Chapter 10. Nonrespiratory Functions of the Lung

The reader understands the nonrespiratory functions of the components of the respiratory system.

• Lists and describes the mechanisms by which the lung is protected from the contaminants in inspired air.
• Describes the “air-conditioning” function of the upper airways.
• Describes the filtration and removal of particles from the inspired air.
• Describes the removal of biologically active material from the inspired air.
• Describes the reservoir and filtration functions of the pulmonary circulation.
• Lists the metabolic functions of the lung, including the handling of vasoactive materials in the blood.

The main function of the respiratory system in general and of the lung in particular is gas exchange. However, the lung has several other tasks. These nonrespiratory functions of the lung include its own defense against inspired particulate matter, the storage and filtration of blood for the systemic circulation, the handling of vasoactive substances in the blood, and the formation and release of substances used in the alveoli or circulation.

Air Conditioning

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.

Olfaction

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.

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.

Reflexes in the Airways

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.

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.

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

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

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.

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.

The pulmonary circulation, strategically located between the systemic veins and arteries, is well suited for several functions not directly related to gas exchange. The entire cardiac output passes over the very large surface area of the pulmonary capillary bed, allowing the lungs to act as a site of blood filtration and storage as well as for the metabolism of vasoactive constituents of the blood.

Reservoir for the Left Ventricle

The pulmonary circulation, because of its high compliance and the negative intrapleural pressure, contains 250 to 300 mL of blood per square meter of body surface area. This would give a typical adult male a pulmonary blood volume of about 500 mL. This large blood volume allows the pulmonary circulation to act as a reservoir for the left ventricle. If left ventricular output is transiently greater than systemic venous return, left ventricular output can be maintained for a few strokes by drawing on blood stored in the pulmonary circulation.

The Pulmonary Circulation as a Filter

Because virtually all mixed venous blood must pass through the pulmonary capillaries, the pulmonary circulation acts as a filter, protecting the systemic circulation from materials that enter the blood. The particles filtered, which may enter the circulation as a result of natural processes, trauma, or therapeutic measures, may include small fibrin or blood clots, fat cells, bone marrow, detached cancer cells, gas bubbles, agglutinated erythrocytes (especially in sickle cell disease), masses of platelets or leukocytes, and debris from stored blood or intravenous solutions. If these particles were to enter the arterial side of the systemic circulation, they might occlude vascular beds with no other source of blood flow. This occlusion would be particularly disastrous if it occurred in the blood supply to the central nervous system or the heart, causing a stroke or a myocardial infarction.

The lung can perform this very valuable service because there are many more pulmonary capillaries present in the lung than are necessary for gas exchange at rest: Previously unopened capillaries will be recruited. Obviously, no gas exchange can occur distal to a particle embedded in and obstructing a capillary, and so this mechanism is limited by the ability of the lung to remove such filtered material. If particles are experimentally suspended in venous blood and are then trapped in the pulmonary circulation, the diffusing capacity usually decreases for 4 to 5 days and then returns to normal. The mechanisms for removal of material trapped in the pulmonary capillary bed include lytic enzymes in the vascular endothelium, ingestion by macrophages, and penetration to the lymphatic system. Patients on cardiopulmonary bypass do not have the benefit of this pulmonary capillary filtration, and blood administered to these patients must be filtered for them.

Fluid Exchange and Drug Absorption

The colloid osmotic pressure of the plasma proteins normally exceeds the pulmonary capillary hydrostatic pressure. This tends to pull fluid from the alveoli into the pulmonary capillaries and keep the alveolar surface free of liquids other than pulmonary surfactant. Water taken into the lungs is rapidly absorbed into the blood. This protects the gas exchange function of the lungs and opposes transudation of fluid from the capillaries to the alveoli. As noted in Chapter 2, type I alveolar epithelial cells may also actively pump sodium and water from the alveolar surface into the interstitium.

