Normal Lung X

RESPIRATORY TRACT DEFENSE MECHANISMS
For the exchange of gases, conditioning of inspired air, and defense against inhaled toxicants to be accomplished simultaneously, highly synergistic interactions between respiratory tract clearance and secretion and biochemical and cellular defense mechanisms are required. In the normal lung, defense functions are mediated by epithelial cells of the airways and alveolar regions, resident alveolar macrophages, and numerous proteins in the extracellular spaces and mucous lining layers. Resident lung macrophages carry out the normal tasks of lung defense by selective phagocytosis of foreign particles; secretion of proteases, oxygen free radicals, and cytokines; and antigen presentation. In the presence of toxicants or other pathologic conditions, infiltration of bloodborne phagocytes, such as neutrophils, and toxicant-specific immunologic mechanisms, such as antibody production by B lymphocytes and cellular cytotoxic actions by T lymphocytes, augment the normal defense functions. Inflammatory cells recruited into the lungs tend to produce indiscriminate injury to resident lung cells and tissues by nonselective release of proteases, oxygen free radicals, and other cytotoxic agents. The lung appears to be designed to clear normal levels of inhaled pollutants without activating these inflammatory patterns, but it can activate them when more severely stressed.
Deposition of Inhaled Gaseous Toxicants
Because the physical mechanisms of transport and chemical uptake vary significantly between different airborne toxicants, no single approach can be used to estimate the pulmonary uptake of all inhaled agents. For instance, formaldehyde and ozone are both highly reactive gaseous toxicants with an inspiratory uptake of greater than 90%. However, the solubility of formaldehyde in aqueous biologic solutions is approximately 12 times greater than that of ozone. Because of their different solubilities, the critical target sites of injury for formaldehyde and ozone are at opposite ends of the respiratory tract. The major sites of uptake and toxic reactions of formaldehyde are in the nose and other parts of the upper respiratory tract. The uptake of formaldehyde in the upper respiratory tract is so rapid that virtually none of it reaches the lower respiratory tract. In contrast, because of the lower solubility of ozone, more of it reaches the lower respiratory tract. Significant uptake of ozone does occur in the nasal passages and upper respiratory tract; however, this uptake is associated with reaction of ozone with components of the thick mucous layer lining this region. The site of greatest injury from inhalation of ozone, and similar oxidant gases, is the alveolar epithelium at the transition between airways and the gas exchange region. In this region, the surface lining fluids are thin, so that the probability of ozone reacting directly with the underlying alveolar epithelial cells is greater. The critical respiratory targets and the toxic responses to all airborne pollutants depend on their inhaled concentrations, the resulting concentration gradient in different regions of the respiratory tract, and the effects of scrubbing and/or detoxification of the reactive gas by the mucous lining layer overlying the epithelial layer in each region.
Deposition of Inhaled Particles
The alveolar septal region is continually bombarded by a variety of organic and inorganic materials ranging from transition metals to animal and human proteins. Although the upper respiratory tract and upper airways filter most inhaled particulate matter, it is well documented that particles of 1 µm in size are not effectively filtered by the upper respiratory tract and that a significant fraction of these particles deposit on the intrapulmonary airways or reach the alveolar region. Normal ambient air can contain on the order of 10,000 respirable particles, defined as less than 10 µm in size with a mass median aerodynamic diameter (MMAD) of 0.3 µm, per cubic centimeter. Up to 30% of these particles deposit on medium and small airways, and about 10% deposit in the alveolar region. Thus, if a minute ventilation of 10 L is assumed, 30 million particles deposit per minute on smaller airways and 10 million particles deposit per minute on alveoli and alveolar ducts. Although the human lung contains 500 million alveoli, the particles tend to deposit proximally, and the load can be estimated to be up to one particle per minute per alveolus in the proximal alveolar ducts. The lung handles this steady, normal load of particulate matter without inducing inflammatory amplification.
These same pollutants would cause a strong inflammatory reaction if injected into another organ, yet they appear to cause virtually no reaction in alveolar septa in normal lungs. This is remarkable when one considers that the alveolar-capillary gas exchange membrane in most regions is thinner than 1 µm. If the organic and inorganic materials reaching the airways and alveolar surface were to stimulate the type of inflammatory reactions that occur in many other tissues, white cells would be rapidly recruited into these spaces and a progressive inflammation would result, leading to acute bronchitis, acute alveolitis, and/or interstitial fibrosis. The absence of an injurious response to normal lung particle burdens appears to be the result, in part, of the unique role of resident lung defense cells, such as alveolar macrophages. Each alveolus contains an average of 12 macrophages, which are thought to process all particles reaching this region under normal conditions. Alveolar macrophages have been shown to have a blunted capacity for antigen presentation and mitogen production compared with other monocytic phagocytes, and thus they are able to process inhaled particles without stimulating excessive immunologic responses or lung inflammation. The lipids and/or proteins of the alveolar surface lining layer have been shown to have anti-inflammatory actions. High particle loads given experimentally have been shown to overload these and other anti-inflammatory defense mechanisms and induce alveolar inflammation. The dose-response relationship for the onset of particle-induced inflammation is not known, nor are the mechanisms controlling this process.
Pulmonary disorders in which particle deposition and/or clearance plays a major role include hypersensitivity pneumonitis, silicosis, asbestosis and other mineral fiber disorders, and a number of metal- and organic antigen-specific disorders. In most of these cases, the biologic association between toxicant dose and health effects has been clearly demonstrated.
Epidemiologic studies demonstrate a significant association between particulate exposure and increases in hospital admissions, morbidity, and mortality. Children, whose small airways are potentially more susceptible to particle-induced inflammation and limitations of air flow, are thought to be at high risk. Airborne particulate levels as low as 150 µg/m3 are statistically associated with increases in elementary school absenteeism. The association between particle concentration and increased mortality appears to be maximal when the experimental results are averaged over a 3- to 5-day period. Such studies have been the primary means of identifying human health risks associated with particle inhalation. These studies taken as a whole suggest that ambient levels of particles on the order of 100 µg/m3 are associated with adverse health effects. Each increase of 10 µg/m3 in the PM10 (particulate matter with an aerodynamic diameter of 10 µm) is associated with an approximate 1% increase in mortality. The increased mortality appears to occur largely among the sick and elderly. The underlying biologic mechanisms responsible for these epidemiologic associations have not been determined. Interactions between particles and other pollutants, such as sulfur dioxide and nitrogen dioxide, and the effects of climate have been suggested as critical factors. High levels of trace metals in the particulate matter from urban and industrial sources have been suggested as possible causative agents. Table 6 illustrates the significant differences that exist in trace element composition between air sampled at a remote natural site and in various North American cities. In cities with a large number of anthropogenic sources, the potentially toxic trace elements of nickel, copper, and zinc are present at substantial levels. Particle samples from natural sites that are not contaminated by anthropogenic sources do not contain significant levels of these elements.

TABLE 6. Comparison of ambient dust concentrations

Deposition of inhaled particles occurs according to physical mechanisms of inertial impaction, gravitational sedimentation, diffusion, and interception. A variety of factors, such as aerosol particle size, density, shape, hygroscopic/hydrophobic character, and electrostatic charge, may also play important roles in determining how these mechanisms control the location and efficiency of deposition in the lungs. Because particles are present in a range of sizes and shapes, an aerosol is typically described by a size distribution or a mass/count weighted mean. In toxicologic evaluations, the Mass Median Aerodynamic Diameter (MMAD) is typically used to describe an aerosol in terms of the aerodynamic behavior of its particles, site(s) of particle deposition, and deposited mass. Particles in the size range of 1 to 10 µm deposit with relatively high efficiency in the upper respiratory tract and large airways, where inertial deposition is driven by high flow rates. Particles in the size range of 0.01 to 0.1 µm deposit by diffusion and are primarily taken up in the alveolar regions, where the large surface area enhances deposition by diffusion and sedimentation. The small airways do not have a single dominant mechanism of deposition.

Both empiric and mathematical approaches have been used to assess the dosimetry of inhaled particles. Direct measurements of deposition demonstrate that the human upper respiratory tract efficiently removes particles with an Mass Median Aerodynamic Diameter (MMAD) of approximately 5 µm. For particles in the 1- to 5-µm range, the total respiratory tract (upper respiratory tract plus conducting airways plus gas exchange region) deposition efficiency is on the order of 20%. Mathematically based estimates of the alveolar deposition efficiency of inhaled 1- and 5-µm aerosol particles are 5.2% and 17%, respectively.

