. The main stem bronchi, blood vessels, lymphatics, and nerves that enter or exit the lung all pass through the hilum.

Each lung is divided into two or three lobes (see Figure 8-28), which are separated by one or more fissures. The right lung has upper, middle, and lower lobes. The left lung has only an upper and a lower lobe. Both lungs have an oblique fissure that begins on the anterior chest at approximately the sixth rib at the midclavicular line. These fissures extend laterally and upward until they cross the fifth rib on the lateral chest in the midaxillary line. The fissures continue to the posterior chest to approximately the third thoracic vertebra. The right lung also has a horizontal or “minor” fissure that separates the upper and middle lobes. This horizontal fissure extends from the fourth rib at the sternal border to the fifth rib at the midaxillary line.

The lungs are elastic organs that can expand when inflated with air and recoil back to their resting volume when exhalation occurs. Lung elasticity stems from surface tension forces in the alveoli and from the elastic properties of the tissues and various connective tissue fibers. Three different fiber systems form a scaffold that supports the structure of the lungs as tension develops in them with inflation.⁵⁸ The axial system, primarily composed of collagen and reticulin fibers, originates in the hilum and extends outward in all of the airway walls almost all the way to the alveolar region. The septal fiber system, composed of collagen, reticulin, and elastin, supports the alveolar walls and capillaries. The peripheral fiber system, primarily composed of collagen, originates in the outer viscera and extends into the lung tissue to divide up the lung tissue effectively into interlobular regions.

Collectively, these connective tissue fibers function to provide support to the airway walls, lungs, and effective gas exchange membrane as it is stretched during inflation. When a lung is removed from the chest cavity, it quickly collapses to a smaller size. The same occurs if air or fluid enters into the pleural space; it is possible that individual lobes can collapse as the result of airway obstruction and gradual diffusion of air from the lobe. This tendency of the lung to collapse is counteracted by the tendency of the thoracic wall to spring outward and to hold the lung inflated. The “tension” developed by these two opposing tendencies results in the development of subatmospheric intrapleural pressure.

Pulmonary Circulation

The pulmonary circulation is supplied with blood from the right heart (Figure 8-30) at a flow rate that is equal to the entire blood volume each minute at rest.⁵⁹ O₂-reduced systemic venous blood flows to the right heart via the inferior and superior venae cavae. This blood is pumped to the lungs by the right ventricle through the pulmonic semilunar valve and on to the trunk of the pulmonary artery. The trunk of the pulmonary artery passes upward and divides into right and left pulmonary arteries just below the point of tracheal bifurcation into left and right main stem bronchi (the carina). The pulmonary arteries accompany the right and left main stem bronchi through the hilar opening into the lungs and continue to divide along with the airways. The pulmonary arteries divide to form two types of arteries: conventional arteries, which continue to follow the airway branching, and supernumerary arteries, which branch at 90-degree angles from the conventional arteries and travel outside the common path. Supernumerary arteries account for about 25% of the cross-sectional area of the pulmonary arterial system. As the arteries continue to divide and become more numerous, they become smaller in diameter and possess greater smooth muscle in their medial walls. Both sets of arteries form arterioles that connect to and supply blood to the microcirculation of the respiratory zone of the lung.

The pulmonary arterial system continues to divide into increasing numbers all the way to the distal airspaces, where they subdivide and form dense “sheetlike” beds of alveolar capillaries that are located within the walls of the alveoli and just below approximately 90% of the alveolar surface (Figure 8-31). The wall of the pulmonary capillary is formed by endothelial cells. At rest, the pulmonary capillary bed contains 60 to 80 ml of blood and can expand to 200 ml through dilation and recruitment of collapsed capillaries during conditions of higher cardiac output (e.g., exercise).⁶⁰ Pulmonary blood is collected from the capillaries by the pulmonary venules, which combine into larger veins. Similar to their arterial counterparts, the veins also form conventional and supernumerary types of veins that drain blood from the pulmonary capillary beds. The pulmonary veins possess less smooth muscle in their medial walls and have thinner walls than similar-sized pulmonary arteries. The veins follow the same connective tissue path that houses the bronchi and arteries and coalesce into larger and fewer vessels. Four major pulmonary veins—superior and inferior veins from each lung—exit through the hila and return arterialized blood to the left atrium of the heart for delivery to the systemic circulation (see Figure 8-30).

Bronchial Circulation

A separate arterial supply called the bronchial circulation supplies blood to the airways from the trachea to the bronchioles and to most of the visceral pleurae.⁶⁴ The metabolic needs of the lung are comparatively low, and much of the lung parenchyma is oxygenated by direct contact with inspired gas. The bronchial circulation is a branch of the systemic circuit and is supplied with blood from the aorta via minor thoracic branches. Blood flow through the bronchial circulation constitutes about 1% to 2% of the total cardiac output.

A single right bronchial artery, which supplies the right lung, arises from the upper intercostal artery, the right subclavian artery, or an internal mammary artery. Two bronchial arteries supply the left lung, and they branch directly from the upper thoracic aorta. Bronchial arteries follow their respective bronchi. Two or three branches accompany each subdivision of the conducting airway. The bronchial arterial circulation terminates in a plexus of capillaries that anastomose with the alveolar-capillary bed. Bronchial venous blood drains through the azygos, hemiazygos, and intercostal veins to the right atrium, and some drains through the pulmonary capillaries to the pulmonary veins and to the right left atrium. Figure 8-32 shows the interrelationship and comingling of the pulmonary and bronchial circulatory systems.

The bronchial and pulmonary circulations share an important compensatory relationship.⁶⁵ Decreased pulmonary arterial blood pressure tends to cause an increase in bronchial artery blood flow to the affected area. This compensation minimizes the danger of pulmonary infarction, as sometimes occurs when a blood clot (pulmonary embolus) enters the lung. Similarly, loss of bronchial circulation can be partially offset by increases in pulmonary arterial perfusion. The adult lung does not require the bronchial circulation to remain viable, as evidenced by the success of lung transplantation, which does not preserve the bronchial circulation. However, this circulation apparently plays a more important role in lung development, helps to preserve gas exchange during various congenital cardiac conditions, and appears to compensate in certain pulmonary diseases (e.g., pulmonary fibrosis) for the gradual obstruction of the pulmonary circulation.

Lymphatics

The lymphatic system of the lungs is an extensive system of lymphatic vessels, lymph nodes, the tonsils, and the thymus gland.⁶⁶ The primary function of the lymphatic system is to clear fluid from the interstitial and pleural spaces to help maintain the fluid balance in the lungs. The lymphatic system also plays an important role in the specific defenses of the immune system. It removes bacteria, foreign material, and cell debris via the lymph fluid and through the action of various phagocytic cells (e.g., macrophages) that provide defense against foreign material and cells that are able to penetrate deep into the lung. It also produces various lymphocytes and plasma cells to aid in defense. Both roles are essential for maintaining normal function of the respiratory system.

