Nose

The nose is mainly an air-conditioning and filtering device. Although the resistance to airflow through the nose is greater than resistance through the mouth, most adults breathe through the nose at times of rest. High nasal resistance from swollen mucous membranes and rapid breathing from exercise usually cause people to switch to mouth breathing. Specialized structures in the nose increase its airflow resistance, but these structures are necessary for the nose to accomplish its filtering, warming, and humidifying functions.

The cartilaginous anterior portion of the nasal septum divides the nasal cavity into two channels called nasal fossae. The vomer and ethmoid bones form the posterior septum (Figure 1-2). The two nasal fossae lead posteriorly into a common chamber (the nasopharynx) through openings called choanae. The nasal septum is often deflected to one side or the other, more often to the left than the right,¹ possibly making the passage of a catheter or artificial airway through this side difficult. Three downward-sloping, scroll-shaped bones called conchae project from the lateral walls of the nasal cavity toward the nasal septum. The conchae create three irregular passages—the superior meatus, middle meatus, and inferior meatus (Figure 1-3). Because they create turbulence, the conchae are also called turbinates. The convoluted design of the turbinates greatly increases the surface area of the nasal cavity. The maxillary bone forms the anterior three fourths of the nasal cavity floor, called the hard palate (see Figure 1-3). Cartilaginous structures form the posterior fourth, called the soft palate. Palatal muscles close the posterior openings of the nasal cavities during swallowing or coughing, isolating the nasal cavities from the oral cavity.

Squamous, nonciliated epithelium lines the anterior third of the nose; pseudostratified, ciliated columnar epithelium interspersed with many mucus-secreting glands covers the posterior two thirds, including the turbinates. This mucus-secreting epithelium is called the respiratory mucosa. Immediately under the mucosa is an extensive capillary network adjoining a system of still deeper, high-capacity vessels. These deep vessels can dilate or constrict and change the volume of blood that flows into the capillaries, altering the mucosa’s thickness. The capillaries have tiny openings or fenestrations that allow water transport to the epithelial surface. These fenestrations are not present in the capillaries of lower airways. Countercurrent blood flow and connections between arterial and venous vessels (arteriovenous anastomoses) improve the ability of the nasal mucosa to adjust the temperature and water content of inspired air. Warm arteriolar blood flows parallel with but in the opposite (countercurrent) direction of cooler blood flowing in the venules, lessening the mucosa’s heat and water-vapor loss. Arteriovenous anastomoses and countercurrent blood flow are not present in airways below the larynx.²

The main functions of the nose are the humidification, heating, and filtering of inspired air. As inspired air passes over the richly vascular epithelial surface (made larger by the presence of the turbinates), its temperature and water content increase rapidly. The turbinates disrupt the incoming airstream and create swirling, chaotic flow, increasing the chances that tiny airborne particles will collide with and adhere to the sticky mucous layer covering the nasal epithelium. Nasal secretions contain immunoglobulins and inflammatory cells, which are the first defense against inspired microorganisms. The nose is so efficient as a filter that most particles larger than 5 µm in diameter do not gain entry to the lower airways.³

By the time inspired air reaches the nasopharynx, it gains considerable water vapor and heat. Exhaled air cools as it leaves the nose, causing water vapor to condense on its structures, which humidifies the subsequent inspired air.

The process of intubation involves the insertion of an artificial airway or endotracheal tube through the nose or mouth and into the trachea (Figure 1-4), which means the air-conditioning function of the nose is lost, and unmodified cool, dry gas directly enters the trachea. This places a heavy burden on the tracheal mucosa, which is not designed to accommodate cool, dry gases.

Connected to the nasal cavities are several empty airspaces within the skull and facial bones called paranasal sinuses. These sinuses are lined with a mucus-secreting epithelium, continuous with the epithelium of the nasal cavities. Mucus from the sinuses drains into the nasal cavity through openings located beneath the conchae. The sinuses are symmetrically paired and located in the frontal, ethmoid, sphenoid, and maxillary bones. Inflammation and infection may swell the membranes lining the sinuses, impairing drainage and increasing sinus cavity pressure. Chronic sinus infections provide a source of bacteria-laden secretions that are sometimes aspirated into the lower respiratory tract, potentially causing lower respiratory infections.