Because of the nature of the mechanisms of deposition, deposited particles are not uniformly distributed on respiratory tract surfaces. Aerosols have been shown to deposit preferentially on the ridges of airway bifurcations, both in theoretical models and in direct observation of aerosol behavior using airways casts. Experimental observations of ciliary activity and mucous flow suggest that the concentration of particles on the ridges of airway bifurcations could, in part, result from trapping of particles on these ridges as they are cleared from more distal airways. Particles on airway ridges or branch points are cleared with a half-life of approximately 1 hour.

Particles deposited in the airways are rapidly cleared by the mucociliary escalator and by airway macrophages. Within 24 hours, most particles with a diameter of 1 µm are cleared from the airways. Particles initially deposited in the alveolar region are primarily cleared by macrophage phagocytosis. Clearance from the alveolar region is considerably slower than clearance from the airways, and removal of insoluble particles may require weeks to months.

Immunologic Responses

Immunologic responses can be classified as nonspecific or innate immune responses (actions of macrophages, monocytes, lymphocytes, and granulocytes) or agent-specific immune responses (immunologic memory of T and B cells). The innate defense mechanisms include a combination of phagocytosis and cytotoxic effects by effector cells and activation of the complement cascade. In the adaptive response, a large population of antigen-specific lymphocytes is produced that results in a potentially greater and prolonged immune system response. The adaptive response occurs when an antigen derived from the toxicant exposure is processed and presented by a dendritic cell, macrophage, or monocyte to a lymphocyte. The lymphocyte then undergoes clonal expansion to produce large numbers of cells that are specific for the particular toxic agent. Cytotoxic T-cell production occurs by this process when major histocompatibility (MHC) is expressed by the antigen-presenting cells in association with toxicant-derived antigen. Activated T cells produce numerous cytokines, such as tumor necrosis factor, that significantly enhances the immune response and the inflammatory responses of resident lung cells. Antibodies specific to the antigen are produced by B cells, which are stimulated by the interleukins to produce memory cells and plasma cells.

The effects of inhaled particles on human health are likely to involve inflammation, hypersensitization, and immunologic memory of T and B cells. These mechanisms are capable of amplifying injury initiated by repeated, low-dose exposures to antigens and therefore have the potential to produce significant effects at ambient levels of exposure. The pulmonary immune system differs from the systemic immune system in its ability to produce localized cell-mediated immune responses on repeated exposure to inhaled antigenic materials. Such localized response may play a significant role in hypersensitivity pneumonitis. Particles that contain metals have been shown to produce these responses. For instance, nickel and other transition metals are highly toxic and known to produce delayed hypersensitivity. Recent studies indicate that T-cell recognition of metal-complexed haptens plays a role in T-lymphocyte immune responses.

The airway epithelium and the alveolar epithelium are the primary lung surfaces on which inhaled toxicants may be initially distributed and/or react. The airway epithelium is a likely critical target site for an inhaled toxicant, as it is the first cellular barrier to inhaled toxicants and the most densely populated of the target surfaces. These aspects are offset to a large extent by the protection afforded by the thick mucous layer overlying airway epithelial cells and the efficient ciliary propulsion system. The alveolar epithelium of the gas exchange region has a large surface with a relatively low density of cells covered by a thin surface film. The thin surface film of the alveolar epithelial layer constitutes a critical site of possible action for pollutants not filtered by proximal airways. The outermost region of the respiratory path is the pleura, and this site is typically involved in toxic processes only after secondary transport following initial uptake of the reactive substance in more proximal air spaces. At each level, the presence or absence of adverse effects of inhaled particles and reactive gases is primarily determined by the unique immune response system in the lung.

Normal Lung IX

Alveolar Macrophages
Alveolar macrophages are the principal means by which the lungs process the normal burden of inhaled particles. Alveolar macrophages are also secretory and regulatory cells and prevent injurious actions of other lung cells. For instance, it has recently been demonstrated that macrophage engulfment of neutrophils significantly contributes to the resolution of pulmonary inflammation. Once phagocytosis of the ingested particle has been accomplished by alveolar macrophages, the cell and/or toxicant is eliminated by internal digestion or mucociliary transport of the macrophage to the oropharynx. In an additional mechanism, particle-laden macrophages have been shown to traverse the interstitial spaces to reach the mediastinal lymph nodes. Figure 17 demonstrates an airway macrophage beneath the electron-dense lining layer of a rat bronchiole. Airway macrophages are approximately five times more numerous per unit of airway surface area than they are per unit of alveolar surface (Table 4). However, because of the large surface area of the alveolar gas exchange region, alveolar macrophages account for approximately 99% of total air space macrophages.

FIG. 17. Electron micrograph of an airway macrophage beneath the electron-dense lining layer of a rat bronchiole.

TABLE 4. Macrophage distribution and number

Alveolar macrophages are unique mononuclear phagocytes. These cells contain numerous lysosomes in their cytoplasm, consume oxygen and secrete neutral proteases at a high rate, and are more active than other tissue macrophages. Although these cells are individually active, they are poor antigen-presenting cells and poor accessory cells. The primary antigen-presenting cell in the lung is a dendritic cell. The primary role of alveolar macrophages is thought to be in defense of alveoli against dust and pathogens. They appear to be able to carry out this role without activating excessive inflammatory processes in the alveolar septa. The vast majority of antigens reaching the small airways and alveolar septa are processed without activation of lymphocyte-based immune recognition and neutrophils. The lung contains very few lymphocytes in alveolar septa.

Alveolar macrophages arise in bone marrow. There is also an interstitial macrophage pool in the lung, and alveolar macrophages proliferate on the alveolar surfaces. Regeneration of the alveolar macrophage population has been shown to occur in all three of these sites.

Mast Cells

Mast cells are a normal, albeit small, component of lung cells. They are identified by the presence of numerous membrane-bound intracytoplasmic granules with variable intragranular inclusions. These granules are 0.6 to 0.8 µm in diameter. The cells also have long filiform microvilli on the surface. Mast cells have high-affinity IgE membrane-bound receptors that are specific for inhaled allergens. On activation, these cells release allergic mediators, such as histamine, prostaglandin D2 (PGD2) and leukotriene C4 (LTC4). Mast cells also produce neutral proteases (tryptase and chymase), lysosomal enzymes, myeloperoxidase, eosinophil chemotactic factor of anaphylaxis, high-molecular-weight neutrophil chemotactic factor, and heparin. Although the specific role of mast cells is unclear, they clearly play a role in airways secretory and bronchoconstrictor responses of hypersensitivity reactions such as anaphylaxis, hay fever, and asthma. Increased numbers of mast cells are found in pulmonary edema and pulmonary fibrosis.

Neutrophils

Neutrophils are terminally differentiated cells that are distributed in the bone marrow, blood, and tissue compartments. In the normal lung, neutrophils are almost exclusively found within the circulation, and almost half of the total body circulating neutrophils may be marginated along the walls of pulmonary capillaries and venules. Neutrophils are found in significant numbers in the pulmonary tissue spaces only in cases of pulmonary inflammation, such as in the adult respiratory distress syndrome (ARDS). Migration into tissue spaces occurs in response to chemotactic agents produced by invading microorganisms, toxin-derived products, and complement-activated chemoattractants, such as C5. Following phagocytosis, invading organisms are killed within neutrophils by an oxidant-mediated mechanism, by microbicidal proteins contained in neutrophil granules, or both. In the oxidant-mediated process, a membrane-bound NADPH oxidase generates O2–, which can enzymatically or spontaneously dismute to generate H2O2. These species react to form hydroxyl radical, another potent oxidant. These agents individually or in combination kill bacteria. Neutrophil granules contain a host of bactericidal agents, including myeloperoxidase, cathepsin G, acid hydrolases, elastase, and lysozyme.

Eosinophils

Eosinophils are not normally present in lung tissue spaces. However, the presence of significant numbers of these cells and their synthesis products has been shown to occur in allergically induced lung inflammation, and they are believed to play a major role in the development of reactive airways disease.

