The respiratory tract is lined with specialized epithelia and encased by specialized support structures.

The main function of the respiratory system is to maintain external respiration. In other words, the respiratory system must enable the body to inhale and exhale air and make the exchange of gases between the blood and the air possible. Various parts of the respiratory system must thus be lined with specialized epithelia that support these functions.

The nasal and tracheobronchial mucosa. The epithelium of the nasal and tracheobronchial mucosa is pseudostratified and contains mucus-secreting and ciliated cells. The mucus-secreting cells produce mucus, which keeps the air spaces moist and also serves as a mechanical protective barrier and a receptacle for foreign particles and bacteria. The submucosa also contains larger mucous glands, which contribute mucus and fluid that covers the surface of the air spaces. Note that the epithelium of the mucosa also contains scattered neuroendocrine cells, the function of which has not been fully elucidated. Stem cells, which are important for the replacement of the more differentiated mucosal cells under both physiologic and pathologic conditions, are also scattered throughout the submucosa.

Because the nasal air spaces and the tracheobronchial tree need to be kept patent, their walls contain cartilage. Bony structures in the nasal air passages have the same protective functions. In the tracheobronchial tree the air spaces contain smooth muscle cells, which are thought to regulate the contraction or dilatation of these air spaces designed for conductance and distribution of air in the lungs.

The caliber of the air spaces diminishes gradually, and as the air duct branches their diameter decreases. Their structure also changes. Most notably, as the bronchi become smaller and smaller they contain less and less cartilage, and ultimately they transform into bronchioli, which are devoid of cartilage. Finally, the smallest air ducts, called terminal bronchioli, transform into respiratory bronchioli, which open up into alveolar sacs and alveoli.

Alveoli. These terminal parts of the respiratory system are lined with type I and type II pneumocytes. Type II pneumocytes produce surfactant, a surface-active substance that maintains alveolar patency. Type I pneumocytes are in close contact with alveolar capillaries and form with them the alveolar-capillary units, the elementary respiratory functional units of the lung.

Lungs are enclosed in the thoracic cage, which protects them from external injury but also contributes to their rhythmic expansion and reduction in size.

The thoracic cage consists of bones and striated muscles (Fig. 5-3). It has two principal functions:

Figure 5-3 Chest wall and respiratory muscles. The lungs are enclosed in the chest wall, which consists of bones (ribs, sternum, clavicles, scapula, and the vertebral column) and muscles. The muscles include inspiratory and expiratory muscles of the thorax, neck, abdomen, and diaphragm.

The lungs receive venous blood, which is oxygenated in the lungs and distributed through the arterial circulation.

The lungs receive the venous blood from the right heart, which in turn is the main confluence of the superior and inferior venae cavae. The blood enters the lungs through the pulmonary artery, which branches into progressively smaller branches. Ultimately the blood enters into capillaries, which are found in the alveolar septa, thus forming the alveolar-capillary units (Fig. 5-4). The red blood cells of the venous blood release CO₂, which enters the alveolar spaces and is exhaled into the outside air. Oxygen inhaled from the air crosses the alveolar membrane that is formed from the attenuated cytoplasm of type I pneumocytes. Thereafter it passes through the capillary membranes, enters the blood, and binds to the hemoglobin of red blood cells. The oxygenated blood leaves the alveolar-capillary units and enters the pulmonary venules, from which it reaches the pulmonary veins, the left heart, and ultimately the arterial circulation.

Figure 5-4 Alveolus and the alveolar-capillary unit. The alveolus is lined with type I and type II pneumocytes, lying on a basement membrane that separates them from the interstitial spaces around the alveolar capillaries. The interstitium contains a few fibroblasts and scattered lymphocytes and macrophages. Some macrophages, called alveolar macrophages, are also normally found inside the alveoli.

Several cellular systems protect the lungs from airborne pathogens, allergens, and harmful particulate material.

The air inhaled through the nose or the mouth contains potentially noxious agents, including viruses, bacteria, and various organic and inorganic particles. The most important protective mechanisms (Fig. 5-5) are as follows:

Figure 5-5 Defense mechanisms of the lungs. The airways protect the body from foreign particulate matter and bacteria. These defense mechanisms include a mechanical barrier, mucus, and mucociliary transport aided by the movement of cilia in the upper respiratory tact, trachea, and bronchi. Mobile phagocytic cells (macrophages) also protect the lungs by secreting cytokines. Lymphocytes of the mucosa-associated system include both B and T cells. Surfactant secreted by type II pneumocytes also protects the alveoli. White blood cells may enter the lungs from the alveolar capillaries to enhance the defense mechanisms.