Pharynx

The pharynx is the space behind the nasal cavities that extends down to the larynx (see Figure 1-1). The term pharynx stems from the Greek word meaning “throat.” The nasopharynx is the portion behind the nasal cavities that extends down to the soft palate. The oropharynx, the space behind the oral cavity, is bounded by the soft palate above and the base of the tongue below. The laryngopharynx is the space below the base of the tongue and above the larynx.

As inspired gas abruptly changes its direction of flow at the posterior nasopharynx, inhaled foreign particles collide with and adhere to the sticky mucous membrane. Lymphatic tissues in the nasopharynx and oropharynx provide an immunological defense against infectious agents. These tissues include the pharyngeal (adenoid), palatine, and lingual tonsils (see Figure 1-3). These tissues may become inflamed and swollen and may interfere with nasal breathing especially in children owing to their smaller airways; chronic inflammation of the tonsils may warrant surgical removal.

The eustachian tubes, also called auditory tubes, connect the middle ear with the nasopharynx (see Figure 1-3). These tubes allow pressure equalization between the middle ear and atmosphere. Inflammation and excessive mucus production in the nasopharynx may block the eustachian tubes and hinder the pressure-equalizing process; this can momentarily impair hearing and cause pain, especially during abrupt changes in atmospheric pressure. Children younger than 3 years of age are especially susceptible to this condition because their eustachian tubes are small and easily occluded; artificial pressure-equalizing tubes, also known as myringotomy tubes, are sometimes placed through the ear’s tympanic membrane (eardrum) to create an alternate route for pressure equalization.

The oropharynx and laryngopharynx accommodate food and air and are lined with nonciliated, stratified squamous epithelium. The laryngopharynx, also called the hypopharynx, separates the digestive and respiratory tracts. Proper function of sensory and motor nerves innervating the pharyngeal musculature is crucial in preventing food and liquid aspiration into the respiratory tract. The pharyngeal reflex has its sensory component in the ninth cranial (glossopharyngeal) nerve and its motor component in the tenth cranial (vagus) nerve. This reflex arc is responsible for the gag and swallowing reflexes.

Deeply unconscious persons sometimes lose the pharyngeal and laryngeal reflexes and aspirate foreign material into their lungs. In such individuals, an artificial airway (endotracheal tube) with an inflatable cuff may be inserted orally or nasally through the larynx and into the trachea. After it is in place, the cuff is inflated to form a seal between the tracheal wall and tube to minimize aspiration of pharyngeal contents (see Figure 1-4). However, even if the cuff is properly inflated, pharyngeal secretions eventually migrate past the cuff into the lower airway, For this reason, mechanically ventilated patients, in whom endotracheal intubation is required, are susceptible to the development of lung infections, or ventilator-associated pneumonia (VAP); the longer the duration of mechanical ventilation, the greater the risk of VAP. Normal pharyngeal muscle tone prevents the base of the tongue from falling back and occluding the laryngopharynx, even in a person who is supine and asleep. Deep unconsciousness may relax pharyngeal muscles enough to allow the base of the tongue to rest against the posterior wall of the pharynx, occluding the upper airway; this is called soft tissue obstruction and is the most common threat to upper airway patency. If the head droops forward, the oral cavity and pharynx-larynx axis form an acute angle that may partially or completely obstruct the upper airway (Figure 1-5). Partial upper airway obstruction produces a low-pitched snoring sound as inspired air vibrates the base of the tongue against the posterior wall of the pharynx. Complete obstruction causes strong inspiratory efforts without sound or air movement. Soft tissues between the ribs and above the sternum may be sucked inward (intercostal and suprasternal retractions) as the person struggles to inhale.

Both forms of soft tissue upper airway obstruction can be easily removed by extending the neck and pulling the chin anteriorly (see Figure 1-5, C). This maneuver pulls the tongue forward out of the airway and aligns the oral and nasal cavities with the pharynx-larynx axis. This is sometimes called the sniffing position.