Most of the pulmonary lymphatic system consists of superficial and deep vessels.⁶⁷ The superficial (pleural) vessels that drain the lung surface and pleural space are more numerous over the lower half of the upright lung. Many of these vessels are broad ribbon-like, reservoir-type vessels that are closely associated with the blind lymphatic capillaries. The deep (peribronchovascular) conduit-like vessels contain bicuspid valves to direct flow and travel through the connective tissue tracts that house the larger pulmonary vessels in the deeper lung tissue. Both drain the blind lymphatic capillaries in the respective regions. The deeper lymph vessels are closely associated with the small airways but do not extend into the walls of the alveolar-capillary membranes. The lymphatic vessels are thin-walled vessels that contain little connective and muscle tissue in their walls.

Lymph fluid is collected by the loosely formed lymphatic capillaries and drains through the lymph vessels toward the hilum. The fluid is propelled through the lymphatic system by the collective actions of the valves that direct flow toward the hilum and by the combined milking actions of smooth muscle contractions in the deeper conduit-like vessels and ventilation, which squeezes the lymphatic vessels.⁶⁸ Lymph fluid flow from the lungs can be increased after an injury to the pulmonary capillaries that results in increased leakage (e.g., acute respiratory distress syndrome) or from pulmonary capillary hypertension secondary to heart disease (e.g., left-sided heart failure).

The lymph vessels emerge from the hilum of each lung and drain lymph fluid through a series of lymph nodes that are clustered about each hilum and the mediastinum. From there, lymph travels through various inferior, superior tracheobronchial and paratracheal lymph nodes within the mediastinum (Figure 8-33). The lymph fluid rejoins the general circulation after passing through the right lymphatic or thoracic duct, which drains into the jugular, subclavian, or innominate veins. The lymph fluid mixes with blood and returns to the heart.

Lymphatic channels are not usually visible on chest radiographs. They may be detected if they are distended or thickened by disease. The “butterfly” pattern that radiates from the hilar region of both lungs during acute development of pulmonary edema is thought to be largely the result of interstitial and lymph vessel distention with fluid. In this situation, the lymphatic drainage system has been overwhelmed by a sudden and excessive surge of fluid from the circulation. The development of a pleural effusion is also evidence that the lymphatic system is unable to remove excess fluid in the lung.

Nervous Control of the Lungs

All of the major structures of the respiratory system are innervated by branches of the peripheral nervous system: the autonomic and somatic branches (Figure 8-34).⁶⁹ The somatic system provides voluntary and automatic motor control and sensory innervation to the chest wall and respiratory muscles. Most of the major motor nerves that carry nervous signaling to the respiratory muscles are summarized in Tables 8-4 and 8-5. The autonomic nervous system signaling to and from the lungs is carried through efferent and afferent pathways. These pathways carry unconscious autonomic nervous system motor signals to smooth muscles and glands and various sensory signals back to the brain.

Autonomic innervation of the lungs is carried from the brainstem through branches of the right and left vagus nerves (cranial nerve X) and from the spinal cord to four or five thoracic sympathetic ganglia that lie just laterally to the spinal cord.⁷⁰ Both contribute fibers to the anterior and posterior pulmonary plexus at the root of each lung. From these plexus, sympathetic and parasympathetic fibers enter the lung through the hilum and innervate various structures.

Efferent Pathways

The parasympathetic nervous preganglionic fibers exit the brainstem via the two vagus nerves. On entry into the chest, the vagus nerve branches to the larynx. This branch is called the recurrent laryngeal nerve. Each vagus nerve also develops a branch called the superior laryngeal nerve. The external branch of this nerve supplies the cricothyroid muscle. The internal branch provides sensory fibers to the larynx. The recurrent laryngeal nerves provide the primary motor innervation to the larynx. Damage to laryngeal nerves can cause unilateral or bilateral vocal cord paralysis, depending on which branches are involved. Hoarseness, loss of voice, and an ineffective cough may result.

After forming ganglia and postganglionic nerve fibers, parasympathetic and sympathetic nerve fibers enter the lung through the hilum and run parallel to the airways as they branch (Figure 8-35). Parasympathetic fibers form their ganglia much closer to the target tissues (e.g., bronchioles, glands, and blood vessels) and have much shorter postganglionic nerve fibers. Most of the sympathetic fibers form their ganglia along the spinal cord and then form longer postganglionic fibers that penetrate the lungs and end on the airway smooth muscle and glands. The largest branches accompany the bronchi. The smallest nerve fibers parallel the pulmonary veins. Both sympathetic and parasympathetic postganglionic efferents innervate the smooth muscle and glands of the airways and the smooth muscles of the pulmonary arterioles. They influence the diameter of the airway by causing more or less tension in the smooth muscles that wrap around the airway and influence glandular secretion. The smooth muscles in the medial wall of the pulmonary arterioles cause constriction when tensed and dilation when relaxed. The combined effects of the parasympathetic and sympathetic nervous activity, which generally oppose each other’s action, result in a balanced control of airway and vessel diameter and glandular secretion.

The parasympathetic postganglionic fibers generally secrete acetylcholine as their primary neurotransmitter when they receive signals from the brainstem. Acetylcholine binds to M₃ muscarinic cholinergic receptors and causes airway smooth muscle constriction, blood vessel dilation, and glandular secretion. The sympathetic postganglionic fibers are much less developed in comparison. The sympathetic postganglionic fibers in the lung primarily secrete norepinephrine, and the adrenal glands release epinephrine into the circulation when they receive sympathetic signals from the spinal cord. Epinephrine and norepinephrine bind to alpha-adrenergic receptors of blood vessels to cause constriction and to beta-adrenergic receptors of the bronchial airway and vessel smooth muscles to cause relaxation and dilation of the airways and blood vessels.

The airways are provided with a third autonomic pathway that is neither parasympathetic nor sympathetic in action.⁵⁸ The nonadrenergic, noncholinergic (NANC) system nerve fibers travel within the vagus nerve to each lung. When active, the NANC nerve endings release a neurotransmitter that promotes the production of nitric oxide, which causes the relaxation of airway smooth muscle and dilation. The NANC system is also thought to be capable of causing bronchoconstriction through the local reflex release of substance P and neurokinin A.

Afferent Pathways

Most afferent fibers follow pathways from the lungs to the central nervous system in the vagus nerve. The vagus afferent pathways are activated by a variety of different receptors within the lung that are sensitive to inflation, deflation, and chemical stimulation.⁷¹ Slow adapting stretch receptors (SARs) are concentrated in the small and medium-sized airways and are closely associated with the airway smooth muscle. Lung inflation and airway stretch stimulate the SARs, and they continue to signal and do not adapt and drop their signaling rate—hence their name. In the mucosal layer of the airway, rapid adapting receptors (RARs) sense changes in tidal volume, respiratory rate, and changes in lung compliance and respond to a wide variety of mechanical and chemical irritants. In addition, a variety of other chemical and congestion sensors, when active, seem to modify the sensation of breathing and modify the breathing pattern (e.g., cough reflex and response to alveolar congestion). Additional receptors are located outside the lungs; they include respiratory muscle proprioceptors that sense the stretch state of the muscles and peripheral chemoreceptors that sense the chemical condition of blood (e.g., O₂, CO₂, and H⁺ concentration) that are involved in the control of ventilation.

