The respiratory tract is divided into the upper respiratory tract (extrathoracic airway passages above the neck) and lower respiratory track (airway passages and lung parenchyma below the pharynx) (Harkema et al., 2006) (Fig. 15-1). The upper respiratory track reaches from the nostril or mouth to the pharynx and functions to conduct, heat, humidify, filter, and chemosense incoming air. Leaving the nasal passage, air is warmed to about 33°C and humidified to about 98% water saturation. Air is filtered in the nasal passages with highly water-soluble gases being absorbed efficiently. The nasal passages also filter particles, which may be deposited by impaction or diffusion on the nasal mucosa. Many species, particularly mice and rats, are obligate nose breathers in which air passes almost exclusively through the nasal passages. Other species, including humans, monkeys, and dogs, inhale air through both the nose and the mouth (oronasal breathers).
Major regions of the respiratory tract and predicted fractional deposition of inhaled particles in the extrathoracic, bronchial, and alveolar region of the human respiratory tract during (solid line) oral or (dashed) nasal breathing. (Adapted from Fig. 8 in Oberdörster et al. (2005) with drawing courtesy of J. Harkema and data from ICRP .)
The surface area of oronasal region has been estimated to be 4700 cm2. In mammals, the nasal passages are separated by a cartilaginous septum and the hard and soft palates form the base. Filtration, heating, and humidification are greatly aided by aqueous layer lining the mucosa and turbinates, which are perturbed from the lateral nasal walls. To warm the air, blood flow in the turbinates is retrograde to the inward direction of the air and can be modulated by pterygopalatine ganglion innervation of the venous plexus.
Turbinates vary in size and shape with the anterior being simple and the posterior being more complex. The airflow through the nasal passage is complex, and the narrowest region (smallest cross-sectional area) is located in the anterior aspect of the anterior turbinate. This region has the highest airflow and can be viewed as a nasal valve (ostium internum). The resistance of this region limits the amount of air that can be inhaled through the nose. In oronasal breathers, oral breathing can be initialed and will vary based on the workload, speech, and nasal congestion.
In humans, three flat turbinates are fairly simple structures. The inferior turbinates are the largest (∼8 cm long) and are responsible for the majority of the control of airflow direction, humidification, heating, and filtering of air inhaled through the nose. The smaller middle turbinates (∼4–6 cm) project downward over the openings of the maxillary and ethmoid sinuses, and protect the sinuses from pressurized nasal airflow. Most of the inhaled air travels between the inferior turbinate and the middle turbinate. The superior turbinates are smaller structures and serve to protect the olfactory bulb. In rodents, the anterior portion of the nasal cavity contains a dorsal nasal turbinate and a ventral maxilloturbinate, both with simple scroll structures. Posterior to these turbinates are complex multiscrolled ethmoturbinates, which contain ∼50% of the surface area of the rodent nasal passage. However, the amount of airflow over the ethmoturbinates region has been estimated to be only 10% to 15% of the air passing through the nose, and thus the complexity of this structure in rodents may contribute little additional risk of contact or damage.
The nasal passages are lined with stratified squamous epithelium in the anterior vestibule, nonciliated cuboidal/columnar epithelium in the anterior chamber, and ciliated pseudostratified respiratory epithelium in the remainder of the passage including the turbinates. The cell types of the nasal respiratory epithelium are similar to the cell types of the conducting airways. The turbinates also contain airflow pressure- and temperature-sensing neural receptors linked to the trigeminal nerve.
In addition to conducting, conditioning, and filtering air to the lower respiratory tract, a major function of the oronasal passage is chemosensory (Morris, 2001; Feron et al., 2001). Nasal epithelia can metabolize many foreign compounds by cytochrome P450 and other enzymes. Humans can distinguish between more than 5000 odors. The detection of odor can be protective and can induce avoidance behaviors. Odorant can be added to the otherwise colorless and almost odorless gas used by consumers (eg, mercaptans to methane), to assist in detecting leaks and thereby preventing fires or explosions.