Eosinophils develop in the bone marrow and are transported via the circulation to the tissue spaces of the gastrointestinal and respiratory tracts. The host defense function is less well defined for eosinophils than for neutrophils. Eosinophils may be capable of some bactericidal activity. However, the principal function of these cells is likely their antiparasitic activity. Eosinophils synthesize and secrete potent inflammatory mediators, such as platelet-activating factor and LTC4.

Innervation of the Lung

Motor neurons in the pulmonary nervous system influence airway tone, pulmonary blood flow, and secretion of mucus. Sensory neurons modulate the cough reflex, the Hering-Breuer reflex, and responses to irritant dusts and gases, and they may respond to interstitial fluid pressure. In addition, a variety of neural peptides released by afferent nerves may modulate airway tone, vascular tone, and airway secretions.

The primary motor and sensory innervation of the lung comes from the vagus nerve (cranial nerve X). In addition, sympathetic fibers arising from the second to the fourth thoracic sympathetic ganglia innervate the lung. Fibers from both the vagus nerve and the thoracic sympathetic plexus comingle as they enter the hilum of the lung and then divide into plexuses that follow bronchi, arteries, and veins. Along the airways, the nerve plexuses lie both internally and externally to the cartilage, with the larger external plexus containing ganglia along the first three bronchial divisions. Nerve fibers continue in airway walls to the level of respiratory bronchioles.

The arterial nerve plexus travels in the media and distally reaches the full extent of muscular arterioles. The venous nerve plexus reaches all the way to the visceral pleura and even supplies subpleural alveolar walls.

In addition, small unmyelinated nerve fibers have been identified in alveolar walls. They are rare, and their source has not been clearly identified. These fibers are thought to represent J (juxtacapillary) receptors, which in animals have been shown to respond to interstitial fluid pressure and certain chemicals. They cause a transitory reflex apnea and shallow rapid respiration.

The primary motor innervation for the lung is parasympathetic (cholinergic). Stimulation of the vagus nerve leads to bronchoconstriction and enhanced secretion of mucus. These actions are blocked by atropine. Parasympathetic nerves arising from the vagus nerve synapse in the ganglia of the first generations of intrapulmonary bronchi. The primary neural inhibitor of bronchial muscular tone is vasoactive intestinal peptide (VIP). This neuropeptide is stored and released by parasympathetic neurons and may coexist with acetylcholine. Thus, the same group of neurons may release acetylcholine, which contracts airway smooth muscle, and VIP, which counteracts the action of acetylcholine to act as a bronchodilator. There are multiple examples of neurotransmitters with opposing actions being released from common nerve elements in the lung; for example, neuropeptide Y, a bronchial and vascular constrictor, coexists in pulmonary adrenergic nerves with norepinephrine. The complex interactions of the parasympathetic, sympathetic, and nonadrenergic, noncholinergic (NANC) nervous systems in the lung and the coexistence of opposing neurotransmitters has made the study of neural control of lung function difficult. It is clear, however, that motor innervation of the airways is predominantly parasympathetic and that there is no significant direct adrenergic innervation of bronchial smooth muscle.

The NANC nerve supply to the lung is thought to regulate primarily mucous secretion and bronchial blood flow. NANC nerves can be either inhibitory or excitatory, and their function is not yet well characterized. The inhibitory functions include relaxation of bronchial smooth muscle, perhaps by the release of nitric oxide or VIP. VIP is a potent relaxant of human bronchi in vitro but appears to have little effect on smaller airways. Excitatory responses of the NANC system include bronchoconstriction, possibly mediated by the release of tachykinins, such as substance P. By means of neural stains and electron microscopy, unmyelinated nerve fibers have been shown to pass through the airway epithelial basement membrane and be distributed between columnar bronchial epithelial cells. These fibers contain neuropeptides thought to be released as a reflex response to activation of local irritant receptors. The major neuropeptides identified in the lung are shown in Table 5. In addition, Kultschitsky neuroendocrine cells may play a role in afferent nerve function. These cells have been found to release neuroactive peptides, including serotonin, calcitonin, and bombesin.

TABLE 5. Neuropeptides in the human lung

Neural control of the pulmonary vascular system has been a substantial area of investigation. Despite this, the role of the nervous system in regulating blood flow in the human lung is not well understood. Nerves arising from both the sympathetic and parasympathetic systems innervate the pulmonary vascular system. In most animals, adrenergic supply of the pulmonary arterial system predominates over cholinergic innervation. Electric stimulation of the nerves of the lung has been shown to cause both vasoconstriction and vasodilation. Pulmonary arterioles are thought to be the primary site for pulmonary vascular resistance. The pulmonary venous system is well innervated and may also play a role in regulating resistance and capacitance of the pulmonary vascular system. Sympathetic stimulation in animals has been shown to cause pulmonary venous constriction.

The sensory system in the lung travels upward through both the vagus nerve and the thoracic sympathetic plexus. Receptors in the main bronchi mediate the cough reflex. Small airways contain irritant receptors that respond to irritant gases, irritant dust, and mechanical stimuli to produce bronchoconstriction, hyperventilation, and chest discomfort. The Hering-Breuer reflex involves mechanoreceptors located in airway walls. These receptors increase their rate of firing under stretch and thus inhibit the central inspiratory center as a progressive reflex response to lung expansion. The nerves mediating this reflex are thought to be located in the smooth muscle of the bronchial walls.

Normal Lung VIII

The proportion of the alveolar septum of the human lung that is interstitium is substantially greater than in many other species, as shown in Fig. 14. The alveolar interstitium increases as a function of age in both rodents and humans. The high amount of interstitium in the human lung likely reflects the substantially longer life span of the human and exposure to environmental air pollutants. The lungs of children have substantially less interstitial connective tissue and interstitial matrix elements than do adult human lungs (Fig. 14.) The alveolar macrophages on the alveolar surfaces in a normal nonsmoking human make up only about 3% of total alveolar cells. The number of alveolar macrophages is substantially elevated in smokers and can be 10% of the alveolar septal cells. The normal human alveolus has a diameter of about 225 µm and a surface area of 120,000 µm2; it is made up of 148 endothelial cells, 106 interstitial cells, and 107 epithelial cells (types I and II) and contains 12 alveolar macrophages. The comparative cellular anatomy of an average alveolus from the mouse to the human is shown in Fig. 15. The relative cell composition of the alveolar septa is similar across species. The larger alveoli of larger species are generally contain more cells of the same average size rather than larger cells. The differences in cellular size and shape between cells of different function are dramatic, as shown in Table 2, with the alveolar type I epithelial cell being four times larger than a capillary endothelial cell and having a sixfold greater surface area. Thus, cellular function, not species or organ size, determines characteristics of each class of cell.

FIG. 14. Composition of the tissues of the alveolar region in mammalian lungs. The ratios of endothelium, interstitium, epithelium, and alveolar macrophages are shown. Note that the human lung has proportionally more interstitium than do the other species illustrated. This is likely related to the extensive environmental pollutants to which human lungs are exposed, leading to microscopic fibrotic interstitial reactions.

FIG. 15. The cellular makeup of alveoli in mouse, rat, rabbit, and human. Numbers along the right vertical axis correspond to the data for human lungs. The typical human alveolus is made up of almost 400 cells.

Pulmonary Circulation

The main pulmonary artery and the next several generations of pulmonary arteries with diameters greater than 0.5 cm are called elastic arteries. The walls of these vessels contain multiple concentric elastic lamina as well as smooth muscle and collagen layers. These vessels enter the lung at the hilum and lie adjacent to and branch with each of the bronchi. Arteries with diameters ranging from 0.1 to 0.5 cm are termed muscular pulmonary arteries. These vessels contain circular smooth muscle located between an internal and external elastic lamina. Muscular pulmonary arteries begin at the level of smaller bronchi, have the same approximate diameter as the bronchi, and travel and branch with the bronchi. These arteries continue to follow bronchioles and respiratory bronchioles and enter into the center of the acinus, branching with alveolar ducts. Their size decreases as they move peripherally, and by the time they reach the acinus they are substantially smaller than the alveolar ducts.

