Every day about 10,000 L of air is inspired into the airways and the lungs, bringing it into contact with approximately 50 to 100 m2
of what may be the most delicate tissues of the body. This inspired air contains (or may contain) dust, pollen, fungal spores, ash, and other products of combustion; microorganisms such as bacteria; particles of substances such as asbestos and silica; and hazardous chemicals or toxic gases. As one reviewer (Green) put it, “Each day a surface as large as a tennis court is exposed to a volume of air and contaminants that would fill a swimming pool.” In this section, the mechanisms by which the lungs are protected from contaminants in inspired air, as well as from material such as liquids, food particles, and bacteria that may be aspirated
(accidentally inspired from the oropharynx or nasopharynx) into the airways, are discussed.
The temperature and the humidity of the ambient air vary widely, and the alveoli must be protected from the cold and from drying out. The mucosa of the nose, the nasal turbinates, the oropharynx, and the nasopharynx have a rich blood supply and constitute a large surface area. The nasal turbinates alone have a surface area said to be about 160 cm2. As inspired air passes through these areas and continues through the tracheobronchial tree, it is heated to body temperature and humidified if one is breathing through the nose.
Because the olfactory receptors are located in the posterior nasal cavity rather than in the trachea or alveoli, a person can sniff to attempt to detect potentially hazardous gases or dangerous material in the inspired air. This rapid, shallow inspiration brings gases into contact with the olfactory sensors without bringing them into the lung. Of course, not all hazardous gases have an odor that can be detected, for example, carbon monoxide.
Filtration and Removal of Inspired Particles
The respiratory tract has an elaborate system for the filtration of the inspired air and the removal of particulate matter from the airways. The filtration system works better if one is breathing through the nose.
Filtration of Inspired Air
Inhaled particles may be deposited in the respiratory tract as a result of impaction, sedimentation, Brownian motion, and other, less important mechanisms. Air passing through the nose is first filtered by passing through the nasal hairs, or vibrissae. This removes most particles larger than 10 to 15 μm in diameter. Most of the particles greater than 10 μm in diameter are removed by impacting in the large surface area of the nasal septum and turbinates (Figure 10–1). The inspired air stream changes direction abruptly at the nasopharynx so that many of these larger particles impact on the posterior wall of the pharynx because of their inertia. The tonsils and adenoids are located near this impaction site, providing immunologic defense against biologically active material filtered at this point. Air entering the trachea contains few particles larger than 10 μm, and most of these will impact mainly at the carina or within the bronchi.
Schematic drawing of the upper airways. (Reproduced with permission from Proctor, 1964.)
Sedimentation of most particles in the size range of 2 to 5 μm occurs by gravity in the smaller airways, where airflow rates are extremely low. Thus, most of the particles between 2 to 10 μm in diameter are removed by impaction or sedimentation and become trapped in the mucus that lines the upper airways, trachea, bronchi, and bronchioles. Smaller particles and all foreign gases reach the alveolar ducts and alveoli. Some smaller particles (0.1 μm and smaller) are deposited as a result of Brownian motion due to their bombardment by gas molecules. The other particles, between 0.1 and 0.5 μm in diameter, mainly stay suspended as aerosols, and about 80% of them are exhaled.
Removal of Filtered Material
Filtered or aspirated material trapped in the mucus that lines the respiratory tract can be removed in several ways.
Mechanical or chemical stimulation of receptors in the nose, trachea, larynx, or elsewhere in the respiratory tract may produce bronchoconstriction to prevent deeper penetration of the irritant into the airways and may also produce a cough or a sneeze. A sneeze results from stimulation of receptors in the nose or nasopharynx; a cough results from stimulation of receptors in the trachea. In either case, a deep inspiration, often near to the total lung capacity, is followed by a forced expiration against a closed glottis. Intrapleural pressure may rise to more than 100 mm Hg during this phase of the reflex. The glottis opens suddenly, and pressure in the airways falls rapidly, resulting in compression of the airways and an explosive expiration, with linear airflow velocities said to approach the speed of sound. Such high airflow rates through the narrowed airways are likely to carry the irritant, along with some mucus, out of the respiratory tract. In a sneeze, of course, the expiration is via the nose; in a cough, the expiration is via the mouth. The cough or sneeze reflex is also useful in helping to move the mucous lining of the airways toward the nose or mouth. The term “cough” is not specific to this complete involuntary respiratory reflex. Coughs can be initiated by many causes, including postnasal drip from allergies or viral infections, asthma, gastroesophageal reflux disease, as an adverse effect of the very commonly prescribed angiotensin-converting enzyme inhibitors, mucus production from chronic bronchitis, infections, and bronchiectasis. Voluntary coughs are not usually as pronounced as the violent involuntary reflex described above.