Pharyngeal anatomy plays a role in the incidence of obstructive sleep apnea (OSA),⁴ as do pharyngeal reflexes and muscle tone. The normal pharynx narrows during sleep, greatly increasing upper airway resistance. Abnormal enlargement of soft tissues can further narrow or occlude the airway, and repetitive cessations of breathing (apnea) may occur during sleep.

Larynx

The larynx is a cartilaginous, cylindrical structure that acts as a valve on top of the trachea. The larynx is sometimes called the voice box because it contains the vocal cords that control the size of the opening into the trachea (glottis [rima glottidis]). The main cartilage of the larynx in the middle of the neck is the thyroid cartilage, sometimes called the Adam’s apple, which is easily palpable in men.

The larynx lies at the level of the fourth through sixth cervical vertebrae in men and is located higher in women and children. The top portion of the larynx is a complex triangular box that is flat posteriorly and composed of an intricate network of cartilages, ligaments, and muscle (Figure 1-6). A mucous membrane continuous with the mucous membrane of the pharynx and trachea lines the interior of the larynx. Nine cartilages (three paired and three unpaired) and many muscles and ligaments form the larynx. The unpaired epiglottis is a thin, flat, leaf-shaped cartilage above the glottis. The lower end of the epiglottis (a long, narrow stem) is attached to the thyroid cartilage. From this attachment, it slants upward and posteriorly to the base of the tongue, where its upper free end is broad and rounded (see Figures 1-3 and 1-6). A vascular mucous membrane covers the epiglottis. The lower base of the tongue is attached to the upper epiglottis by folds of mucous membrane, forming a small space (the vallecula) between the epiglottis and tongue (Figure 1-7). The vallecula is an important landmark used during the insertion of a tube into the trachea (intubation).

Besides speech, the major function of the larynx is preventing the lower airway from aspirating solids and liquids during swallowing and breathing. The epiglottis does not seal the airway during swallowing.⁵ Instead, the upward movement of the larynx toward the base of the tongue pushes the epiglottis downward, which causes it to divert food away from the glottis and into the esophagus. The free portion of the upper epiglottis in an adult lies at the base of the tongue, but in a newborn it lies much higher, behind the soft palate. This position of the upper epiglottis helps

to account for preferential nose breathing in newborns and why it is difficult to achieve effective deposition of inhaled aerosolized medications in the lower airways of a newborn.⁶

The vascular mucous membrane covering the epiglottis may become swollen and enlarged if inflamed by infectious agents or mechanical trauma. A swollen epiglottis may severely obstruct or occlude the laryngeal air passage of a small newborn. Inflammation of the epiglottis (epiglottitis) is a life-threatening emergency in infants and requires immediate placement of an artificial airway by skilled medical personnel.

The thyroid cartilage is the largest of all laryngeal cartilages, enclosing the main cavity of the larynx anteriorly (see Figure 1-6). The lower epiglottis attaches just below the notch on its inside upper anterior surface.

The cricoid cartilage, just below the thyroid, is the only complete ring of cartilage that encircles the airway in the larynx or trachea. The cricothyroid ligament connects the cricoid and thyroid cartilages (see Figure 1-6). The cricoid limits the endotracheal tube size that can pass through the larynx. The cricoid ring is the narrowest portion of the upper airway in an infant. Inside the larynx, the vocal cords lie just above the cricoid cartilage.

The membranous space between the thyroid and cricoid cartilages, the cricothyroid membrane (see Figure 1-6), is sometimes the puncture site for an emergency airway opening when structures above it are occluded. A longer term surgical opening into the airway (tracheostomy) is generally located 1 to 3 cm below the cricoid cartilage.

The remaining cartilages (arytenoid, corniculate, and cuneiform) are paired. These cartilages are in the lumen of the larynx and serve as attachments for ligaments and muscles (see Figure 1-6). The arytenoids are attachment points for vocal ligaments that stretch across the lumen of the larynx and attach to the thyroid cartilage.

The vocal folds consist of two pairs of membranes that protrude into the lumen (inner cavity) of the larynx from the lateral walls (see Figures 1-3 and 1-7). The upper pair is called the false vocal cords; the lower pair is called the true vocal cords because only these folds play a part in vocalization. The true vocal folds form a triangular opening between them that leads into the trachea below. This opening is called the rima glottidis, or glottis (see Figure 1-7).