Mucociliary clearance. The mucus produced by the goblet cells in the nasal mucosa or the tracheobronchial epithelium covers the entire surface of the air-conducting tubular part of the respiratory system. The bronchi also contain mucous glands. The mucus they secrete consists of glycosaminoglycans, glycoproteins, and complex carbohydrates. The mucus can bind living pathogens and other particulate matter. Bactericidal substances in the mucus, such as properdin, or immunoglobulin A, act on bacteria. Mucus also contains macrophages, which phagocytose or kill bacteria. These bacteria and other particulate matter are moved up the tracheobronchial tree through the ciliary movement of the columnar cells in the tracheobronchial epithelium. This mucociliary escalator system will, under normal circumstances, eliminate most of the particles that measure 2 to 10 μm in diameter, but particles that are smaller than 2 μm may reach the alveoli. Such particles are usually taken up by alveolar macrophages and either are expectorated or enter into the interstitial spaces and ultimately are carried by the lymph into the local lymph nodes.

Lymphatic clearance. Foreign material taken up by the alveolar macrophages is transported by the lymphatics. Although the alveoli do not contain lymphatics, well-formed lymphatic channels are recognizable at the level of alveolar ducts. The lungs have an extensive lymphatic drainage system, which extends from the alveolar ducts, along the interlobular septa, to the connective tissue surrounding the blood vessels and bronchi. The lymph from both lungs, except for the left upper lobe, drains into the right lymphatic duct; the left upper lobe drains into the thoracic duct.

Pulmonary immune response. Along the intrapulmonary lymphatics and in the mucosae of the bronchi are aggregates of nonencapsulated lymphoid tissue that form the so-called mucosa-associated lymphoid tissue (MALT). These lymphoid follicles serve as mechanical barriers but are also the main source of immune cells that protect the lungs from bacteria and foreign allergens. The immune response typically includes both T and B cells. The lungs also contain numerous resident macrophages and antigen-presenting cells such as Langerhans cells. Hence some cell-mediated immune reactions, such as those that occur in response to exposure to Mycobacterium tuberculosis or fungi, result in granuloma formation.

Ventilation is a process during which the air moves in and out of the lungs.

Oxygen enters the blood in the lungs from the inhaled air in the alveoli and is transported thereafter bound to the hemoglobin in red blood cells. At the same time carbon dioxide is released from venous blood and is exhaled through the lungs. Total ventilation (V_E) is expressed as the volume of air that enters and leaves the lungs in a minute, depending on the frequency of breath per minute (f) and the tidal volume of air inspired/expired per minute V_T:

The air entering the lungs follows the basic physical laws defined by Boyle and Dalton. According to Boyle’s law the pressure and volume of a gas are directly related if the temperature is constant. According to Dalton’s law the partial pressure of a gas in a gas mixture equals the pressure that the gas would exert if it occupied the entire volume. Thus the sum of partial pressures of gases—which for the inhaled air is 21% oxygen and 79% nitrogen—must equal 100%. The tension of oxygen can thus be increased by increasing the pressure over the normal pressure under which the air enters the lungs (760 mm Hg at sea level) or by increasing the concentration of oxygen. This principle is used when applying machine-assisted artificial respiration. At high altitude, however, the total atmospheric pressure decreases and can thus result in hypoxia.

Partial pressure of gases is the key determinant of external and internal respiration.

External respiration takes place in the lungs. During this process the O₂ from the inhaled air is transferred to the blood and the CO₂ diffuses from blood into the air. Internal respiration refers to cellular processes that allow the transfer of O₂ from red blood cells through the capillary wall into the tissues and thereby for use within the cell. Both processes depend on the partial pressures of O₂ and CO₂ (Fig. 5-6). Note in Figure 5-6 that the consumption of O₂ leads to major fluctuations in the partial pressure of O₂, which drops from 100 mm Hg in the arterial blood to 40 mm Hg in venous blood. In contrast, the fluctuations of CO₂ are much smaller, from 40 mm Hg in arterial blood to 46 mm Hg in venous blood.

Figure 5-6 External and internal respiration. The lungs play a pivotal role in gas exchange between the air and the blood (external respiration). The oxygen (O₂) is transported to the periphery, where the internal respiration takes place in the tissues. The pressure of oxygen varies from 160 mm Hg in the inhaled air to 100 mm Hg in the terminal air spaces (alveoli). Note also that the air is humidified, which lowers the pressure of oxygen from 160 to 150 mm Hg. Carbon dioxide (CO₂) formed inside the tissues is carried by the blood from the tissues and exhaled in the lungs. PO₂, partial pressure of oxygen; PCO₂, partial pressure of carbon dioxide.