Pulmonary veins travel in the peripheral walls of acini and along the connective tissue planes of sublobular and lobular septa. Thus, blood enters the acinus alongside the airways and then moves outward across the acinus to the periphery, where pulmonary veins collect blood from multiple adjacent acini. Each vein drains a much larger zone than is supplied by a single small muscular pulmonary artery.

A separate circulation and nutrient supply to the bronchi and the walls of their adjacent pulmonary arteries arises from the systemic circulation via bronchial arteries. These arteries come directly from the aorta or from the internal mammary, subclavian, or intercostal arteries. This systemic arterial supply to the bronchi travels as small vessels in the walls of the bronchi and extends to the level of the bronchioles. Bronchial veins exist only in the most central bronchi and empty into the azygos and hemiazygos veins. The remainder of the bronchial arterial circulation drains into pulmonary veins and moves by that circuit to the left atrium.

The relative surface areas and volumes of different components of the pulmonary vascular bed are given in Table 3. The volume of blood in the lung is normally approximately equally distributed between the arterial system, capillary network, and venous system. Ninety-six percent of the pulmonary vascular surface area is in the capillary bed. The capillary network has the capacity for substantial expansion if all capillary beds are recruited and functional, as under conditions of exercise. When the capillary network is fully recruited, the proportion of the pulmonary blood volume in the capillary bed can increase from 30% to 50%–60%.

TABLE 3. Human pulmonary vascular system

The pulmonary vascular system is a low-pressure circulation, and the pulmonary arteries are substantially more distensible than are systemic arteries. Pulmonary veins are also highly distensible at relatively low transmural pressures. Distensibility of the pulmonary vascular bed makes it possible for the blood volume to change readily in response to vasomotor stimuli or hydrostatic/orthostatic conditions. The pulmonary vascular bed acts as a capacitance reservoir for the left side of the heart. Sufficient blood is contained in the elastic reservoir to support two to three heartbeats. Pulmonary blood volume can increase 30% during a change of position from standing to lying. Up to half of the pulmonary blood volume can be forced out of the lungs by Valsalva's maneuver (increasing intrathoracic pressure against a closed glottis).

The vertical height of a normal human lung is about 25 cm, with the hilum situated about one-third the distance from the top of the lungs (Fig. 2). Pulmonary capillary pressure varies from the top to the bottom of the lung. With an average pulmonary arterial pressure of 20 cm H2O, the pulmonary arterial pressure from the top to the bottom of the lung varies from 12 cm H2O to 36 cm H2O. Pulmonary venous pressure varies from approximately 0 at the top of the lung to 24 cm H2O at the bottom, with a mean pressure of 6 to 8 cm H2O at the hilum. Thus, with a highly distensible pulmonary vascular bed, pulmonary blood volume is preferentially distributed toward the dependent portions of the lung. The effects of gravity and distensibility are balanced by vasomotor tone regulating blood flow across the pulmonary vascular bed. Because muscular arteries extend into the acinus, local vasomotor control can influence distribution of blood flow to each lung unit and thereby determine the ventilation-perfusion ratio of each of these units.

Blood flow in the pulmonary capillaries is pulsatile except under conditions of severe pulmonary hypertension. Blood flow in the capillary network has been estimated to have a velocity averaging about 1000 µm/sec.

The pulmonary capillary bed is made up of an extensive network of interconnected small tubules. There has been substantial debate regarding whether pulmonary capillary blood flow is best modeled as tubular flow or sheet flow. Anatomically, as illustrated in Fig. 16, the capillary bed is a combination of the two. The capillary network crosses multiple alveoli as blood flows from the central arteriole in an acinus to the venules at the acinar margins. This creates a fairly long path length over which gas exchange can occur. The average transit time of a red cell through the pulmonary capillary bed has been estimated to be 0.1 to 0.5 sec. Under normal resting conditions, red blood cells are fully saturated with oxygen during the first third of their transit through the pulmonary capillary bed. The lung has a sufficient gas exchange reserve that even heavy exercise does not produce arterial desaturation, and in fact increased blood flow throughout the entire capillary bed generally results in an increased arterial partial pressure of oxygen (PaO2) under conditions of exercise. Red cells are likely to leave the capillary bed not fully saturated with oxygen only when the inspired oxygen tension is low or when disease prevents adequate ventilation of individual gas exchange units. One of the important ventilation-perfusion regulatory pathways in the lung is hypoxic pulmonary vasoconstriction. Relative hypoxemia in small gas exchange units leads to constriction of the corresponding muscular pulmonary arteries, which maintains balanced ventilation-perfusion ratios. The pulmonary venous system also contains smooth muscle and has been shown to be equally sensitive to vasoactive mediators, thus regulating venous pooling in the lung.

FIG. 16. Schematic illustration of the pulmonary capillary bed showing the high density of short, highly interconnected capillary segments in the alveolar walls. The distribution of collagen and elastin fibers in the lung parenchyma is also shown. The drawing illustrates the high concentrations of connective tissue fibers along the alveolar duct septal edges that form the alveolar duct walls. Elastin fibers tend to be located over the major collagen bundles lining the alveolar entrance rings. Thus, the alveolar entrance rings are rich in both elastin and collagen. The alveolar walls contain thin collagen strands that interconnect adjacent alveoli by weaving between capillary segments.

The pulmonary capillary bed acts as an efficient filter of the systemic vascular system. Approximately three quarters of the blood volume of the body is contained in the systemic venous system. This blood passes through the pulmonary capillary bed on each circulation, and any microemboli forming in the systemic venous system will therefore be filtered by the lung. These microemboli produce no dysfunctional or pathologic effects in the lung and are rapidly cleared by lytic pathways or the pulmonary reticuloendothelial system. The physiologic effects of resection of one lung clearly demonstrate that up to half the pulmonary vascular system can be obstructed or removed without serious change in the hemodynamics of the remaining pulmonary vascular bed. This design of the pulmonary vascular system allows it to be an efficient filter of the body's blood supply.

Capillary endothelial cells form a continuous lining of alveolar capillaries. These cells are connected by tight junctions that, however, are more permeable to macromolecules than are the junctions between airway epithelial cells. Endothelial cell junctions contain one to three junctional strands, in which discontinuities exist. In comparison, airway epithelial cell junctions have three to five junctional strands. In addition, because alveolar type I epithelial cells are substantially larger (Table 2) and cover a much greater surface area per cell than do capillary endothelial cells, the total junctional area over which fluid and macromolecular transport can occur is substantially lower at the alveolar epithelium than it is along the pulmonary capillary endothelium. The impermeability of the alveolar epithelium to fluid and electrolyte movement explains why pulmonary vascular congestion (failure of the left side of the heart) leads to pulmonary interstitial edema substantially sooner than intra-alveolar pulmonary edema occurs.

The pulmonary capillary epithelium has a number of metabolic functions. Because it is the only capillary bed that receives the entire blood flow of the body during each circulation, the pulmonary capillary bed is in a critical position to regulate reactive bloodborne materials. Pulmonary endothelium plays a role in either activating or degrading a number of vasoactive mediators. Some substances are metabolized by enzymes on the capillary endothelial cell surface, whereas others require uptake into the endothelial cells. For example, angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II on the surface of pulmonary capillaries, producing a vasoconstrictive molecule of substantially greater physiologic potency. The same enzyme, ACE, inactivates bradykinin. Bradykinin is a highly potent, locally released vasodilator, and its inactivation in the lung prevents it from causing systemic hypotension. Other mediators, such as serotonin and norepinephrine, are metabolized by endothelial cells but require uptake into the cellular cytoplasm. Pulmonary capillary endothelium also synthesizes prostacyclin and tissue plasminogen activator. These cells are a rich source of thrombomodulin, a cell surface protein with anticoagulant properties. The endothelium secretes nitric oxide, a local vasorelaxant, and secretes endothelins, which are potent vasoconstrictor peptides. Vascular endothelium metabolizes adenonucleotides and both prostaglandins E2 and F2a. Vascular endothelium also plays a role in regulating phagocytic cell function via the expression of cell surface adhesion molecules. The adhesion molecules interact with receptors on phagocytic cells and regulate the movement of phagocytic cells through the vascular bed as well as their migration into subjacent tissues.