Pulmonary stretch SARs and RARs progressively discharge during lung inflation and are linked to inhibition of further inflation. This is a type of negative feedback known as the inflation reflex. It was originally described by Hering and Breuer and continues to bear their names. The inflation reflex is thought to be actively involved with controlling the depth of breathing. Studies in animals indicate that these receptors influence the duration of the expiratory pause between breaths. The inflation reflex is probably very weak or absent during quiet breathing in healthy adults, but there appears to be evidence of its activity in newborns.⁷²

Another reflex that is associated with SAR and RAR activity is the Head paradoxical reflex.⁷³ This reflex stimulates a deeper breath rather than inhibiting further inspiration. It may be the basis for occasional deep breaths or gasps. Deep breaths or sighs occur with normal breathing, presumably preventing alveolar collapse. Head reflex may also be responsible for gasping in newborn infants as they progressively inflate their lungs.

Irritant or mechanical RARs are found mainly in the posterior wall of the trachea and at bifurcations of the larger bronchi. These receptors respond to various mechanical, chemical, and physiologic stimuli and behave as irritant receptors. The stimuli include physical manipulation or irritation, inhalation of noxious gases, histamine-induced bronchoconstriction, asphyxia, and microembolization of the pulmonary arteries. Stimulation of the irritant RARs can result in bronchoconstriction, hyperpnea, glottic closure, cough, and sneeze.⁷⁴ Stimulation of these receptors can also cause a reflex slowing of the heart rate (bradycardia). This response is referred to as the vagovagal reflex. It may occur during tracheobronchial suctioning, intubation of the airway, or bronchoscopy. These procedures can cause significant mechanical irritation of the airway.

Unmyelinated slow-conducting C-fiber endings (also known as juxtacapillary or J receptors), which are present in the walls of the bronchial and terminal airway region, have been linked to a breathing reflex pattern associated with mechanical stretch, pulmonary congestion, and exposure to various chemicals (e.g., capsaicin, phenylbiguanide, CO₂, and autacoids).75,76 When C-fibers become activated, signals are sent back to the brainstem via the vagus nerve. Rapid, shallow breathing results. C-fiber activation has also been shown to cause bradycardia, hypotension, bronchoconstriction, mucus production, and apnea in experimental animals.⁷⁷ Stimulation of these receptors may contribute to the sensation of dyspnea and, in severe cases, the vagovagal reflex, which can complicate pulmonary edema, pulmonary embolism, and pneumonia.

Nasal Cavity and Sinuses

There are two flared openings called alae that form the external nares. The alae enclose a space on each side called the vestibule. The vestibules have hairs that act as a gross filter. Located posterior to the vestibules are the openings to the internal nose, or the anterior nares. The left and right nasal cavities are formed by cartilage and numerous skull bones. The roof is formed by the nasal, frontal, sphenoid, and ethmoid bones. The septum separating the two cavities is formed by cartilage and the ethmoid and vomer bones. The lateral walls are created by the maxilla, lacrimal, and palatine bones. The floor of the cavity, or palate, is primarily formed by the maxilla. Three shelflike bones protrude into the cavity from the lateral walls. These bony shelves are called the superior, middle, and inferior conchae, or turbinates.

The conchae function to increase the surface area and complexity of the nasal cavity, enabling the nasal cavity to work as a passageway, filter, humidifier, and heater of inhaled airway. The posterior openings of the nasal cavity are called the internal nares and are formed in part by the flexible soft palate.

The surface of the nasal cavity is covered with epithelia. The anterior portion is covered with stratified squamous cells and possesses hair follicles and hair. This is the same type of tissue that forms the epidermis of skin. The middle portion of the cavity is covered with a mucous membrane that is composed of ciliated pseudostratified epithelia and goblet cells. The mucous membrane functions to secrete mucus, to humidify inhaled air, and to trap inhaled particles. Just below the mucous membrane is an extensive network of veins that form a venous plexus. These vessels supply water and heat to the gas within the nasal cavity. Inflammation of this mucous membrane is brought on by irritation or infection. This is produced by vasodilation and increased vessel leakage. The consequence of nasal cavity inflammation is partial or complete blockage of the air passage. The vessels of the venous plexus can rupture as a result of breathing dry air or the passage of foreign bodies through the nose. Rupture of these vessels can cause considerable nasal bleeding. The posterior portion of the nasal cavity is covered with stratified squamous epithelium similar to the tissue covering of the nearby oral cavity.

Within the skull bones and around the nasal cavity are the sinuses (Figure 8-37). These hollow spaces are named for the bones in which they are found.⁸⁰ The sinuses are lined with a mucous membrane and drain into the nasal cavity through numerous ducts. They function to reduce the weight of the skull, to strengthen the skull, and to modify the voice during phonation.

The nasal cavity functions to conduct air to and from the respiratory tract, to condition inhaled gas, to act as a region to which sinus and eye fluid drain, and to contain olfactory sensors for the sensation of smell. Conditioning inhaled gas helps to defend the respiratory tract and involves filtering, heating, and humidifying air. Filtration of inhaled air is carried out by the hair in the anterior portion of the cavity and the sticky mucous membrane that covers the complex surface of the cavity. Filtration is enhanced by the flow pattern through the nasal cavity. Inspired gas is accelerated to a high velocity through the anterior nares. It changes direction sharply as it enters the internal nasal cavity. This pattern causes particles larger than 10 µm in diameter to have an impact on the nasal mucosa. Ciliary action or nose blowing clears these particles. Past the external nares, the cross-sectional area increases; this results in a decrease in gas velocity. Turbulence increases because of the narrow convolutions of the passages. Low velocity and turbulence combine to remove any remaining particles. Filtration is based on impaction, sedimentation, and diffusion of various sized particles.

Surface fluids originate from the goblet cells and submucosal glands. This fluid lining has mild antibacterial properties. Mucosal fluids also remove water-soluble irritant gases such as sulfur dioxide. Ciliary activity in the nasal mucous membranes helps to transport the mucus produced so that it can be cleared. Foreign matter is typically cleared from the nasal cavity by sniffing and swallowing. During exhalation, the heated and moist expired air passes over the concha and is cooled, and the excess moisture deposits on the concha as condensation to help retain and recycle water. These defense and conditioning mechanisms help to ensure that inspired air is free from particulate and bacterial contamination and that it is heated and humidified to 37° C and 100% relative humidity by the time it reaches the trachea. In addition, the mucous membrane contains chemoreceptors that send signals to the olfactory nerve for the sensation of smell in the superior portion of the cavity just above each of the superior conchae.

Oral Cavity

Air can also enter and exit from the respiratory tract through the oral cavity (Figure 8-38). The anterior roof of the oral cavity is called the hard palate and is formed by the maxillary bone. The posterior portion is known as the soft palate because of its soft tissue composition and ability to move upward to seal off the nasal cavity. The end of the soft palate hangs down into the posterior portion of the oral cavity. This part of the soft palate is called the uvula. The walls of the oral cavity are formed by the cheeks, and the floor is dominated by the tongue.