The vocal cords’ ability to open and close the airway is essential for generating and releasing high pressure in the lung during a cough (an extremely important lung defense mechanism). Artificial airways such as endotracheal and tracheostomy tubes render a cough ineffective because they prevent the vocal cords from sealing the airway.

The vocal cords are wider apart during quiet inspiration than expiration. During deep inspiration, the vocal cords offer little airflow resistance. The glottis is the narrowest part of the adult larynx. Swelling (edema) of the vocal cords increases resistance to airflow, especially in an infant. Glottic and subglottic edema secondary to viral infections, also known as croup, is a common cause of upper airway obstruction in infants and young children. During inspiration, croup causes a characteristic high-pitched crowing sound called stridor. This sound is created by high-velocity air flowing through a narrowed glottis.

The laryngeal mucous membrane is composed of stratified squamous epithelium above the vocal cords and pseudostratified columnar epithelium continuous with the mucosa of the trachea below the vocal cords. Branches of the tenth cranial (vagus) nerve provide motor innervation for all intrinsic muscles of the larynx through the recurrent laryngeal nerve.

This nerve passes downward around the aorta and returns upward to the larynx. Intrathoracic disease or surgery may injure this nerve, causing partial or complete paralysis of the vocal cords. Paralyzed vocal cords move to the midline, increasing airway resistance.⁷ Sensory innervation of the larynx is also supplied by the vagus nerve except for the sensory nerves of the anterior surface of the epiglottis, which are supplied by the ninth cranial (glossopharyngeal) nerve. The laryngeal reflex, which has sensory and motor components in the vagus nerve, causes the vocal cords inside the larynx to close the tracheal opening (laryngospasm). Laryngospasm occurs if anything except air enters the trachea. Drowning victims often have little water in their lungs because of laryngospasm.

Trachea and Main Bronchi

The trachea begins at the level of the sixth cervical vertebra and in an adult extends for about 11 cm to the fifth thoracic vertebra. It divides there into the right and left mainstem bronchi, one for each lung (Figure 1-9). The point of division is called the carina. Inspired air becomes 100% saturated with water vapor and is warmed to body temperature (37° C) after it passes through two or three airway subdivisions below the carina⁸; the point at which this occurs is known as the isothermic saturation boundary (ISB) (Figure 1-10). Above the ISB, the temperature and humidity of gas in the airways fluctuates, decreasing with inspiration and increasing with exhalation. Below the ISB, gas temperature and humidity remain constant at body temperature and 100% relative humidity. Cold air or mouth breathing moves the ISB deeper into the airways but never by more than a few generations.

The anterior (ventral) part of the trachea is formed primarily by 8 to 20 regularly spaced, rigid, horseshoe-shaped cartilages. Stretched across the open posterior ends of the tracheal cartilages, the ligamentous membrane forms a flat dorsal surface contacting the esophagus (see Figures 1-6, B, and 1-9). This membrane contains horizontally oriented smooth muscle, the trachealis. Contraction of the trachealis pulls the ends of the horseshoe-shaped cartilages closer together, slightly narrowing the trachea and making it more rigid. Rigidity of the trachea is important for preventing collapse from external pressure, especially during vigorous coughing. Coughing exerts a collapsing force only on the part of the trachea inside the thoracic cavity, the part below about the sixth tracheal cartilage.⁷ Above this level, the trachea is outside the thorax and not influenced by intrathoracic pressure.

At the carina, the right mainstem bronchus angles only 20 to 30 degrees away from the midline, forming a more direct continuation of the trachea than the left mainstem bronchus. The left mainstem bronchus breaks away more sharply, forming a 45- to 55-degree angle with the vertical tracheal midline (see Figure 1-9). The left bronchus is smaller in diameter than the right but twice as long.

If an endotracheal tube is inserted too far during the process of intubation, its tip is more likely to enter the right bronchus than the left. If this occurs, the left lung cannot be ventilated, which the clinician can detect by using a stethoscope to compare the intensity of breath sounds between left and right sides of the chest while manually ventilating the lung. Diminished breath sounds on the left side of the chest in this context are associated with right mainstem bronchial intubation. It is a standard procedure to listen to breath sounds with a stethoscope (auscultation) immediately after intubation.