Normal Lung VII

The alveolar epithelium is covered primarily by type I and type II epithelial cells. The characteristics of the alveolar septal wall in normal human lung is shown in Fig. 12. Type I epithelial cells are thin squamous epithelial cells having an average surface area of approximately 7000 µm2 (Table 2). Their highly attenuated cytoplasm has an average thickness of only 0.36 µm. The alveolar epithelium contains approximately equal numbers of type I and type II cells. The type II cell is cuboidal in shape and is commonly found at junctions of alveolar septa and along the alveolar surfaces surrounding intrapulmonary vascular and airway structures. Alveolar type II epithelial cells have conspicuous mitochondria and an extensive Golgi apparatus, indicating a high synthetic role for these cells. They are characterized chiefly by the presence of large numbers of small microvilli on the apical surface (Fig. 13) and of unique secretory granules, known as lamellar bodies. Each type II cell contains 100 to 200 lamellar bodies. These are composed of tightly packed whirls of surfactant, which give these bodies their lamellar appearance on cross-section. The continued secretion of lamellar contents replenishes surfactant at the alveolar air-liquid interface. Alveolar type II cells are connected to adjacent type I cells with a relatively impermeable tight junction. These junctions contain three to five junctional strands on electron microscopy of freeze-fracture replicas. Type II cells have four known primary functions: (1) They secrete surfactant. (2) They act as an ion pump, moving fluid from the alveolar spaces into the subjacent interstitial spaces. Type II cells move sodium from the alveolar lumen to the interstitium via an apical sodium channel regulated by cyclic AMP. Water passively follows the sodium movement. (3) They repair alveolar injury. These cells are the progenitor cells for alveolar epithelium and can regenerate alveolar type I epithelium. (4) They control alveolar inflammation. Type II alveolar epithelial cells secrete antiinflammatory cytokines. They also secrete antioxidants, including the extracellular superoxide dismutase enzyme. Type II cells have been shown to secrete nitric oxide by the activation of nitric oxide synthase. The secretion of both antioxidant enzymes and nitric oxide by type II cells is induced by the proinflammatory cytokines interferon-g and tumor necrosis factor-a, suggesting a role for these cells in the control of inflammatory functions.

FIG. 12. Transmission electron micrograph showing the alveolar septum from a normal human lung. An efficient exchange of O2 and CO2 between inspired air and red blood cells is promoted by the large gas exchange surface with minimal distances (arrow) across the epithelial, interstitial, and endothelial components of the alveolar septa. I, type I alveolar epithelial cell; II, type II alveolar epithelial cell; c, capillary endothelial cell. Bar = 1 µm.

TABLE 2. Characteristics of alveolar septal cells in normal human lung

FIG. 13. Scanning electron micrograph of the alveolar septal surface showing several type II alveolar epithelial cells surrounded by type I epithelium. Type II cells are identified by their distinctive microvilli. In this micrograph, the overlying surfactant layer was removed by fixatives.

The shape of alveoli in vivo approximates a smooth partial circle. Smoothing of the folds on the alveolar surface is accomplished by folding of alveolar septal membranes into the capillaries and by filling of tissue depressions with alveolar lining fluid containing surfactant at its surface. Changes in alveolar size are thought to occur primarily by folding and unfolding of the alveolar pleats, and this process minimizes stress tension on alveolar septal cells.

Stability of alveoli with their small radius of curvature requires a highly surface-active material at the air-liquid interface. La Place's Law describes the relationship of the alveolar pressure (P) required to keep an alveolus open with alveolar surface tension (t) and radius of curvature (r):

According to this principle, as the radius falls during exhalation, the surface tension must also fall, or the required pressure to maintain open alveoli would rise. As alveolar pressure falls during exhalation, this scenario would result in alveolar collapse with each breath. Surfactant prevents alveolar collapse. As the radius of alveoli decreases, the surfactant phospholipids are packed more tightly and surface tension is reduced. Thus, alveolar surface tension and the radius of alveoli in vivo fall synchronously, and alveolar stability is maintained.

Surfactant is a complex mixture of lipids and proteins synthesized by alveolar type II epithelial cells. The primary lipids include saturated phosphatidylcholine and phosphatidylglycerol. Surfactant also contains a number of proteins, three of them identified as surfactant proteins A, B, and C. Each of these facilitates the spreading and recycling of surfactant. A fourth surfactant protein, SP-D, is produced and secreted by type II cells but is not known to be a part of surfactant. It is thought to play a role in antibacterial defense.

Normal Lung VI

Acini
All the gas exchange structures distal to a single terminal bronchiole represent an acinus. Thus, an acinus is a parenchymal lung unit in which all structures participate in gas exchange. The human lung fairly consistently has three generations of respiratory bronchioles that are followed by a number of divisions of alveolar ducts. Rats have from three to 13 divisions of alveolar ducts, and the human lung has a similar alveolar ductal architecture, with approximately nine generations of alveolar ducts.
A typical normal human lung contains approximately 30,000 to 40,000 terminal bronchioles and, by definition, the same number of acini. Each acinus is approximately 6 mm in diameter and has a volume of approximately 0.50 mm3. Acini vary substantially in size and typically contain 10,000 to 12,000 alveoli (Table 1).

TABLE 1. Structural characteristicsof the normal human lung

In older literature, divisions of the lung into primary and secondary lobules is described. The primary lobule refers to all respiratory tissue distal to a final respiratory bronchiole, and thus contains only alveolar ducts and alveolar sacs. Some animal species, such as the rat, have only rudimentary respiratory bronchioles, and in this situation a primary lobule is a useful concept to define aspects of ventilation and gas distribution in specific lung units. In the human, the primary lobule is not a very useful concept, because the acinus divides into multiple respiratory bronchioles and a high degree of collateral ventilation occurs between these subunits. Secondary lobules are lung units delineated by connective tissue septa; they are about 1 cm3 in size. They form structures that are clearly visible on the pleural or cut surface of the lung. The secondary lobule is supplied by a bronchiole with a diameter of about 1 mm that divides into five to 12 terminal bronchioles, and thus into a similar number of acini.

Alveoli

The gas exchange region of the lung is made up of approximately 500,000,000 alveoli having a total surface area of approximately 100 m2. These alveoli are highly vascularized, with the alveolar septal capillary bed having a vascular surface area of approximately 70 m2. The normal alveolar septa are approximately 10 µm thick. The alveolar air-capillary barrier is made up of variable thin and thick segments. The thin segment is composed of an alveolar epithelium, a fused epithelial and endothelial basement membrane, and a capillary endothelium. Because both type I epithelial cells and capillary endothelial cells are highly attenuated, the combined thickness of this air-blood barrier can be as little as 0.5 µm. The alveolar walls contain connective tissue, primarily collagen, which weaves through the capillary mesh. This and other cellular and acellular components of the interstitium create the thicker portions of the alveolar septal walls. Three-dimensional reconstructions of alveolar septal walls from rats have demonstrated that the alveolar entrance rings are particularly rich in both collagen and elastin. Alveolar mouths form the boundary of alveolar ducts (Fig. 10), and their entrance rings are linked together into a connective tissue structure that spirals down alveolar ducts, providing a connection between the openings or mouths of individual alveoli. Elastic tissue is most prominent along the alveolar duct openings. Collagen strands or fibers interlace across the alveolar walls and connect adjacent alveoli along a single alveolar duct as well as connect alveoli between two adjacent alveolar ducts.

FIG. 10. Scanning electron micrograph of the alveolar duct region from a rat lung. The alveolar duct walls are made up of alveolar mouth openings surrounded by flattened alveolar septal edges forming the entrance rings around the alveolar openings. The primary collagen and elastin network lining the alveolar ducts is under tension in this fully expanded lung.

Based on morphologic evidence of collagen and elastin distributions and the effects of surfactant depletion on the structure of alveoli and alveolar ducts, Wilson and Bachofen developed a model of lung micromechanics comparing the contributions of alveoli and alveolar ducts to lung elasticity. This model suggests that elastic components abundant in the walls of alveolar ducts are primarily responsible for the function of alveolar ducts, whereas surface tension effects are primarily responsible for the tension in alveoli. Three-dimensional reconstructions of alveoli and alveolar ducts as transpulmonary pressure is raised from 0 to 30 cm H2O demonstrate that at low lung volumes alveoli make up 80% of the parenchymal lung volume and dominate the gas volume changes. As pulmonary pressure increases, the contributions to changes in volume by both alveoli and alveolar ducts converge (Fig. 11). This suggests that at high lung volumes connective tissue elements, both between and within the alveolar ducts, come under tension and act to equalize further changes in volume between alveoli and alveolar ducts. This both limits overextension of alveoli and enhances lung stability by distributing stress among all contributing units of an alveolar duct interconnected by elastic and collagenous structures.