Tracheobronchial Secretions and Mucociliary Transport: The “Mucociliary Escalator”
The entire respiratory tract, from the upper airways down to the terminal bronchioles, is lined by a mucus-covered ciliated epithelium, with an estimated total surface area of 0.5 m2. The only exceptions are parts of the pharynx and the anterior third of the nasal cavity. A typical portion of the epithelium of the airways (without the layer of mucus that would normally cover it) is shown in Figure 10–2.
Scanning electron micrograph of the surface of bronchiolar epithelium. Ci = cilia; MV = microvilli on surface of unciliated cell. A secretion droplet can be seen at far left. (Reproduced with permission from Weibel, 1998.)
The airway secretions are produced by goblet cells and mucus-secreting glands. The mucus is a complex polymer of mucopolysaccharides. The mucous glands are found mainly in the submucosa near the supporting cartilage of the larger airways. In pathologic states, such as chronic bronchitis, the number of goblet cells may increase and the mucous glands may hypertrophy, resulting in greatly increased mucous gland secretion and increased viscosity of mucus.
The cilia lining the airways beat in such a way that the mucus covering them is always moved up the airway, away from the alveoli, and toward the pharynx, as shown in Figure 10-3. The mucus comprises 2 layers, an outer gel layer with trapped inspired particles and a sol layer that directly covers the ciliated epithelium. The mucus is normally 5- to 100-microns thick and has a fairly low pH of 6.6 to 6.9. Exactly how the ciliary beating is coordinated is unknown—the cilia do not appear to beat synchronously but instead probably produce local waves. The mucous blanket appears to be involved in the mechanical linkage between the cilia. The cilia beat at frequencies between 600 and 900 beats/min, and the mucus moves progressively faster as it travels from the periphery. In small airways (1–2 mm in diameter), linear velocities range from 0.5 to 1 mm/min; in the trachea and bronchi, linear velocities range from 5 to 20 mm/min. Several studies have shown that ciliary function is inhibited or impaired by cigarette smoke.
Diagram of a part of the mucociliary escalator. Note the particles trapped in the gel layer, with the cilia in the sol layer below the gel layer. (Redrawn from West JB. Pulmonary Pathophysiology: The Essentials. 7th ed. Baltimore: Lippincott Williams & Wilkins; 2008:128.)
The “mucociliary escalator” is an especially important mechanism for the removal of inhaled particles that come to rest in the airways. Material trapped in the mucus is continuously moved upward toward the pharynx. This movement can be greatly increased during a cough, as described previously. Mucus that reaches the pharynx is usually swallowed, expectorated, or removed by blowing one’s nose. It is important to remember that patients who cannot clear their tracheobronchial secretions (an intubated patient or a patient who cannot cough adequately) continue to produce secretions. If the secretions are not removed from the patient by suction or other means, airway obstruction will develop.
Dendritic cells, like the alveolar macrophages discussed in the next section, are mononuclear phagocytic cells. They inhabit the airways all the way from the trachea to the terminal respiratory units. “Immature” dendritic cells can phagocytize bacteria and other antigens or ingest them by pinocytosis. After contact with antigens, they “mature” and migrate to lymphoid tissues to promote tolerance to the antigen and prevent the immune response by releasing anti-inflammatory cytokines, or if the antigen is recognized as a pathogen, activate T-lymphocytes and the immune response and inflammation by releasing stimulatory molecules.
Defense Mechanisms of the Terminal Respiratory Units
Inspired material that reaches the terminal airways and alveoli may be removed in several ways, including ingestion by alveolar macrophages, nonspecific enzymatic destruction, entrance into the lymphatics, and immunologic reactions.