The cartilage of the mainstem bronchi resembles the cartilage of the trachea initially, except that cartilage completely surrounds the bronchi at their entry point into the lung tissue, and the posterior membranous portion disappears. As the bronchi continue to branch, the cartilage becomes more irregular and discontinuous, no longer encircling the airway in complete sections (see Figure 1-9).

Conducting Airway Anatomy

All airways down to the level just before alveoli first appear are called conducting airways (Figure 1-11). No gas exchange between air and blood occurs across airway walls; they serve merely to conduct air to the alveoli—the gas-exchange surface of the lung. Beginning with the trachea, each of these conducting airways undergoes dichotomous branching until 23 to 27 subdivisions are formed.

The mainstem bronchi divide to form lobar bronchi, which undergo several divisions to form segmental and subsegmental bronchi. Segmental bronchial anatomy (Figure 1-12) is the basis for the application of chest physical therapy, in which a person is positioned for gravitational drainage of secretions from the various lung segments. Chest physical therapy is a respiratory therapy modality often used in treating lung diseases that produce large quantities of airway secretions.

Beyond the third generation of airway divisions, the bronchi enter the parenchyma, the essential supportive tissue composing the lung. Elastic fibers of the parenchyma surround and attach to the airways; their natural recoil forces act as tethers that hold the airways open during forceful exhalation. These tethering forces also limit the degree to which smooth muscle contraction (bronchospasm) can narrow the airway; diseases that weaken parenchymal recoil forces make the airways prone to more severe narrowing or collapse, especially during exhalation. The natural elastic recoil forces of the lung are extremely important in keeping the small, noncartilaginous airways open.

The conducting airway subdivisions produce approximately 1 million terminal tubes at the level where alveoli (the gas-exchange units) first appear (see Figure 1-11). This enormously expansive branching gives rise to a massive increase in the cross-sectional area of the airways from the trachea (3 to 4 cm²) to the alveolar surface (approximately 50 to 100 m²—half the area of a tennis court—or about 40 times the surface area of the body).

A complex engineering design is required to distribute air uniformly and rapidly through millions of tubes of various lengths and diameters without creating too much frictional resistance to air movement. The design of the tracheobronchial tree is so efficient that an airflow rate of 1 L per second, commonly achieved during a resting inspiration, requires a pressure difference of less than 2 cm H₂O between the trachea and alveoli.

The volume of conducting airway gas must be relatively small so that most of the inhaled breath can contact the gas-exchange membrane. The volume of this gas (including the upper airways) is only about 150 mL in the average adult compared with a total inhaled volume per breath of about 500 mL. Because the conducting airways do not participate in gas exchange, they are called the anatomical dead space

Bronchioles are airways less than 1 mm in diameter that contain no cartilage in their walls. Their patency depends on the tethering retractile forces of the lung’s elastic parenchymal tissue. Bronchial and bronchiolar smooth muscle is oriented in a circular, spiral fashion, facilitating airway narrowing when it contracts (Figure 1-13). Strong smooth muscle contractions or spasms may nearly collapse the bronchioles, especially if disease weakens the lung’s opposing elastic tethering forces. In contrast, tracheal smooth muscle is transversely oriented between the two ends of its horseshoe-shaped cartilages (see Figures 1-6, B, and 1-9).

At the nineteenth or twentieth generation, the terminal bronchioles divide to form several generations of respiratory bronchioles, marking the beginning of the respiratory, or gas-exchange, zone (see Figures 1-11 and 1-13). The respiratory bronchioles are tubes containing thin, saclike pouches called alveoli in their walls. Alveoli are the gas-exchange membranes that separate air from pulmonary capillary blood. Alveolar ducts open into

blind terminal units called alveolar sacs and alveoli. The airways beyond the terminal bronchiole are collectively called the acinus, which is the functional respiratory unit of the lung (i.e., all alveoli are contained in the acinus) (see Figure 1-13). In other words, each terminal bronchiole gives rise to an acinus.