FIG. 11. Volume ratios of alveoli and alveolar ducts as a function of the transpulmonary extending pressure. These pressure-volume relationships were determined using morphometric point-counting procedures to estimate the relative contributions of alveoli and alveolar ducts during lung expansion. At low lung volumes, alveoli make up the majority (80%) of the lung parenchyma. As lung volume increases, alveolar ducts initially show the greatest change in volume, and they increase from 20% to almost 50% of the volume of the lung parenchyma. At about 10 cm of water pressure, the two curves converge, showing that changes in volume of these two compartments are proportionally similar from intermediate to high lung volumes or pressures. The convergence of these two curves at higher pressures suggests that the connective tissue elements within and between the alveolar ducts are under tension and help stabilize the lung by equally distributing further increases in lung volume.

Normal Lung V

Bronchioles
Bronchioles are defined by the absence of cartilaginous structures in the bronchial wall. Smooth muscle continues along bronchiolar walls and reaches the terminal bronchioles. The bronchial smooth muscle spirals around the airways and does not form a continuous coat in the bronchial wall. Thus, there is no true muscular mucosa in bronchi. The connective tissue surrounding bronchial walls is termed the lamina propria. The lamina propria includes vascular structures, lymphatics, loose fibrous tissue, and modest numbers of inflammatory cells. Adipose tissue may also be found in the walls of bronchi, particularly in older individuals.
The airway epithelium of bronchioles is simple columnar and is made up of two primary types of cells, ciliated cells and nonciliated secretory cells. The latter cell type commonly is termed a Clara cell. Unlike the arrangement in the bronchial epithelium, ciliated cells and Clara cells in the bronchioles have extensive contact with both the luminal and basement membrane surfaces. Mucus-secreting cells are not found in bronchioles under normal conditions. Chronic exposure to tobacco smoke can cause proliferation of mucous cells, which are then found in bronchioles and likely account for the higher density of viscous small-airway secretions in smokers. The production of mucus in small airways in response to chronic irritation is an adaptive response that would have the effect of absorbing or reacting with inhaled pollutants, thereby providing better protection of the underlying bronchiolar epithelium. The function of Clara cells is still being defined. These cells are thought to be involved in production of the thin serous fluid that normally lines small airways, in the detoxification of chemicals depositing in small airways, and in regulating the immune or inflammatory responses in airways. Their products include surfactant apoproteins A, B, and D, antileukoproteinase, and a unique 10-kD protein that has been found to bind to environmental pollutants. Clara cells are also thought to be a stem cell involved in the regeneration or repair of epithelial injury in bronchioles.
The number of cells per unit area of epithelial basement membrane for human airways is shown in Fig. 7. The cells populating the airway epithelium change significantly as the airways narrow and a transition occurs from a pseudostratified epithelium (with an extensive population of basal and goblet cells) to a simple columnar epithelium in bronchioles. The pseudostratified arrangement of cells in the epithelium of human bronchi creates a total epithelial cell density almost twice that of the more distal bronchioles. In addition, the cell composition changes, from larger numbers of goblet and basal cells in bronchi to larger numbers of Clara cells in bronchioles.

FIG. 7. The number of cells per unit area of epithelial basement membrane for human airways. Human airway cell populations change dramatically from the pseudostratified epithelium of bronchi, which have a large proportion of basal (bas) and goblet (gob) cells, to the simple columnar epithelium of bronchioles, composed primarily of ciliated (cil) and secretory (sec) cells.

Bronchial Branching

A terminal bronchiole represents, on average, 16 generations or branchings from the trachea. Most of the path lengths are shorter and can consist of as few as six to eight generations. The longest path length is the axial path to the posterior caudal tip of the right lower lobe, with 20 to 25 generations. Human lung airways are characterized by an asymmetric, dichotomous branching pattern in which the two (or three) daughter branches at most junctions are not of the same diameter and do not form a consistent, symmetric branching angle with the parent airway (Fig. 8). Pulmonary arteries follow the airways, whereas pulmonary veins lie in the boundaries between gas exchange units. This position allows the veins to accept blood from multiple adjacent gas exchange units (Fig. 9). An important result of the vascular supply following the airways is that each segmental bronchus with its pulmonary segment has its own vascular supply. Thus, a pulmonary segment can be resected as an anatomically discrete subdivision. Resection of one or more pulmonary segments does not compromise the blood flow to adjacent lung segments.

FIG. 8. Airway anatomy of the human tracheobronchial tree. This figure illustrates typical branching along one of the longer paths to a right lower lobe segment. In the normal human lung, there are approximately five to 15 branch points from a segmental bronchus to a terminal bronchiole. In a completely binary, symmetric branching system, 14 to 15 branch points from the trachea would be required to create the 40,000 terminal bronchioles in a human lung. Because many paths are shorter, there are also path lengths with greater than 15 branch points from the trachea. Segmental bronchi are characterized by the presence of cartilaginous plates in their walls, whereas bronchioles contain smooth muscle in their walls but no cartilage.

FIG. 9. Vascular supply and branching anatomy of the human acinus. Respiratory bronchioles typically show up to three branch points, whereas alveolar ducts have up to nine branches. Pulmonary arterioles travel with the respiratory bronchioles and alveolar ducts into the center of the acinus. The capillary network radiates outward from the arterioles to form anastomoses with the venous system, for which the major channels lie on the surface of the acinus.

Normal Lung IV

FIG. 5. Electron micrographs of secretory, basal, and intermediate cells from human bronchi. A: Secretory cells (S) containing electron-dense granules (arrows). B: Several desmosomes (d) and keratin filaments (f) of a basal cell (B). C: An intermediate cell (I) with the same features as a basal cell (i.e., desmosomes, keratin filaments, and a high nucleus-to-cytoplasm ratio) but no basement membrane contact. Whereas a prominent nucleolus is typically found in basal cell nuclei, two nucleoli, as illustrated in the intermediate cell in C, were noted only in intermediate cells. Bar at the bottom right represents 2 µm.

Mucous Lining Layers
It has long been known that the lung clears or removes inhaled particulate matter by means of a mucociliary escalator mechanism. The mucous lining of the lung airways is composed of at least two physically and morphologically distinct layers: an underlying serous layer, in which the cilia beat (sol layer), is blanketed by a viscous layer (gel layer). Whether a continuous gel layer exists throughout the airways is a matter of debate. In general, studies focusing on the nasal epithelium and upper airways have found a continuous blanket, whereas studies focusing on more distal airways and bronchioles have not. More recent studies have demonstrated that the mucous lining layer of the airways contains a surface-active film at the air-fluid interface in addition to the two layers originally described.
The bronchial epithelium plays a critical role in both producing and moving mucus out of the lung. The rate of movement of mucus is slowest in the small airways and fastest in the large bronchi and trachea. The normal adult produces substantial quantities of lung secretions daily, virtually all of which are transported by ciliary clearance to the posterior pharynx, where they are unconsciously swallowed. The outer layer of the mucous coat is a highly viscous gel containing glycoproteins with molecular weights of several million daltons. In addition to mucous glycoproteins, the airways secretions contain immunoglobulins (primarily IgA), proteinase inhibitors, and antibacterial proteins (lysozyme and lactoferrin). Sixty to eighty percent of the cells in the airway epithelium are ciliated cells; the remaining cells are either basal or secretory cells.
Methods for preserving the mucous lining layer have included direct visual observation on dissected airway specimens, fixation by immersion, vascular perfusion fixation, quick freezing, and osmium tetroxide vapor fixation. Of these different methods of preservation, vascular perfusion fixation is the most generally applicable, as mechanical disruption from immersion or airway instillation of fixative is eliminated. Because the extensive capillary bed of the lungs is used to place the fixative in the immediate vicinity of the fluid lining layers, this method has been shown to improve significantly the preservation of mucous lining layers in the airways and the surface-active film of the alveolar region. Figure 6 demonstrates the changes in the mucous lining layer along the respiratory tract of a lung fixed by a combination of osmium vapor and vascular perfusion fixation. The gel layer is present in the airways from the trachea to the bronchi. In the distal and terminal bronchioles, the gel layer is attenuated and not always present. Tubular myelin and other surfactant debris are commonly found in both the gel layer of the upper airways (trachea to bronchi) and near the surface of the sol layer of the more distal airways, where the gel layer may be absent.