The uvula and the surrounding walls control the flow of air and fluid and food during eating, drinking, sneezing, coughing, and vomiting. The tongue is involved in mechanical digestion, taste, and phonation. The posterior surface of the tongue is supplied with many sensory nerve endings. These nerves produce a vagal gag reflex when stimulated, which protects the lungs from aspiration. This reflex must be considered when passing tubes or instruments through the mouth in conscious or semiconscious patients. The lingual tonsils are located at the base of the tongue.

The mucosal surfaces of the oral cavity also provide humidification and warming of inspired air. These surfaces are much less efficient than the nose. Saliva is produced by major and minor salivary glands. Saliva functions primarily as a wetting and digestive agent for food but provides some humidification of inspired gas. The oral cavity ends at a double web on each side, called the palatine folds. The palatine tonsils sit between these folds on each side (see Figure 8-38). The palatine tonsils are vascularized lymphoidal tissues that play an immunologic role, especially in childhood.

Reflexes of the mouth, pharynx, and larynx help to protect the lower respiratory tract during swallowing.⁸¹ These protective functions can be severely compromised during anesthesia or unconsciousness. Loss or compromise of these important reflexes can result in aspiration of bacteria-colonized saliva or food and can cause pulmonary infection and asphyxiation in severe cases.

Pharynx

The posterior portion of the nasal and oral cavities opens into a region called the pharynx. The entire pharynx is lined with stratified squamous epithelium. The pharynx is subdivided into the nasopharynx, oropharynx, and hypopharynx, or laryngopharynx. The nasopharynx lies at the posterior end of the nasal cavity and extends to the tip of the uvula. Numerous foreign particles impact the surface of the nasopharynx. Located in this region are the two pharyngeal tonsils (also called the adenoids) that are on either side of the lateral and posterior walls of the pharynx. They function to monitor and interact with the particles inhaled through the actions of the lymphoid cells located here. In the same region, there are two openings into the left and right eustachian tubes that link the upper airway with the middle ear (see Figure 8-36). The eustachian tubes drain fluid out of the middle ear and allow gas to move in or out of the middle to equalize pressure on either side of the tympanic membrane.

The oropharynx is located in the posterior region of the oral cavity that spans the space between the uvula and the upper rim of the epiglottis. This region is also equipped with a pair of palatine tonsils that are located on the lateral walls of the oropharynx. These tonsils can become chronically swollen and cause partial airway obstruction. If the swelling is excessive and the individual has numerous repeat throat and ear infections, these tonsils can be removed by the surgical procedure known as a tonsillectomy.

The region below the oropharynx is known as the hypopharynx. It extends from the upper rim of the epiglottis to the opening between the vocal cords. The tissues of the nasopharynx and hypopharynx can move and undergo large changes of shape during speech and swallowing. Immediately below the hypopharynx, the digestive and respiratory tracts separate.

During unconsciousness, the muscles of the tongue and hypopharynx can relax and allow the tongue and other soft tissues to collapse and occlude the opening of the hypopharynx. This condition can result in partial to complete blockage of the upper airway and limit air movement to and from the respiratory tract. This condition is a primary cause of obstructive sleep apnea.

Larynx

The larynx lies below the hypopharynx and is formed by a complex arrangement of nine cartilages and numerous muscles (Figure 8-39).⁸² Generally, it functions to protect the respiratory tract during eating and drinking and in phonation. The thyroid cartilage forms most of the upper portion of the larynx and is generally referred to as the Adam’s apple. This cartilage is named for the thyroid gland that lies over its outer surface. Just below the thyroid cartilage is the cricoid cartilage, which is the only laryngeal structure that forms a complete ring of cartilage around the airway and is the most narrow region of the upper airway in infants. A membrane of connective tissue called the cricothyroid ligament spans the space between the thyroid and cricoid cartilage. This membrane is occasionally used as the location for placement of an emergency prosthetic airway in patients who have a life-threatening blockage of the upper airway.

The cartilaginous and leaf-shaped epiglottis lies within and is attached to the thyroid cartilage by a flexible joint. In adults, it is 2 to 4 cm long, 2 to 3 cm wide, and 2 to 5 mm deep. It is not easily visualized in adults, but it can be seen in small children and crying infants because of its higher position. While air breathing, the thyroid cartilage slides down and remains apart from the epiglottis, allowing air to move in and out of the respiratory tract. The epiglottis functions to help prevent liquids and food from entering the respiratory tract by forming a tight seal with the thyroid cartilage during swallowing. The act of swallowing is a complex series of muscular contractions that results in early closure of the vocal cords, upward motion of the thyroid cartilage, and movement of the epiglottis down and back to form a tight seal as food is propelled to the back of the mouth and toward the esophagus.82,83

The inlet to the larynx lies below and behind the base of the tongue. Figure 8-40 shows the inlet as it appears when viewed with a laryngoscope. The base of the tongue is attached to the epiglottis by three folds. These folds form a space between the tongue and the epiglottis called the vallecula, which is a key landmark in oral intubation (see Figure 8-36).

Within the thyroid cartilage and just above the cricoid cartilage are the arytenoid cartilages. The vocal ligaments or true cords span the opening in the larynx by attachments to the thyroid and movable arytenoid cartilages that lie posteriorly. Just above and laterally are the vestibular folds or false cords. The true vocal cords are composed of connective tissue and muscle and covered with a mucous membrane. They have poor lymphatic drainage and are susceptible to inflammation, which can result in airway obstruction. In the same region are the corniculate and cuneiform cartilages that function to support the soft tissue on either side of the vocal cords. The opening formed between the vocal cords is called the glottis. During swallowing, the vocal cords close to help to protect the lower airways. Damage to the cricoarytenoid joint, which allows the arytenoid cartilages to rotate, can result in inability to open the vocal cords properly and cause difficulties with speaking and breathing. Laryngeal spasm and resultant partial or total temporary airway closure is brought about by laryngeal stimulation and reflex spasm of various laryngeal muscles that cause closure of the false and true vocal cords.

The muscles of the larynx are innervated by the inferior laryngeal nerve, which is also called the recurrent laryngeal nerve. It is a motor nerve that branches from the vagus nerve. Impulses carried by this nerve are important in phonation and swallowing. Injuries to this nerve can cause partial or complete paralysis of the vocal cords and inability to swallow correctly. This nerve injury results in difficulty with speech and in severe cases can cause airway obstruction as a result of vocal cord closure.

Patent Upper Airway

The relative positions of the oral cavity, pharynx, and larynx are crucial to the patency of the upper airway in unconscious patients. In upright subjects, the head and neck form a 90-degree angle with the axis of the pharynx and larynx (Figure 8-41, B). With loss of consciousness, the head flexes forward and decreases this angle (see Figure 8-41, A). This positional change can partially or completely obstruct the upper airway. Extension of the head and lower jaw into the “sniff” position alleviates this obstruction (see Figure 8-41, C). Extension of the head moves the tongue away from the rear of the pharynx. This technique is used to maintain the airway in unconscious patients and facilitates placement of artificial airways.