Drugs or chemical substances that readily pass through the alveolar-capillary barrier by diffusion or by other means rapidly enter the systemic circulation. The lungs are frequently used as a route of administration of drugs and of anesthetic gases, such as halothane and nitrous oxide. Aerosol drugs intended for the airways only, such as the bronchodilator isoproterenol, may rapidly pass into the systemic circulation, where they may have large effects. The effects of isoproterenol, for example, could include cardiac stimulation and vasodilation.

The lung was once thought of as an organ with little metabolic activity. The main function of the lung, gas exchange, is accomplished by passive diffusion. Movement of air and blood is accomplished by the muscles of respiration and the right ventricle. Because the lung appeared to do little that required energy and did not appear to produce any substances utilized elsewhere in the body, it was not believed to have any metabolic requirements other than those necessary for the maintenance of its own cells.

Metabolism of Vasoactive Substances

Many vasoactive substances are inactivated, altered, or removed from the blood as they pass through the lungs. The site of this metabolic activity is the endothelium of the vessels of the pulmonary circulation, which constitute a tremendous surface area in contact with the mixed venous blood. For example, as shown in Table 10–2, prostaglandins E1, E2, and F2α are nearly completely removed and almost 50% of endothelin1 is removed in a single pass through the lungs. On the other hand, prostaglandins A1, A2, and I2 (prostacyclin) are not affected by the pulmonary circulation. Similarly, about 30% of the norepinephrine in mixed venous blood is removed by the lung, but epinephrine and isoproterenol are unaffected.

These alterations of vasoactive substances in the lung imply several things. First, some substances released into specific vascular beds for local effects are inactivated or removed as they pass through the lungs, preventing them from entering the systemic circulation. Other substances, apparently intended for more general effects, are not affected. Second, in the case of those substances that are affected by passing through the lungs, there may be profound differences in the response of a patient receiving an injection or infusion of one of these substances, depending on whether it is administered via an arterial or venous catheter.

Formation and Release of Chemical Substances for Local Use

Several substances that produce effects in the lung have been shown to be synthesized and released by pulmonary cells. The most familiar of these is pulmonary surfactant, which is synthesized in type II alveolar epithelial cells (and partly in Clara cells) and released at the alveolar surface, as shown in Figure 10–6. Surfactant plays an important role in reducing the alveolar elastic recoil due to surface tension and in stabilizing the alveoli, as discussed in Chapter 2. A number of factors may modulate surfactant secretion, including glucocorticoids, epidermal growth factor, cyclic adenosine monophosphate, and distention of the lung. Histamine, lysosomal enzymes, prostaglandins, leukotrienes, platelet-activating factor, neutrophil and eosinophil chemotactic factors, and serotonin can be released from mast cells in the lungs in response to conditions such as pulmonary embolism and anaphylaxis. They may cause bronchoconstriction or immune or inflammatory responses, or they may initiate cardiopulmonary reflexes. If there is a chemical mediator involved in hypoxic pulmonary vasoconstriction, it is produced in and acts in the lung. As discussed in Chapter 4, it is currently believed that hypoxia acts directly on the pulmonary vascular smooth muscle cells by causing decreased permeability to potassium ions, thereby decreasing the efflux of potassium ions and depolarizing the cells. This response, however, may be modulated by mediators released locally. Many substances are also produced by cells of the lung and released into the alveoli and airways, including mucus and other tracheobronchial secretions, the surface enzymes, proteins and other factors, and immunologically active substances discussed earlier in this chapter. These substances are produced by goblet cells, submucosal gland cells, Clara cells, and macrophages.

Formation and Release into the Blood of Substances Produced by Lung Cells

Bradykinin, histamine, serotonin, heparin, prostaglandins E2 and F2α, and the endoperoxides (prostaglandins G2 and H2) are all produced and/or stored by cells in the lung and may be released into the general circulation under various circumstances. For example, heparin, histamine, serotonin, and prostaglandins E2 and F2α are released during anaphylactic shock.

Other Metabolic Functions

The lung must be able to meet its own cellular energy requirements as well as respond to injury. The type II alveolar epithelial cell also plays a major role in the response of the lung to injury. As type I alveolar epithelial cells are injured, type II cells proliferate to reestablish a continuous epithelial surface. Studies in animals have shown that these type II cells can develop into type I cells after injury.