FIG. 6. Changes in the mucous lining layer along one airway path from trachea to alveolar surface. The thickness decreases from 10 to 20 µm in the trachea to 0.1 µm on the alveolar surface.

Normal Lung III

Upper Respiratory Tract
The upper respiratory tract plays a critical role in conditioning air entering the lungs. Most of the air moving through the nasal cavity has turbulent flow characteristics. In addition, air moving downward into the trachea encounters a right-angle turn at the posterior nasopharynx (Fig. 3). Because of these characteristics of nasopharyngeal anatomy and air flow dynamics, most airborne particulate matter and highly reactive gases impact or are absorbed along the mucosal surfaces and so are removed in the upper airways. Aggregates of lymphoid tissue in the posterior pharynx (pharyngeal tonsils) also play a role in clearing the large amounts of airborne material deposited in the nose and other regions of the upper respiratory tract. Most airborne materials deposited in the upper airway tract are moved posteriorly along the nasal mucous coat to the posterior pharynx, where the secretions are eventually swallowed. The upper respiratory tract also plays a role in warming and humidifying the air. This process is continued in the large airways. For gases of low reactivity and particles of 1 µm in size, upper respiratory tract clearance is less efficient. A significant fraction of these airborne pollutants is deposited in the small airways and alveolar regions.

FIG. 3. Anatomy of the upper and lower respiratory tracts

Trachea and Bronchi

The trachea and main bronchi contain U-shaped rings of hyaline cartilage. The dorsal wall of the trachea is made up of a smooth muscle coat (the trachealis muscle). The main bronchi are fully encircled with cartilage for only four to six generations. Thereafter, the cartilaginous rings of intrapulmonary bronchi contain islands of cartilage that are not contiguous. The number and size of these cartilaginous islands diminish as the airways become smaller and more peripheral. This organizational pattern of cartilage has the advantage of assisting in an effective cough mechanism. The cough is initiated when intrapulmonary pressure is raised against a closed glottis, causing the smaller bronchi to narrow in size. The abrupt opening of the glottis with the onset of cough leads to high pressure and rapid flow through narrow airways, which can facilitate removal of obstructing secretions. Under normal breathing conditions, the intrapulmonary bronchi do not collapse because they are tethered to surrounding alveolar tissue with elastic and cartilaginous interconnections. The incomplete cartilage rings provide support for the intrapulmonary airways while still permitting them to narrow.

Intrapulmonary bronchi contain a subepithelial elastic layer. Outside this, smooth muscle bundles form a narrow spiral around the airways, with the smooth muscle extending to the level of the respiratory bronchiole. The tight spiral organization of the smooth muscle causes airway narrowing when the smooth muscle contracts. A loose connective tissue layer surrounds the muscular coat, and bronchial glands and cartilage plates lie in this space.

The bronchial epithelium is a stratified epithelium that includes a number of cell types. Predominant among these are secretory cells, which in the large airways are primarily mucus-secreting cells. Ciliated epithelial cells and nonciliated basal cells make up the other two major airway epithelial cell types. The bronchial epithelium also contains neurosecretory cells, termed Kultschitsky cells or K cells. They are similar to the Kultschitsky cells found in the gastrointestinal tract. These cells, which occur singly or in clusters of four to 10 cells termed neuroepithelial bodies, are thought to have a neuroendocrine secretory function. These endocrine cells are found in both bronchi and bronchioles. Kultschitsky cells are most distinctively recognized by their large numbers of fine, dense core granules aggregated in the basal part of the cells. The granules are secreted basally into the peribronchial connective tissue and surrounding smooth muscle. Various products identified with the neuroendocrine cells influence smooth muscle contraction, secretion of mucus, and ciliary beat.

Cilia are the principal means for clearing inhaled toxicants deposited in the mucous lining layers of the nasal passages and airways. Dysfunction in cilia is known to predispose individuals to respiratory infections and bronchiectasis. Ciliated cells are densely distributed in the airways, and the cilia greatly increase their apical surface area. The plasma membrane surface of the cilia accounts for approximately 80% of the plasma membrane surface in airways. Thus, the cilia themselves are a primary filter and/or target for inhaled toxicants that react with cell membranes. In the serous fluid layer in which they beat, the cilia make up 40%–50% of the volume. Each ciliated cell contains approximately 200 cilia; these beat in a biphasic stroke consisting of a fast forward flick and a slower recovery motion. Coordinated strokes by adjacent ciliated cells produce a proximally directed wave of motion in the mucous lining layer. The beating cilia produce mucociliary transport rates that vary from approximately 20 mm/min in the large bronchi to a distinctly slower rate of approximately 1 mm/min in the bronchioles. This gradient in transport rates has been assumed to be the result of a corresponding gradient in ciliary density, with fewer cilia in the small airways and greater numbers in the larger airways, to prevent piling up of mucus on the relatively small surface area of the larger airways. However, direct measurements of the density of ciliated cells and their cilia do not support this hypothesis. The mechanism or mechanisms responsible for the higher transport rate of mucus in larger airways remain to be determined.

Ciliated cells not only mechanically move mucus but also have a secretory function. These epithelial cells contain ion pumps that move sodium away from the bronchial lumen and chloride toward it. This allows water to follow the resulting osmotic gradient and thereby control the thickness and viscosity of the serous fluid layer. Proteins controlling this ion flux are encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene is a highly regulated chloride channel in the apical membrane of ciliated epithelial cells. Mutations in this gene cause cystic fibrosis.

Mucous cells (goblet cells) and mucous glands both produce mucus, but the volume coming from glands is substantially greater than that derived from mucous cells under normal conditions. The mucous glands are compound tubular glands lining the submucosa of the bronchi between cartilage plates. The glands are connected by a secretory tubule to the airway lumen. Plasma cells are often found around these secretory tubules. The plasma cells contain both IgA and IgG, although the primary immunoglobulin in mucus is 11S secretory IgA. Two IgA molecules, both of which are produced by plasma cells, are joined by the J protein. These molecules are then complexed with a secretory piece by epithelial cells lining the secretory tubules, and the complex is transported into the tubular lumen and into the mucous layer.

Examples of airway epithelium and mucous layer architecture from human bronchi are shown in the electron micrographs of Fig. 4. Characteristic profiles of ciliated and goblet cells are illustrated in Fig. 4A. In Fig. 4B, a goblet cell is in the process of secreting into the mucous lining layer. The mucous lining layer in this micrograph has a well-defined electron-dense surface film at the top of the sol layer. Examples of other secretory and basal cells in human airways are shown in Fig. 5. Secretory cells other than goblet cells are typically found in highly clustered groups, as illustrated in Fig. 5A, showing a group of secretory cells containing electron-dense granules. A basal cell with numerous desmosomes (d) and keratin filaments (f) appears in Fig. 5B. An intermediate cell (I) with the same features as a basal cell (i.e., desmosomes, keratin filaments, and a high nucleus-to-cytoplasm ratio) but no basement membrane contact is shown in Fig. 5C. The layered arrangement of cells in human bronchi is principally attributable to the basal cell layer, which accounts for approximately 90% of the cell surfaces making contact with the basement membrane. In the pseudostratified epithelium of human bronchi, the average basement membrane contact of a ciliated, goblet, or other secretory cell is significantly smaller than that of basal cells. The large concentration of keratin filaments and hemidesmosomes found in basal cells suggests that these cells play a primary role in the attachment of columnar cells to the basal lamina.

FIG. 4. Electron micrographs of the airway epithelium and mucous lining layers from human bronchi. A: Ciliated cells showing mitochondria concentrated in the apical portion of the cell and cilia extending into the mucous lining layer. One goblet cell is shown with its secretory granules distributed across the upper half of the cell. B: Two goblet cells in the process of releasing electron-lucent secretory granules from their apical surface into the mucous lining (arrow). This micrograph also illustrates a region in which the gel (or electron-dense) layer above the cilia is absent.