Lower Respiratory Tract

The airways of the tracheobronchial tree extend from the larynx down to the airways that participate in gas exchange. Types of airways and their dimensions are summarized in Table 8-7. Each branching of an airway produces subsequent generations of smaller airways. The first 15 generations are known as conducting airways because they function to convey gas from the upper airway to the structures that participate in gas exchange with blood. The microscopic airways beyond the conducting airways that carry out gas exchange with blood are classified as the respiratory airways.

Trachea and Bronchi

The trachea extends from its connection to the cricoid cartilage down through the neck and into the thorax to the articulation point between the manubrium and body of the sternum (angle of Louis). At this point, it divides into two main stem bronchi (Figure 8-42). The adult trachea is approximately 12 cm long and has an inner diameter of about 2 cm. Figure 8-43 shows the different layers of tissue that form the trachea. The outermost layer is a thin connective tissue sheath. Below the sheath are numerous C-shaped cartilaginous rings that provide support and maintain the trachea as an open tube. The typical adult trachea has 16 to 20 of these rings. The inner surface of the trachea is covered with a mucous membrane. In the posterior wall of the trachea is a thin band of tissue, called the trachealis muscle, that supports the open ends of the tracheal rings. The esophagus lies just behind the trachea.

The trachea moves normally. The cartilaginous rings armor the trachea so that it does not collapse during exhalation. Some compression occurs when the pressure around the trachea becomes positive. During a strong cough, the trachea is capable of some compression and even collapse. The negative pressure generated around the trachea during inhalation causes it to expand and lengthen slightly.

The trachea lies midline in the upper mediastinum and branches into right and left main stem bronchi (see Figure 8-42). At the base of the trachea, the last cartilaginous ring that forms the bifurcation for the two bronchi is called the carina. The carina is an important landmark that is used to identify the level where the two main stem bronchi branch off from the trachea; this is normally at the base of the aortic arch. The right bronchus branches off from the trachea at an angle of about 20 to 30 degrees, and the left bronchus branches with an angle of about 45 to 55 degrees (Figure 8-44). The lower angle of branching of the right bronchus results in a greater frequency of foreign body passage into the right lung because of the more direct pathway.

Mini Clini

Only Ventilating the Right Lung

The placement of an endotracheal tube through the upper airway and into the trachea is a common airway management technique to facilitate mechanical ventilation.

 Problem

After placement of an endotracheal tube in a 70-kg patient who is having a myocardial infarction, it is noted that breath sounds are heard in the right chest only and that the patient’s oxygenation is deteriorating. Is the airway placement the cause of the problem? How can this problem be avoided?

Answer

Ideally, an endotracheal tube of proper diameter should be placed in the trachea so that the distal end of the airway is 3 to 5 cm above the carina. If the endotracheal tube is advanced too far, as in this case, it more often enters the right main stem bronchus because of the straighter path that this bronchus offers. The left main stem bronchus branches from the trachea at a greater angle and is less likely to be intubated. A right main stem intubation results in right lung ventilation only, and the left lung continues to receive pulmonary blood flow but does not oxygenate it adequately. To avoid the problem in this patient, the airway should not be advanced more than 24 cm past the lips. This is the typical depth that the endotracheal tube is advanced in a 70-kg patient. At this point, the patient is auscultated with a stethoscope to confirm breath sounds in both lungs, and then a chest radiograph can be taken to confirm the airway position.

Each bronchus carries gas to and from one lung. It enters the lung with the pulmonary vessels, lymph vessels, and nerves through the hilum. The bronchus branches repeatedly within each lung to supply gas to separate regions of each lung.

Lobar and Segmental Pulmonary Anatomy

The lungs have an apex and a base and are subdivided by fissures into lobes.⁵⁵ The lobes are subdivided further into bronchopulmonary segments (Table 8-8 and Figure 8-45). Each segment is supplied with gas from a single segmental bronchus. Controversy exists over the exact number of segments; some anatomists accept that each lung has 10 segments, whereas others maintain that the right has 10 and the left has 8. Knowledge of segmental anatomy is important in the physical examination of a patient to identify the location of a defect such as an infection site or a tumor mass in the lungs.

TABLE 8-8

Bronchopulmonary Segments*

Segment	Number	Segment	Number
Right Upper Lobe		Left Upper Lobe
Apical	1	Upper division
Posterior	2	Apical-posterior	1 and 2†
Anterior	3	Anterior	3
Right Middle Lobe		Lower division (lingula)
Lateral	4	Superior lingula	4
Medial	5	Inferior lingula	5
Right Lower Lobe		Left Lower Lobe
Superior	6	Superior	6
Medial basal	7	Anterior basal	7 and 8
Anterior basal	8	Lateral basal	9
Lateral basal	9	Posterior basal	10
Posterior basal	10

^*The subdivisions of the lung and bronchial tree are fairly constant. Slight variations between right and left sides are noted by combined names and numbers.

^†Some authors believe that the left lung should be numbered so that there are eight segments, where the apical-posterior is numbered 1 and the anteromedial is numbered 6.

 Rule of Thumb

The 60-to-40 Rule

The right lung is slightly larger than the left lung because of the location of the heart. The right lung has a sizable middle lobe, and the left lung has a smaller lingular segment in the left upper lobe. For purposes of estimating the contribution of the right and left lungs to ventilation and to gas exchange, the 60-to-40 rule is sometimes used. The right lung is assumed to provide 60% of the ventilation/gas-exchange capacity, and the left lung is assumed to provide the remaining 40%. For example, if a patient required removal of the entire left lung (pneumonectomy), a 40% decrease in lung volume would be expected.

The airways continue to divide as they penetrate deeper into the lungs. The segmental bronchi bifurcate into about 40 subsegmental bronchi, and these divide into hundreds of smaller bronchi. Thousands of bronchioles branch from the smaller bronchi. Bronchioles do not possess cartilage in their walls. Tens of thousands of terminal bronchioles arise from the bronchioles. Terminal bronchioles are the smallest conducting airways and function to supply gas to the respiratory zone of the lung.

With further divisions, the number of airways increases tremendously. The cross-sectional area of the conducting system increases exponentially. At the level of the terminal bronchioles, the cross-sectional area is approximately 20 times greater than that at the trachea. Gas flow in these airways conforms to the laws of fluid physics. Increased cross-sectional area reduces the velocity of gas flow during inspiration. When inspired gas reaches the level of the terminal bronchiole, its average velocity has fallen to about the same rate as the speed of diffusing gas molecules.⁸⁵ Low-velocity gas movement at the level of the terminal bronchiole and beyond is physiologically important for two reasons. First, laminar flow develops, which minimizes resistance in the small airways and decreases the work associated with inspiration. Second, low gas velocity facilitates rapid mixing of alveolar gases. This mixing provides a stable partial pressure of O₂ and CO₂ in the alveolar environment that supports stable diffusion and gas exchange.⁸⁶

Histology of the Airway Wall

All of the conducting airways from the trachea to the bronchioles have walls that are constructed of three layers (Figures 8-46 and 8-47): an inner layer that forms a mucous membrane called the mucosa, which is primarily composed of epithelia; a submucosa composed of connective tissue, bronchial glands, and smooth fibers that wrap around the airway; and an outer covering of connective tissue called the adventitia.⁸⁷ The cartilaginous rings and plates found in larger airways are located in the adventitia.