Transfer of gases in the alveolar-capillary unit occurs by simple diffusion.

The transition of O₂ from air into the blood and CO₂ from blood to the air occurs through diffusion across the alveolar lining and the basement membranes of the alveolar capillaries (Fig. 5-7). This process is governed by Fick’s law as stated here:

Figure 5-7 Alveolar-capillary unit. CO₂ from the venous blood is exhaled and O₂ from the inhaled air is taken up into the blood, which leaves the alveolar-capillary unit as oxygenated as arterial blood. PCO₂, partial pressure of carbon dioxide; Ph₂O, partial pressure of water vapor; PO₂, partial pressure of oxygen.

Fick’s law indicates that the diffusion of gases is directly proportional to the surface area of the alveoli and inversely proportional to the thickness of the tissue that prevents diffusion. In practice this diffusion rate is determined by measuring the inhalation efficiency of CO, a gas that has high solubility in blood and can be readily measured after inhalation in both the alveolar spaces and the blood.

Oxygen pressure in inspired dry air is higher than in the humidified air in the trachea or the alveoli or the oxygenated arterial blood leaving the lungs.

Assuming that the air contains 21% O₂, at sea level the oxygen pressure in dry inhaled air is 160 mm Hg (760 × 0.21 = 160). This air is humidified during its passage through the nose and trachea, which brings down the oxygen pressure to 150 mm Hg (see Fig. 5-7). As the air passes into the alveoli, the oxygen pressure drops to 100 mm Hg. This is in part due to the fact that oxygen diffuses rather rapidly into the blood and is also diluted with CO₂ diffusing from the venous blood into the alveoli.

Theoretically the oxygen pressure in the alveoli should be the same as that in the pulmonary artery branches. However, the arterial oxygen pressure is lower than that in the alveoli, and thus the ventilation/perfusion ratio (/) is normally 0.8. This defect results from the admixture of venous bronchial blood entering the pulmonary veins and a small amount of pulmonary venous blood that bypasses the alveoli through a physiologic right-to-left shunt and is not oxygenated. Approximately 2% of the normal cardiac output bypasses the alveoli. / ratio is reduced in many lung diseases.

Breathing is an involuntary action that is under the control of the respiratory center in the brainstem.

Breathing is a vital function that is tightly controlled by the central nervous system, which receives impulses from the periphery and then sends efferent signals to the periphery (Fig. 5-8). The key anatomic foci of the respiratory control sensory and effector system are as follows:

Figure 5-8 Neural control of respiration. Respiration is under the control of the medullary centers, which contain a sensitive area responding to chemical stimuli and receive impulses from the peripheral nervous system. The cortical centers also may influence respiration. The efferent stimuli from the respiratory center are transmitted to respiratory muscles, primarily the intercostals and the diaphragm. A, apneustic; E, expiratory center; I, inspiratory; P, pneumotaxic.

Respiratory centers. Respiration is controlled by three centers in the brainstem: the medullary respiratory center, the apneustic center, and the pneumotaxic center. Automatic respiratory movements are under the control of the inspiratory center in the dorsal medulla, which receives the stimulatory impulses from the peripheral sensors, mostly through the glossopharyngeal and vagus nerves. Efferent signals are sent to the diaphragm through the phrenic nerve. The expiratory center located in the ventral medulla is dormant because expiration is normally a passive process. It becomes activated, however, during exercise. The inspiratory center also receives positive stimuli from the apneustic center in the lower pons. This center prolongs the inspiratory gaps (“apneusis”) by prolonging the contraction of the diaphragm. The pneumotaxic center in the upper pons inhibits respiration by reducing the tidal volume, but it does not affect the rhythmicity of breathing.

Cerebral cortex. Respiration can be controlled to a certain extent by voluntarily cortical stimuli. Hyperventilation can be induced relatively easily, but once the arterial partial pressure of carbon dioxide (Paæ{₂) falls below a critical level, the person loses consciousness and automatic respirations resume. Hypoventilation can also be induced but it does not last long because the reduction of the arterial partial pressure of oxygen (Pa{₂) and increased Paæ{₂ are strong stimuli for the resumption of respiration.

Chemoreceptors. Chemoreceptors can be classified as central or peripheral.

Mechanoreceptors. Receptors responding to stretch in the smooth muscles of the bronchi activate the Hering-Breuer reflex, which slows down respiration by prolonging the expiratory time. Stretch receptors found in the skeletal muscles and joints may also increase the respiratory rate.