Normal Lung II

Pleura
The normal visceral pleura is a thin translucent sheet of mesothelial tissue. It is contiguous with the parietal pleura at the hilum, the parietal pleura being the surface covering of the chest wall. Pleural spaces are filled with a minimal amount of fluid ranging from 1 to 20 mL. The movement of fluid into and out of the pleural space depends on the combined effects of hydrostatic, colloid osmotic, and tissue pressures in the parietal and visceral pleura. The parietal pleura contains lymphatics that drain into the internal mammary artery, periaortic arteries, and diaphragmatic lymph nodes. Pleural fluid is thought to arise primarily from the capillaries lining the parietal pleura. This fluid circulates back across the parietal pleura, where it is cleared by lymphatics. Tracer studies have suggested that the parietal pleura accounts for most fluid movement into and out of the pleural spaces under normal conditions. Visceral pleural capillaries and visceral pleural lymphatics do not normally play a major role in fluid fluxes through the pleural space.
In total, the driving force withdrawing fluid from pleural spaces is greater than the net force moving fluid out of the pleural capillaries and into the pleural spaces. This results in the pleural space remaining relatively dry. Fluid does not normally accumulate in the pleural space unless hydrostatic pressure is elevated in the pulmonary capillary bed or an inflammatory condition of the pleura causes protein leakage into perivascular and pleural spaces, decreasing the oncotic pressure gradient and thereby the major force favoring extraction of fluid from the pleural spaces.
Anatomically, the pleura is made up of mesothelium. Mesothelial cells are characterized by their long microvilli, up to 2 µm in length. These cells contain desmosomal intracellular attachments (macular adherens) and also intermediate filaments in their cytoplasm (cytokeratin). Mesothelial cells have a well-developed endoplasmic reticulum, which suggests that they are metabolically active. Beneath the mesothelial cells is a thin, loose connective tissue structure containing both capillaries and lymphatics. There is also a deeper layer of elastic fibers between the relatively thin visceral pleura and the immediately subjacent alveolar septal tissues. The parietal pleura has a similar architecture, except that the underlying connective tissue layer is substantially thicker and overlies intercostal muscle, fat, and vascular structures.
Lung Lymphatics
Tissue fluids in the lung move centrally toward the hilum. In alveolar tissue, alveolar septal junctions create spaces through which fluid is thought to move until it reaches the walls of an airway or vascular structure in which lymphatic structures are present. These intrapulmonary lymphatics, termed deep lymphatics, drain the bronchovascular bundles toward the lung hilum. The superficial pleural lymphatics carry fluid along the pleural surfaces to the point at the hilum where the visceral pleura reflects into the parietal pleura. These superficial lymphatics also follow interlobular septa and thereby interconnect with the deep pulmonary lymphatic system. The deep pulmonary lymphatic system can be clearly identified anatomically beginning at about the level of respiratory bronchioles.
Lymph nodes are abundant in the pulmonary hilum and along the trachea and extrapulmonary bronchi. Lymphatic fluid drains through anastomosing channels that connect these lymph nodes and moves upward along the trachea. The lymphatics on the right side re-enter the systemic circulation through the subclavian vein near its junction with the jugular vein. Pulmonary lymphatics on the left side return to the systemic circulation through the thoracic duct or by directly emptying into the left subclavian vein.
Four major groups of lymph nodes exist in the lung. These include intrapulmonary nodes adjacent to lobar, segmental, and smaller bronchi and small nodes (1 to 3 mm) located in subpleural regions, often at junctions with interlobular septa. Extrapulmonary nodes are situated in the subcarinal region near the bifurcation of the main bronchi. They are also found along the walls of the trachea and main bronchi. The intrapulmonary nodes, which are part of either the pleura or small intrapulmonary airways, are termed N1 nodes. Extrapulmonary nodes along the main bronchi may also be termed N1. Subcarinal and ipsilateral tracheal nodes are termed N2, whereas contralateral hilar, tracheal, or bronchial nodes are termed N3.
The lung also can contain aggregates of lymphoid tissue along all levels of large and small airways. This tissue is called bronchus-associated lymphoid tissue (BALT). BALT contains lymphoid follicles with germinal centers but does not have the fibrous capsule and capsular sinus characteristic of lymph nodes. The question has been raised as to whether BALT occurs normally in humans or rather develops only after stimulation. Its specific role in immune regulation is not yet well defined.

Normal Lung I

INTRODUCTION
Inhalation of approximately 10,000 L of air is necessary to meet the daily gas exchange requirements of the adult human lung. The normal lung has an extraordinary respiratory reserve. Arterial oxygenation commonly improves with exercise, and even under heavy work conditions, pulmonary gas exchange in a normal adult is rarely a cause of limitation to aerobic performance. To accomplish the efficient extraction of oxygen and exchange of carbon dioxide, the lung has an internal surface area approximately equal to that of a tennis court. The upper and lower respiratory tracts act to condition the inhaled air, and the lung has developed unique defense pathways to allow it to maintain its fine, delicate gas exchange surface while being continuously exposed to potentially injurious reactive or infectious agents in inhaled air. This chapter reviews the normal anatomy of the human lung and focuses on the unique structural characteristics that allow the lung to maintain normal function while being continuously exposed to inhaled reactive gases and particles.
THE NORMAL RESPIRATORY TRACT
Two normal adult lungs at maximal capacity contain 5 to 6 L of air and weigh an average of 850 g in men and 750 g in women. Blood makes up a substantial fraction of the lung weight, and in vivo the lungs have been estimated to contain as much as 360 mL of blood. Lung weight is approximately 1% of total body weight in a normal adult. Ninety percent of the volume of the lungs is made up of gas exchange regions or lung parenchyma, whereas lung weight is approximately equally divided between the parenchyma and structures other than parenchyma (airways and large vessels).
The right lung is commonly slightly larger than the left, comprising about 53% of the volume of both lungs on average. Each lung is completely covered by a visceral pleura. The visceral pleura subdivides each lung, although incompletely, into lobes. The right lung has three lobes, and the left is divided into two lobes. Incomplete fissures between the lobes commonly allow for some collateral ventilation between lobes. The bronchopulmonary segments are defined by the primary segmental bronchi that branch off the lobar bronchi. Lobar segments are not commonly subdivided by pleura. There are 10 segments in the right lung (Fig. 1) and eight in the left. Common terminology identifies 10 segments in each lung, with the first and second (apical posterior) segments of the left upper lobe being a combined segment and the anterior basal and medial basal segments being combined in the left lower lobe. The left lingula is anatomically part of the left upper lobe and is not commonly separated by a pleura-containing fissure. The fissure separating the right middle lobe from the right upper lobe is termed the horizontal fissure and can occasionally be recognized as a horizontal line on an anterior-posterior chest radiograph. The oblique or major fissures separating the upper and lower lobes of both the left and right lungs can be identified on lateral chest radiographs. The left major fissure commonly lies slightly apically and anteriorly to the right major fissure (Fig. 2). However, this apparent position can be easily altered by small variations in the orientation of a left lateral chest radiograph.

FIG. 1. Location of bronchopulmonary segments from anterior, lateral, and medial views. See color plate 1.

FIG. 2. Left lateral view of the lungs. Partially translucent image of the left lung allows the right lung to be seen. The location of the major fissures and the horizontal fissure of the right lung are illustrated in the positions in which they would appear on a left lateral chest radiograph. Note that the major fissure on the right side lies slightly anterior and apical to the major fissure on the left side.

A common variant in the lobation of the lung is the presence of a horizontal fissure partially demarcating the superior segment of either the right or left lower lobes. Another variant occurs when during development the azygos vein moves into the apical portion of the right pleural cavity. This displaces parietal pleura into the lung, producing a fissure in the apex of the upper lobe of the right lung. This partially separated lung lobe, known as an azygos lobe, occurs in slightly less than 1% of the population. The lingula of the left lung may also be demarcated by an anomalous fissure.
Contours along the lung surfaces for the heart, mediastinal structures, and major vessels are illustrated in Fig. 1. A fold of tissue containing connecting tissue and vessels that extends inferiorly from the hilum on both sides is termed the pulmonary ligament.