The mucosa is composed of many different types of specialized epithelial cells that sit on top of a basement membrane. The most common type of epithelia are the numerous pseudostratified, ciliated, columnar epithelia.⁸⁸ The pseudostratified epithelial cells are held together toward their surface or apical end through three types of junctions—apical tight junctions, zonal adherens junctions, and desmosome-type junctions—and they anchored in place to the basement membrane.⁸⁹ The junctions, especially the tight junctions, play an important role in the maintenance of fluid and electrolyte (e.g., Cl⁻) transport across the mucous membrane. These junctions prevent the movement of fluids and electrolytes between the apical surface and basal surfaces of the airway. Disturbances in this transport (e.g., Cl⁻ transport malfunction in cystic fibrosis transport receptor membrane channels) can lead to mucus and mucus transport abnormalities.

Near the base of the pseudostratified cells are large numbers of basal cells. The basal cells contribute to the appearance of a “pseudostratified” cellular layer. Basal cells mature into pseudostratified cells and are thought to play an important role in repair of the mucous membrane after diseases and injury. Dispersed between the pseudostratified epithelia are mucus-producing goblet cells and serous cells (in newborns) and the openings of submucosal bronchial glands. The bronchial glands are exocrine glands formed by secretory epithelial cells that sit on the basement membrane, which extends down into the lamina propria and into the submucosa. The bronchial glands are wrapped with myoepithelial cells. Myoepithelial cells contract and squeeze the bronchial gland when they receive signals from parasympathetic nerve fibers. In this region are neuroendocrine cells (also known as Kulchitsky cells) that are often organized into small clusters called neuroepithelial bodies.⁹⁰ Neuroendocrine cells are connected to the vagus nerve and are thought to function during lung development, are hypoxia and stress-strain sensors, and secrete various bioactive chemicals (e.g., serotonin, calcitonin, and gastrin-releasing peptide). Lymphocytes are also found intermixed with these cells, and it is thought that they may be migratory in nature.

Below the epithelial and basement membrane of the mucosa is the lamina propria.⁸⁹ The lamina propria is composed of loose fibroelastic connective tissue, lymphoid tissue, and a dense layer of elastic fibers. Below the lamina propria lies the submucosa. The submucosa of large airways contains bronchial glands, a capillary network, smooth muscle, some elastic tissue, and cartilage in larger airways. Bronchial glands vary in size up to 1 mm in length and connect to the bronchial surface via long, narrow ducts. The number of these glands increases significantly in diseases such as chronic bronchitis. Mast cells are also found in the submucosa and release numerous and potent vasoactive and bronchoactive substances such as histamine.⁹¹ Histamine causes vasodilation and bronchoconstriction, acting directly on smooth muscle. The triggering of mast cell release of its various substances and the resultant inflammation and bronchospasm of the airway are characteristic of the pathologic changes of asthma.

The various secretory cells (primarily goblet cells) of the mucosa and bronchial glands of the submucosa contribute to the production of mucus.⁹² Normally, the respiratory tract produces about 100 ml of mucus per day. Most of the mucus formed in the larger airways is produced by the bronchial glands. Goblet cells contribute more in the smaller airways. The amount and composition of mucus produced can increase and change with airway irritation and diseases such as chronic bronchitis and asthma.⁹³ Mucus is spread over the surface of the mucus membrane to a depth of about 7 µm and is propelled by the ciliated epithelia toward the pharynx. The outer layer of mucus is more gelatinous and is called the gel layer. The inner layer is much more fluid-like and is referred to as the sol layer. The mucus normally produced is a nearly clear fluid with greater viscosity than water. It is a mixture of 97% water and 3% solute.⁹² The solute portion is produced primarily by goblet cells and bronchial glands; it is called mucin and is composed of protein (predominantly glycoproteins, proteoglycans, and IgA and IgG), lipids (primarily neutral lipids), and minerals (mainly inorganic electrolytes). The glycoprotein, lipid, and water content of mucus provides its viscoelastic gel nature. Viscoelastic refers to the ability of mucus to deform and spread when force is applied to it.

Mucus functions to protect the underlying tissue. It helps to prevent excessive amounts of water from moving into and out of the epithelia.⁹² It shields the epithelia from direct contact with potentially toxic materials and microorganisms. It acts like sticky flypaper to trap particles that make contact with it. This makes mucus an important part of the pulmonary defenses. The production of mucus is stimulated by local mechanical and chemical irritation, release of proinflammatory mediators (e.g., cytokines), and parasympathetic (vagal) stimulation.

The ciliated pseudostratified epithelia play a crucial role in the defense of the respiratory tract by propelling mucus toward the pharynx. Ciliated cells are found in the nasal cavity and all the airways from the larynx to the terminal bronchioles. Each of the pseudostratified cells possesses about 200 cilia on its luminal surface.⁸⁹ Under the electron microscope, the surface of the mucus membrane looks like a “shag carpet” of cilia with about 1 to 2 billion cilia per square centimeter. Each cilium is an extension of the cell with an average length of about 6 µm and diameter of about 0.2 µm. A cross-sectional view through the cilium reveals it to be constructed of one inner and nine outer pairs of microtubules that are encased in the cell membrane. The outer pairs of microtubules are interlinked by a filamentous protein called nexin. From each of the outer pairs of microtubules, protein filaments called dynein extend toward the adjacent pair of microtubules. Each of the outer pairs also extends a protein spoke toward the central pair of microtubules. The presence of Mg²⁺ and ATP within the cilium causes the dynein arms and spokes to attach and slide along the outer and inner microtubules, similar to the action of actin and myosin. This action results in rapid bending of the cilium that resembles a whipping motion (Figure 8-48).

The cilia “stroke” at a rate of about 15 times per second, which produces a sequential motion of the cilia called a metachronal wave.⁹⁴ The metachronal “wavelength” is approximately 20 µm and propels surface material in a specific direction. In the nose, this motion propels material back to the pharynx. From the bronchioles up to the larynx, it moves material toward the pharynx. The stroking action of millions of cilia propels the surrounding mucus at a speed of about 2 cm/min. This action is commonly referred to as the mucociliary escalator. In healthy lungs, this mechanism allows inhaled particles to be removed within 24 hours. The control and coordination of ciliary motion are not totally understood and represent some of the many fascinating properties of pulmonary tissues.

The production of mucus and the rate of ciliary beating are sensitive to various conditions and chemicals. Mucus production increases when the respiratory tract is irritated by particles and by various chemicals and during increased parasympathetic nervous stimulation.⁹³ Ciliary beating can be effectively slowed or stopped if the viscosity of the sol layer is increased by exposure to dry gas. Ciliary motion is also slowed or stopped after exposure to smoke, high concentrations of inhaled O₂, and drugs such as atropine.