Irritant receptors in the mucosa of the bronchi react to chemical stimuli and particles, causing bronchoconstriction, which also increases the rate of respiration. Irritant receptors are important for initiating coughing, which can, however, also be triggered by the stimuli reaching the mechanoreceptors. Likewise, the irritant receptors in the nose are important for the initiation of sneezing. Irritant receptors are linked to C type nerve fibers, which also transmit pain.

The volume of air entering and leaving the lungs during inspiration and expiration can be measured objectively under controlled circumstances.

Normal breathing occurs in a cycle that includes four phases: rest, inspiration, a rest phase, and expiration. By measuring the volume of air entering the lungs during inspiration and leaving it during expiration the critical aspects of respiratory capacity can be defined as illustrated in Figure 5-9. By convention these static lung volumes are defined as follows:

Figure 5-9 Respiratory volumes. The lungs have an enormous respiratory reserve and can increase their function when needed. The capacity of the lung to increase gas exchange can be measured and expressed as total lung capacity (TLC). Other lung volumes include vital capacity (VC), residual volume (RV), inspiratory capacity (IC), functional reserve capacity (FRC), inspiratory reserve volume (IRV), tidal volume (V_T), and expiratory reserve volume (ERV).

Dyspnea is a sensation of breathlessness out of proportion to the level of physical activity.

Dyspnea, also known as shortness of breath, is a subjective sensation of difficult breathing. The patients describe it as strained breathing or simply state that they are “short of breath.” As stated by a famous pulmonary physician, “Dyspnea is not tachypnea, hyperpnea, or hyperventilation but difficult labored and uncomfortable breathing.”

Elemental sensations include tightness in the chest, excessive ventilation, excessive frequency, and trouble breathing. These sensations have an objective aspect based on the integration of physiologic sensory impulses reaching the respiratory centers of the brainstem and a subjective aspect depending on the cortical perception of the efficiency of respiration. The objective impulses from central and peripheral chemoreceptors responding to blood oxygen levels, CO₂ content, and pH, and mechanoreceptors in the pulmonary parenchyma, airways, and respiratory muscles, can be measured. The subjective perception is, however, less quantifiable and varies from one person to another.

As discussed in Chapter 4, dyspnea can be classified as cardiac or noncardiac, acute or chronic. The most important causes of dyspnea are listed in Table 5-2.

Table 5-2 Causes of Dyspnea

Patients can usually grade their dyspnea as mild, moderate, or severe, and whether it is related to physical activity or also occurs at rest. The precipitating cause can often be identified.

Patients also can describe the time of onset and the duration of shortness of breath. The timing of dyspnea provides important diagnostic clues, as listed in Table 5-3.

Table 5-3 Classification of Dyspnea by Type of Onset

Cough involves a reflex that can be triggered by a wide variety of stimuli.

Cough is a defense mechanism based on a reflex, which can be initiated by chemical or mechanical irritants or by voluntary action. The irritants, such as chemicals or foreign bodies reaching the larynx or the lower respiratory tract mucosa, act on mechanoreceptors and nociceptors. These receptors are connected to C type nerve fibers that serve as the conduit for pain impulses, leading them into the medulla oblongata through the vagus nerve. In the medulla the impulses trigger the efferent reaction that has three phases:

Cough may be clinically classified as acute, lasting a few days or a week or two, or chronic if it last more than 3 weeks. It may be accompanied by bleeding or sputum production (productive cough). Some irritants that cause cough may also cause bronchospasm, and in such cases cough is associated with wheezing (e.g., in asthma). Cough may be the only complaint, but often it is just one of the symptoms of a complex disease such as asthma or bronchopneumonia. The most important causes of cough are listed in Table 5-4.

Table 5-4 Causes of Cough

Hemoptysis may present as mild, in the form of blood-stained sputum, or massive and life-threatening.

Hemoptysis is defined as expectoration of blood from the respiratory tract. Most often it originates from the bronchial arterial circulation, but it may have other sources as well. Remember that the bronchial arteries are part of the greater arterial system, and the blood in these arteries circulates under much higher pressure than the blood in the pulmonary venous or arterial circulation, which are low-pressure systems. Hence, if these vessels rupture, the bleeding occurs under much higher pressure than if it stemmed from pulmonary arteries and veins. However, if the pressure inside the pulmonary circulation rises, as in pulmonary hypertension, bleeding may occur from other vessels as well. Tumors may cause bleeding by eroding into any blood vessel. Autoimmune diseases, such as Wegener’s granulomatosis or Goodpasture’s syndrome, may cause vascular lesions, leading to a rupture of various blood vessels from small capillaries to larger arteries and veins. The most important causes of hemoptysis are listed in Table 5-5.

Table 5-5 Sources and Causes of Hemoptysis

SITE	LESION/CAUSE	DISEASES
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