Alveolar macrophages are large mononuclear ameboid cells that inhabit the alveolar surface. Inhaled particles engulfed by alveolar macrophages may be destroyed by their lysosomes. Most bacteria are digested in this manner. Some material ingested by the macrophages, however, such as silica, is not degradable by the macrophages and may even be toxic to them. If the macrophages carrying such material are not removed from the lung, the material will be redeposited on the alveolar surface on the death of the macrophages. The mean life span of alveolar macrophages is believed to be 1 to 5 weeks. The main exit route of macrophages carrying such nondigestible material is migration to the mucociliary escalator via the pores of Kohn and eventual removal through the airways. Particle-containing macrophages may also migrate from the alveolar surface into the septal interstitium, from which they may enter the lymphatic system or the mucociliary escalator. Macrophage function has been shown to be inhibited by cigarette smoke. Alveolar macrophages are also important in the lung’s immune and inflammatory responses, as was discussed with dendritic cells, both in suppressing the immune response to recognized nonpathogenic antigens and activating the immune response and inflammation in response to recognized pathogens. They secrete many enzymes, arachidonic acid metabolites, immune response components, growth factors, cytokines, and other mediators that modulate the function of other cells, such as lymphocytes. A scanning electron micrograph of an alveolar macrophage is shown in Figure 10–4.
Scanning electron micrograph of an alveolar macrophage (MA) on the epithelial surface of a human lung. Arrows point to the advancing edge of the cell. (Reproduced with permission from Weibel, 1998.)
Other Methods of Particle Removal or Destruction
Some particles reach the mucociliary escalator because the alveolar fluid lining itself is slowly moving upward toward the respiratory bronchioles. Others penetrate into the interstitial space or enter the blood, where they are phagocytized by interstitial macrophages or blood phagocytes, or they enter the lymphatics.
Particles may be destroyed or detoxified by surface enzymes and factors in the plasma and in airway secretions. These include lysozymes, found mainly in leukocytes and known to have bactericidal properties; lactoferrin, which is synthesized by polymorphonuclear lymphocytes and by glandular mucosal cells and is a potent bacteriostatic agent; α1-antitrypsin, which inactivates proteolytic enzymes released from bacteria, dead cells, or cells involved in defense of the lung (eg, neutrophil elastase); interferon, a potent antiviral substance that may be produced by macrophages and lymphocytes; and complement, which participates as a cofactor in antigen-antibody reactions and may also participate in other aspects of cellular defense. Taken together these are considered the innate immunity system.
Finally, many biologically active contaminants of the inspired air may be removed by antibody-mediated or cell-mediated immunologic responses (the adaptive or acquired immunity system). A diagram summarizing bronchoalveolar pulmonary defense mechanisms is shown in Figure 10–5; respiratory system defense mechanisms are briefly summarized in Table 10–1.
Schematic diagram of bronchoalveolar defense mechanisms. (Reproduced with permission from Green, 1977.)
Table 10–1. Overview of Pulmonary Defense Mechanisms ||Download (.pdf)
Table 10–1. Overview of Pulmonary Defense Mechanisms
- Physical and mechanical
- “Air conditioning” heats and humidifies inspired air
- Olfaction can detect some potential hazards in inspired air
- Reflexes such as bronchospasm and laryngospasm may prevent penetration of liquids and other materials deeper into the lung
- Filtration and impaction remove particles from inspired air
- Sneeze and cough can expel particles trapped in mucus
- Epithelial barriers and mucus limit particle penetration through airway walls
- Mucociliary escalator transports particles toward pharynx
- Innate immunity
- Antibacterial proteins and peptides in airway surface liquid help prevent infection (lactoferrin, lysozymes, defensins)
- Airway epithelial cells recognize structures on microbes and release chemokines, cytokines, and lipid mediators
- Mediators recruit polymorphonuclear leukocytes and monocytes
- Airway, interstitial, and alveolar macrophages, polymorphonuclear leukocytes, and dendritic cells phagocytose particulates, organisms, and debris
- Surfactant proteins bind to microbes and enhance phagocytosis and release of immune response mediators by macrophages.
- Adaptive immunity
- Humoral immunity
- B lymphocytes produce specific antibodies against non-self antigens “remembered” from previous exposure
- Antibodies neutralize toxins and pathogens, activate complement, and promote phagocytosis and pathogen elimination
- Cell-mediated immunity
- T lymphocytes kill tumor cells and cells infected with pathogens