Collateral air channels called pores of Kohn connect adjacent alveoli with one another (see Figure 1-13). The canals of Lambert connect terminal bronchioles and nearby alveoli. These collateral air passages make it possible for the acinus supplied by a mucus-plugged bronchiole to receive ventilation from neighboring airways and alveoli.

Sites of Airway Resistance

Dichotomous branching of the airways through many generations creates an enormous increase in the total airway cross-sectional area. Therefore, the velocity of airflow is sharply reduced as inspired gas approaches the alveoli. Flow velocity is so low in small, distal airways that molecular diffusion is the dominant mechanism of ventilation beyond the terminal bronchioles. Airways less than 2 mm in diameter account for only about 10% of total resistance to airflow because of their huge cross-sectional area (Figure 1-14). (Table 1-1 shows the relative size of airway cross sections at different levels.) Although the resistance of a single terminal bronchiole is greater than the resistance of a single lobar bronchus, the cross-sectional area of all terminal bronchioles combined greatly exceeds the cross-sectional area of all the lobar bronchi combined. For this reason, upper airway resistance is normally much greater than lower airway resistance.

Other Epithelial Cells

Other bronchial epithelial cells include basal cells, serous cells, Kulchitsky cells, brush cells, Clara cells, and intermediate (or undifferentiated) cells. Serous cells may transform to goblet cells if chronically exposed to air pollutants, including cigarette smoke. Cigarette smoke causes all mucous cells to proliferate and spread into the small bronchioles, where they are usually absent. Cigarette smoke also ultimately reduces ciliary activity. Kulchitsky cells are endocrine cells more prominent in newborns than adults and are apparently precursors of carcinoids and small cell bronchogenic carcinomas.⁹ Clara cells, found in the terminal and respiratory bronchioles, are nonciliated secretory cells bulging upward into the airway lumen. These cells are normally the sole source of secretions at this level because mucous cells are absent. Their secretions apparently also form part of the alveolar liquid lining. Injury to the epithelium at this level may cause the Clara cells to differentiate into ciliated or mucous cells.⁹

Mucociliary Clearance Mechanism

Each ciliated epithelial airway cell contains about 250 cilia beating about 1300 times per minute, moving the sheet of mucus toward the pharynx at a rate of approximately 2 cm per minute. The cilia have a rapid, forward, propulsive stroke, reaching up high into the viscous gel layer of mucus with their tips and pulling the mucous blanket up the airway. The recovery stroke is slower, and the flexible cilia bend as they are pulled backward (tips down) through the lower, less viscous sol layer of mucus (see Figure 1-15). The gel layer traps microbes and inhaled particles on its sticky surface.

Normal ciliary function and mucous composition are crucial for the effective function of this important lung clearance mechanism, often called the mucociliary escalator. It is the lung’s main method for removing microbes and inhaled particles that have gained access to the bronchial tree. The combined actions of the mucociliary mechanism, a functional glottis that prevents aspiration, and an intact cough mechanism are remarkably effective in keeping the lower airways of healthy individuals sterile.¹⁰

Airway mucus is a viscoelastic, sticky substance; it has an elastic recoil property that facilitates mucokinesis, or mucous movement. When cilia pull the sheet of mucus forward, it stretches and then snaps forward in the direction of the pull. If the delicate balance between mucous water content and airway humidity is disrupted, the mucous sheet may become dehydrated, thick, and immobile. Conversely, overhydration causes mucus to become thin and watery, destroying the ciliary propulsive mechanism.

Approximately 100 mL of mucus is secreted per day in normal, healthy people. This volume greatly increases in individuals with acute and chronic airway inflammation. In chronic bronchitis, asthma, pneumonitis, and cystic fibrosis (CF), production of abnormally thick, sticky mucus is increased, impairing ciliary function and mucokinesis. Mucus builds up, partially blocks or plugs airways, and becomes a stagnant breeding ground for infectious microorganisms.

Ciliary disorders also impair mucous transport. Immotile cilia syndrome, also known as ciliary dyskinesia, is a genetic disorder that causes a lack of normal beating activity. People with this syndrome are predisposed to multiple chronic respiratory infections that may eventually cause bronchiectasis, a disease process that weakens and dilates bronchial walls. This disease causes permanent anatomical airway dilations that tend to collect secretions, which become infected, creating further airway damage.