The smooth muscle of the airways varies in location and structure. In the large airways (e.g., the trachea), smooth muscle is bundled in sheets. In smaller airways, smooth muscle forms a helical pattern that wraps the airway in bundles in decreasing quantities as the airways branch and become smaller. Muscle fibers crisscross and spiral around the airway walls. This placement reduces the diameter of the airway and shortens it when the muscle contracts. This pattern of smooth muscle continues but thins out on reaching the smallest bronchioles. The tone of the smooth muscle is increased and results in bronchospasm by the activity of the parasympathetic nervous system (release of acetylcholine) and proinflammatory mediator release from mast cells, inflammatory cells, and neuroendocrine cells.

The adventitia is a sheath of connective tissue that surrounds the airways. It is interspersed with bronchial arteries, veins, nerves, lymph vessels, and adipose tissue. Between the submucosa and adventitia of the large airways are incomplete rings or plates of hyaline cartilage, which provide structural support for the larger airways. The small airways depend on transmural pressure gradients and the “traction” of surrounding elastic tissues to remain open. During a forced expiration, pressures across the walls of the small airways exceed the supporting forces of the elastic tissues. As a result, the small airways can collapse. The cartilage in the larger airways prevents their collapse during such maneuvers.

The cells of the respiratory mucosa change as they progress into the smaller airways (Figure 8-49). As the thickness of the airway walls decreases, bronchial glands become fewer in number. At the bronchiolar level, the number of ciliated cells decreases. Simple columnar and cuboidal epithelial cells begin to predominate and are interspersed with goblet cells. In this region, large numbers of Clara cells, nonciliated cuboidal cells with apical granules, are found. It is thought that these cells play a role in degrading various xenobiotic oxidants via cytochrome P-450, contribute proteins for surfactant production, synthesize various lipids, and play a role in lung repair by being able to differentiate into other important epithelial cells in the mucosa after injury.⁹⁵

Respiratory Zone Airways

The terminal bronchioles begin about 12 to 15 generations beyond the trachea (Figure 8-50).⁹⁶ There are about 16,000 terminal bronchioles with airway opening diameters of about 700 µm. This yields a combined cross-sectional area opening that is almost 100 times that of the main stem bronchi. All of the airways down to and including the terminal bronchioles carry or conduct gas flow to and from the airways that participate in gas exchange with blood. The airways from the nares to and including the terminal bronchioles constitute the conducting zone airways, which do not participate in gas exchange. These airways constitute the anatomic dead space of the respiratory system, which is rebreathed with each breath. In an adult human, the volume filling the airways of the anatomic dead space is approximately 2 ml/kg of lean body weight, or about 150 ml in a typical adult.

Branching of the terminal bronchioles gives rise to unique airways called respiratory bronchioles. Respiratory bronchioles are approximately 0.4 mm in diameter and have walls that are formed largely from flattened squamous epithelia and a thin outer layer of connective tissue. They have some ciliated cells at the connection with the terminal bronchiole, generally lack mucus-producing cells, and have rings of smooth muscles where they branch to form alveolar ducts. Respiratory bronchioles have a dual function. Similar to conducting airways, they not only conduct gas flow but also have small outpouchings known as alveoli in their walls. The alveoli and their pulmonary capillary bed enable the respiratory bronchioles to carry out gas exchange. The respiratory bronchioles constitute a transitional zone type of airway.

A single terminal bronchiole supplies a cluster of respiratory bronchioles. Collectively, this unit is referred to as the acinus, or primary lobule. Each acinus comprises numerous respiratory bronchioles, alveolar ducts, and approximately 10,000 alveoli (Figure 8-51). The adult lung is thought to contain more than 30,000 acini. Each acinus is supplied with pulmonary blood flow from a pulmonary arteriole, and blood is drained away from several acini through a pulmonary venule. In addition, each acinus is equipped with a lymphatic drainage vessel and nervous fibers. These features make the primary lobule the functional unit of the lungs. Gas molecule movement in this region is largely via diffusion rather than convective flow, which occurs in larger airways.

Millions of alveolar ducts branch from the respiratory bronchioles (Figure 8-52). Alveolar ducts are tiny airways only 0.3 mm in diameter, and their walls are composed entirely of alveoli. Each alveolar duct ends in a cluster of alveoli, which is frequently referred to as an alveolar sac. Each alveolar sac opens into about 16 or 17 alveoli, and about one-half of the total number of alveoli are found in this region.

Alveoli

More recent estimates suggest that the number of alveoli in adult lungs range from 270 to 790 million, with an average of about 480 million.³² The number of alveoli increases with the height of the subject. Alveolar size varies with lung volume and averages about 0.2 mm in diameter when the lung is inflated to its functional residual volume. Figure 8-53 shows alveoli in a normal rat lung at different states of inflation and how their shapes change. When inflated at and beyond the functional residual volume (see Figure 8-53A-C), alveoli have a polyhedral shape that results from numerous flat walls rather than a curved spherical structure. Alveoli found in the apical regions of the vertical lung have greater diameters than alveoli in the basal regions as a result of the gravitational effects. Alveoli in the basal regions are partially collapsed as a result of the weight of the organ.

The alveolar walls or septa are formed by various cell types that are arranged to provide a thin surface for gas exchange and strength.⁹⁷ The alveolar septa are covered with extremely flat squamous epithelia called type I pneumocytes (Figure 8-54). Although they represent only about 8% of all the cells found in the alveolar region, type I cells cover about 93% of the alveolar surface.⁹⁸ These cells form a “patchwork”-like surface that covers the alveolar capillaries and forms the gas exchange surface of the alveolus. At their edges where they meet one another, they form tight junctions that help to limit the movement of material into the alveolar airspace from the interstitial space just below. They are held in place and supported from below by a network of collagen and elastin fibers. They are susceptible to injury and apoptosis (programmed cell death) from inhaled particles (e.g., cigarette smoke), bacterial infection, and excessive concentrations of inhaled O₂.

Interspersed on the alveolar surface and concentrated in the corners of the alveolar septa are type II pneumocytes, which are cuboidal epithelia with apical microvilli (Figure 8-55). These cells are twice as numerous as the type I cells, but they occupy only 7% of the alveolar surface.⁹⁸ Type II cells do not function as gas exchange membranes as the type I cells do. They (along with the Clara cells) manufacture surfactant, store it in vesicles called lamellated bodies, and secrete it onto the alveolar surface.⁹⁹ Surfactant is primarily composed of phospholipids (dipalmitoylphosphatidylcholine) and proteins (surfactant proteins A through D). It functions to reduce the surface tension of the alveolus, sheds water from the alveolar surface, helps to prevent alveolar surface tension-driven collapse, improves lung compliance, reduces the work of breathing, and protects the alveolar surface. Normally, surfactant is removed from the alveolar space continuously by type II cells and macrophages. The type II cells recycle about 50% of it, whereas the macrophages primarily remove it through catabolism.¹⁰⁰

Although the lungs do not have stem cells in the classic sense, the type II cells do have a “stem cell”–like action. They can proliferate and differentiate into type I cells to repopulate and repair the alveolar surface after injury.¹⁰¹ They are also involved in alveolar defense through surfactant production and the release of some cytokines that trigger inflammation.