• Alveolar ventilation brings thousands of liters of air each day into the airways and alveoli, which must be protected from contaminants, microorganisms, low humidity, and cold temperatures.
• Metabolic functions of the lung include alterations of many vasoactive substances as they pass through the pulmonary vascular endothelium; formation and release of substances for use in the lungs, such as pulmonary surfactant, or elsewhere in the body; and repair of the alveolar surface in response to injury.

A 5-year-old boy is seen by a pediatrician because of a chronic cough producing thick viscous mucus, wheezing, dyspnea on exercise, recurrent respiratory and sinus infections, abdominal pain, and digestive problems.

He is thin and small for his age, with a low body mass index. His fingers appear to be mildly clubbed. A younger sibling is beginning to develop similar problems. The pediatrician suspects that the boy has cystic fibrosis and refers him to a pediatric pulmonologist.

His chest radiograph shows hyperinflation and signs of mucus plugging and bronchiectasis (dilation and partial destruction of large airways). Pulmonary function tests show a mixture of obstructive and restrictive disease: low lung volumes and capacities, low FEV1 and FVC, and a low FEV1/FVC. Blood gas analysis shows a low

Cystic fibrosis is the most common cause of chronic pulmonary disease in young adults in the United States. It is a hereditary autosomal recessive disease caused by abnormalities in a membrane chloride channel found in the epithelial cells of the ducts of almost all of the exocrine glands of the body, including the mucous glands of the respiratory system; the exocrine glands of the pancreas, liver, bile ducts, and intestine in the gastrointestinal (GI) tract; and the sweat glands. Mutations of the channel, called the cystic fibrosis transmembrane regulator (CFTR) protein, cause decreased or absent ability of the epithelial cells of the airways to secrete chloride ions into the lumen and cause increased reabsorption of sodium ions and water, resulting in thick viscous mucus. In the sweat glands, the epithelial cells of the sweat gland ducts are unable to reabsorb sodium and chloride from the sweat as it is produced. Effects in the GI tract depend on the organ. Hundreds of different mutations of the gene that codes for CFTR have been discovered, although about 60% of clinical cases involve a mutation referred to as ΔF508.

The patient’s pulmonary problems relate to the mucus in the airways, which is thick and viscous because it has much less water content and because of accumulated DNA from dead neutrophils and other cells from inflammation and infections. The mucociliary escalator is less capable of moving the mucus toward the pharynx, and it is more difficult to clear the mucus by coughing, expectorating, or swallowing it. Accumulation of mucus in the airways decreases their effective diameters, causing airway obstruction, as demonstrated by the lower than predicted FEV1/FVC. Enough mucus may accumulate in small airways to occlude them and lead to atelectasis, intrapulmonary shunt, and hypoxemia; the increased work of breathing may lead to CO2 retention and a respiratory acidosis, partly compensated for by bicarbonate reabsorption in the kidneys. Hypoxemia leads to clubbing, as discussed in the clinical correlation for Chapter 6.

The mucus that accumulates in the airways is an excellent medium for bacterial growth and explains the recurrent infections experienced by the patient. Repeated damage of the larger airway by the infections causes bronchiectasis.

Digestive problems, along with the increased work of breathing, make adequate nutrition of the patient difficult and explain the boy’s low body mass index and small stature.

Cystic fibrosis is a fatal disease, but improvements in treatment have extended the life expectancy of many patients with cystic fibrosis to well over 30 years of age. Treatment includes improved clearance of mucus by postural drainage, and chest percussion or vibration; decreasing the viscosity of the mucus by inhaling nebulized hypertonic saline and by using recombinant DNase to break down the viscous DNA that enters the mucus from airway inflammation and dead neutrophils; using corticosteroids to suppress inflammation of the airways; using long- and short-term antibiotics to suppress infection; and using inhaled bronchodilators. Some patients have received transplanted lungs. Death usually occurs from pulmonary complications such as pneumonia, or respiratory failure and or cor pulmonale (see Clinical Correlation from Chapter 11).