Nonepithelial Cells in the Airway

Inflammation of the lung causes various white blood cells such as eosinophils and neutrophils to enter the airways. Allergic asthma, a chronic inflammatory airway disease, is associated with increased eosinophils in airway secretions. Bacterial infections cause neutrophils, sometimes called pus cells, to migrate into the airways where they engulf or phagocytize the bacteria. The resulting cellular debris is a stringy, sticky, purulent (pus-containing) substance that increases mucus viscosity and impairs mucociliary transport.

Mast cells are located on the epithelial surface of the airways and in the airway walls near smooth muscle. Mast cells have granules in their cytoplasm that contain preformed inflammatory agents. These agents include histamine, various prostaglandins, leukotrienes, thromboxane, and platelet-activating factor. Besides increasing the permeability of mucosal epithelium to water, inflammation causes the mucosa to swell and smooth airway muscle to contract (bronchospasm).

Mast cells release their inflammatory agents when activated by a process called immune sensitization, which is common in people who have certain allergies. Inhaled irritants or antigens, such as ragweed pollen, cause the plasma B cells to synthesize immunoglobulin E (IgE), which is an abnormal response to the antigen (Figure 1-16). IgE first binds to specific receptor sites on the mast cell surface, sensitizing the mast cell. The antigen combines with IgE molecules attached to the surface of the mast cell, which inactivates the antigen. However, in this process, the antigen cross-links two IgE molecules, which causes the mast cell membrane to rupture and release inflammatory agents into the airway tissues (see Figure 1-16). Histamine causes the normally tight, impermeable cell wall junctions of the airway epithelium to open, allowing it to penetrate deeply, breaking down more mast cells and creating more vascular leakage, mucosal swelling, and bronchospasm. Mast cell breakdown, airway inflammation, and subsequent bronchospasm are features of asthma, a condition characterized by chronic airway inflammation and hypersensitivity. Clinical Focus 1-7 discusses asthma and the basis for its pharmacological management.

Epithelial Chloride Channel Regulation and Secretion Viscosity

Water movement into the airway lumen is an osmotic process influenced by epithelial cell membrane secretion of chloride ions.¹⁰ Chloride ions are secreted into the airway through specialized epithelial channels. Positively charged sodium ions follow the negatively charged chloride ions into the airway. Transmembrane secretion of ions provides the osmotic force for water flow into the airway lumen and plays a major role in hydrating the mucus and facilitating normal ciliary function. This mechanism is defective in cystic fibrosis (CF), a disease characterized by thick, immobile airway secretions (see Clinical Focus 1-8).

Various neurohumoral and pharmacological agents regulate epithelial chloride channels. Among these agents are those that increase intracellular concentrations of cyclic adenosine monophosphate (cAMP).¹⁰ Beta-adrenergic agonists increase intracellular cAMP levels, causing epithelial chloride channels to open and chloride secretion to increase. Increased levels of cAMP also cause smooth airway muscle relaxation and bronchodilation. Beta-adrenergic drugs, commonly administered for their bronchodilating properties, stimulate chloride secretion in normal airway cells.¹⁰ This action may account for the enhanced mucociliary clearance observed clinically when beta-adrenergic bronchodilators are administered. (Chapter 2 discusses adrenergic receptors in more detail.)

Epithelium-Derived Relaxing Factor

Damaged or dysfunctional epithelial cells may be partly responsible for the smooth airway muscle hyperreactivity characteristic of diseases such as asthma. The normal epithelium generates

a substance that causes smooth muscle relaxation, called epithelium-derived relaxing factor (EpDRF). EpDRF apparently modifies the responsiveness of airway smooth muscle to various stimuli. In theory, patients with damaged or dysfunctional airway epithelium do not produce EpDRF, and the response of the smooth muscle to various stimuli goes unchecked. Therefore, the airways are hyperreactive and prone to bronchospasm. EpDRF may help regulate smooth muscle tone by modifying autonomic neural impulses.¹⁶