Macrophages are another common cell found in the alveolar region.⁹⁸ They can move from the pulmonary capillary circulation by squeezing through openings in the alveolar septa and then move out onto the alveolar surface. They are defensive cells that patrol the alveolar region and phagocytize foreign particles and cells (e.g., bacteria). They can present portions of the foreign particles and bacteria to lymphocytes as part of the immune response and contain various digestive enzymes (e.g., trypsin) that break down the material they engulf.

Within the interalveolar septum is an interstitial space that contains matrix material and the pulmonary capillaries. Also found in the interstitial space are bands of elastin fibers and a collagen fiber matrix.⁵⁸ These fibers support the alveolar cells and the shape of the alveolus. Small openings are located in the alveolar septa. Some of the openings allow gas to move from one alveolus to another. These are called the pores of Kohn. Other openings connect alveoli with secondary respiratory bronchioles. These passageways are called the canals of Lambert. All of these alveolar openings and passageways facilitate the collateral movement of gas and help maintain alveolar volume.¹⁰²

Blood-Gas Barrier

Gas exchange between alveolar gas and pulmonary capillary blood occurs across the alveolar-capillary membrane. In a typical adult, this blood-gas barrier stretches over a surface area of approximately 140 m² and is less than 1 µm thick over most of that area.¹⁰³ This makes the membrane more than 50 times larger than the area covered by skin and more than 2000 times thinner.

The blood-gas barrier is composed of many different layers through which O₂ and CO₂ diffuse (Figure 8-56). The outermost layer is a very thin film of fluid composed primarily of surfactant that forms into a tubular myelin matrix. Below the surfactant fluid layer is the thinly stretched type I cell. The delicate structure of type I cells makes them highly susceptible to injury from toxins carried to them by either airborne or blood-borne routes. The interstitial space and its contents lie below. Within this space are basement membranes, matrix material connective tissue fibers, and the alveolar capillary.⁵⁸ The capillary wall is formed from thin, flat squamous epithelia called endothelial cells that form a thin tube by connecting together at their edges with tight junctions. Within the capillary lies the plasma and, finally, the erythrocytes. Both O₂ and CO₂ cross through the membrane via partial pressure-driven diffusion.

The blood-gas barrier is not equal in thickness and chemical content from side to side (see Figure 8-56). On one side of the alveolar wall, the type I cells and capillary endothelial cells lie close together with a thin interstitial space. This part of the blood-gas barrier is, on average, 0.2 to 0.3 µm thick, and it is where the alveolar capillary bulges into the alveolar space.¹⁰³ On the other side, where there is a thicker interstitial space with greater fiber, matrix, and nuclear material content, the barrier can be more than 3 to 10 times thicker. This difference between the two sides functionally results in “faster-weaker” and “slower-stronger” diffusion sides of the blood-gas barrier.

The interstitial space within the alveolar septum contains a network of fibers that form a kind of connective tissue skeleton that holds the alveolar structures in place and together.¹⁰⁴ The fibers within the alveolar septum are part of the continuum of connective tissue fibers that are found in the pleural surface and in the airway walls that extends all the way to the root of the lung in the hilar region. Elastin and collagen fiber bands are formed by fibroblasts into a network within the interstitial space into which the capillaries are woven. Also around the fibers and capillaries is a nonliving matrix of fluid and solutes. The weaving path taken by the capillaries passes them from the thick to the thin sides of the blood-gas barrier as they extend through the septum. In the thin side, the basement membranes of the endothelial and type I cells fuse into a structure called the lamina densa, which is formed from type IV collagen.¹⁰⁵ In the thick side, thick bands of type I collagen and elastin are found. The type I cells and endothelial cells are attached to either side of the lamina densa by a series of protein fibers collectively known as laminins. Laminins effectively bind together the blood-gas barrier into a three-part laminate that results in a relatively strong and thin structure that can normally, with the additional support offered by the capillary network, withstand the everyday stress of alveolar and capillary stretch.¹⁰⁶

However, conditions of pulmonary hypertension (e.g., capillary pressure >30 mm Hg during congestive heart failure and high-altitude pulmonary edema) and excessive tidal volume and airway pressure during positive pressure ventilation (e.g., tidal volume >6 ml/kg and airway pressures >30 cm H₂O) can result in stress failure of the blood-gas membrane. Stress failure results in endothelial or type I cell stretching and shearing injuries. Extreme examples are known to occur in racehorses that experience exercise-induced pulmonary hemorrhaging as a result of developing excessively high pulmonary vascular pressures (e.g., pulmonary capillary pressures 100 mm Hg).

 Rule of Thumb

The 30 : 30 Rule

Pulmonary hypertension (e.g., capillary pressure >30 mm Hg) and excessive tidal volume and airway pressure during positive pressure ventilation (e.g., tidal volume >6 ml/kg and airway pressures >30 cm H₂O) can result in stress failure of the blood-gas membrane.

Summary Checklist

• Many different genes regulate the development of the respiratory system from conception through adult life. Many pulmonary diseases are caused by genetic abnormalities.

• The development of the respiratory system follows a well-defined schedule; interruptions or insults in the course of development can result in respiratory disease at birth and in adulthood.

• Fetal circulation and respiration differ markedly from circulation and respiration in the postnatal period.

• The transition from intrauterine to extrauterine life involves a nonaerated, fluid-filled lung converting to an efficient air-filled organ of gas exchange.

• Closure of the foramen ovale and ductus arteriosus are important events in the transition to extrauterine life.

• The thorax houses and protects the lungs; it is also a movable shell that makes ventilation possible.

• The diaphragm is the primary muscle of ventilation; together with the accessory muscles and thoracic structures, it provides the ability to move large volumes of gas into and out of the lungs.

• The lungs receive blood flow from the pulmonary circulation for gas exchange and the bronchial circulation to support airway and pleural tissue metabolism.

• The pulmonary circulation is capable of acting as a reservoir, removing blood clots and numerous mediators and activating important vasoactive agents.

• Motor and sensory neurons innervate the muscles of ventilation and various lung tissues. Autonomic neurons conduct motor and sensory signaling to control various tissues and sense various activities.

• The upper respiratory tract heats and humidifies inspired air. Its various structures also protect the lungs against foreign substances.

• The lower respiratory tract conducts respired gases from the upper airway to the respiratory zones of the lung. It contains many structures that help clear and defend the lung.

• The airways branch into lobes in both the right and the left lungs; these lobes consist of various segments.

• The respiratory bronchioles, alveolar ducts, and alveoli provide a large, yet extremely thin membrane for the exchange of O₂ and CO₂ between air and blood. Disruption of the blood-gas barrier can occur from excessive capillary pressures and lung inflation and from exposure to various toxins (e.g., 100% O₂).