Antiproteases in Lung Tissues and Airway Secretions

Airway secretions and lung tissues contain inhibitors of proteolytic enzymes, known as antiproteases. In people with chronic airway inflammation (patients with CF, chronic bronchitis, asthma, or emphysema and cigarette smokers), neutrophils invade the airways and release neutrophil elastase (NE), a powerful proteolytic enzyme.¹⁷ NE is designed to destroy bacteria and other microorganisms that might be present in the airway; however, when it is chronically present, NE degrades elastin and collagen, which are major structural components of the healthy lung. Healthy people have natural antiproteases in the blood, lung tissues, and secretions, the major one being alpha₁ protease inhibitor (A1PI), also known as alpha₁-antitrypsin. Secretory leukoprotease inhibitor is another antiprotease found in healthy airway secretions, which, along with A1PI, protects the lung from the NE released during episodes of airway inflammation.¹⁷ However, in chronic inflammatory lung conditions, NE overwhelms the antiproteases, and lung tissue damage occurs. Balance between the proteases and antiproteases is important for normal lung function.

Type II Cells and Surfactant Secretion

Type II cells have short, blunt projections (microvilli) on their alveolar surfaces and contain many internal organelles, including organelles known as lamellar bodies (see Figure 1-18). The lamellar bodies are the source of alveolar surfactant phospholipid, an agent that reduces surface tension and is essential for keeping the alveoli open. (See Chapter 3 for the properties of pulmonary surfactant.)

Alveolar Macrophages and Alveolar Clearance Mechanisms

Alveolar macrophages are large migratory phagocytes wandering freely throughout the alveolar airspaces and interstitium (see Figure 1-18). Their main function is to engulf and digest microorganisms and foreign material. The alveolar macrophage is the major lung clearance mechanism distal to the terminal bronchiole.

The acinus is the most ineffective area for lung clearance. Inorganic dusts such as coal or silica dust (from coal mines and stone quarries) tend to be retained in the acinus because of extremely slow clearance rates.

Alveolar macrophages in the acinus engulf foreign material (organic and inorganic), destroying bacteria and entrapping inorganic particles. Some phagocytized material is dissolved, and some is simply surrounded and isolated. Macrophages synthesize potent enzymes and oxidizing agents that kill bacteria, viruses, and fungi. These oxidizing agents are extremely lethal to microorganisms, even in small quantities. Enzyme systems in the macrophage chemically reduce oxygen in a stepwise fashion, generating large amounts of superoxide ions (O₂⁻), hydrogen peroxide (H₂O₂), hydroxyl ions (OH⁻), and ultimately water (H₂O). The mitochondria of other tissue cells produce minute quantities of these toxic oxygen radicals in the process of normal oxidative (aerobic) metabolism. However, these cells normally contain catalytic enzymes that speed up the oxygen reduction process, preventing accumulation of toxic radicals. Overproduction of these toxic oxygen radicals occurs in the presence of high inspired oxygen concentrations, leading to alveolar tissue injury, a condition known as oxygen toxicity.

After ingesting foreign matter, the macrophage may (1) migrate into the airways, where ciliary activity moves it to the pharynx; (2) migrate into the interstitial space and remain there; (3) enter the lymphatic system; or (4) simply die and remain in the alveolus.

The lung interstitium has the slowest macrophage clearance rate; particles carried to the interstitium by macrophages are most likely to cause lung tissue damage. Sharp inorganic crystals can damage and kill macrophages, releasing toxic substances, which attract cells called fibroblasts that synthesize and lay down collagen fibers over the area. Eventually, excessive fibrous tissue accumulates in the interstitium, and a condition called pulmonary interstitial fibrosis develops. The fibrous lung becomes stiff and difficult to inflate, increasing the work of breathing and impairing gas diffusion.

Cigarette smoke increases phagocytosis and the release of powerful proteases by macrophages and neutrophils (proteases are enzymes that can eventually degrade and destroy surrounding cellular protein and elastic tissue).¹⁷ Although the lung normally contains protective antiprotease enzymes, these enzymes may be overwhelmed by the continual activation of alveolar macrophages and neutrophils caused by chronic smoking. A state of chronic inflammation and alveolar destruction develops, which is the primary feature of emphysema, an irreversible airway obstructive disease.