Although the detection threshold concentrations can be low, a concentration only 10 to 50 times above the detection threshold value often is the maximum intensity that can be detected by humans. In contrast, the maximum intensity of sight or hearing is about 500,000 times and 1 to 10 trillion times that of the threshold intensity. For this reason, smell often identifies the presence or absence of odor rather than quantifies concentration. In addition, odor thresholds vary greatly between individuals (>1000 fold) and can be altered by allergies or nasal infections, and individuals can acclimate to odors. Some individuals cannot smell certain odors, for example, 0.1% cannot detect mercaptans in natural gas. Olfactory acuity also decreases with age (decreasing by 20%, 60%, and 70% at age of 20, 60, and 80 years). Therefore, about 30% of the elderly cannot detect mercaptans in natural gas. Lastly, odor thresholds for many compounds (eg, chlorinated solvents) are often higher than the Occupational Safety and Health Administration (OSHA) Permissible Exposure Limits (PELs). Therefore, odor should not be used as a measure of safety.
Chemosensory function of the nasal passages is accomplished by a wide variety of specialized receptors in major subtypes including (1) olfactory, (2) trace amine–associated receptors (TAARs), (3) membrane guanylyl cyclase GC-D, (4) vomeronasal, and (5) formyl peptide receptors (FPRs) (Table 15-1).
Table 15-1Oronasal Sensory Receptors I ||Download (.pdf) Table 15-1 Oronasal Sensory Receptors I
|RECEPTOR PROTEIN FAMILY ||SYMBOL ||LIGAND ||HUMAN ||MOUSE |
|Olfactory receptor ||OR ||Odorants ||>400 ||>1200 |
|Trace amine-associated receptor ||TAAR ||Amines ||6 ||15 |
|Guanylatecyclase, type D ||GUCY ||Natriuretic peptides ||1 ||2 |
|Vomeronasal receptor ||VN1R/VN2R ||Pheromones ||2* ||226 |
|Formyl peptide receptors ||FPR ||N-Formyl-peptides ||3 ||8 |
The olfactory epithelium contains specialized chemosensory olfactory neurons located above superior turbinates. Airflow in this region of the nasal passage is typical low, thus sniffing can increase perception. This may enable the assessment of multiple odors and strength of a smell through intermediate sampling. Capable of regeneration, olfactory neurons form the first cranial nerve and directly lead to the olfactory bulb in the brain. These cells have surface olfactory receptor proteins in cilia that interact with odorant molecules (DeMaria and Ngai, 2010). Olfactory receptors are 7-transmembrane domain G-protein–coupled receptors that mediate transduction of odorant signals through formation of cyclic adenosine monophosphate (cAMP) (Fleischer et al., 2009). The olfactory receptor gene family is one of the largest in the genome, with over 400, 850, 1100, and 1200 members in humans, dogs, mice, and rats, respectively. Olfactory receptors are also involved in developmental events, including the patterning of the olfactory sensory neuron synaptic connections in the brain.
Also in the olfactory region and originally identified because of activation by amine, TAARs detect trace amine (including 2-phenylethylamine, tyramine, tryptamine, and octopamine) and other substances (Fleischer et al., 2009). Low-molecular-weight amines have a fishy or putrid odor. These odorants can be found in foods (including fish, chocolate, alcoholic beverages, cheese, soy sauce, sauerkraut, and processed meat) and can be generated during fermentation or decay. Certain trace amines are neurotransmitters and are found in the brain. Compared to olfactory receptors, the number of distinct TAAR subtypes is low (15 in mice and 6 in humans). In mouse urine, trace amine concentration varies by gender or during stress, suggesting that TAARs might be involved in the detection of “urine-borne” signals.
Another olfactory sensory neuron receptor is the membrane guanylyl cyclase GC-D receptor, which contains a cyclic guanosine monophosphate (cGMP)-dependent phosphodiesterase PDE2A and a cGMP-sensitive cyclic nucleotide-gated ion channel (Fleischer et al., 2009). These receptors are localized to olfactory sensory neuron apical cilia and detect the natriuretic peptides: uroguanylin (which is also found in urine) and guanylin. In mice, GC-D receptors also can detect carbon dioxide by conversion into bicarbonate via carbonic anhydrase. In contrast to rodents, carbon dioxide is odorless to humans, and the GC-D gene is a pseudogene (ie, a gene that is present but does not yield a functional protein) in humans and other primates.
The main olfactory bulb is accompanied by the accessory olfactory bulb. Neurons from these two systems do not interconnect and the two systems function separately in the integration of specific chemicals. In rodents, the accessory olfactory bulb contains olfactory neurons that lead to the vomeronasal organ in the nose. Vomeronasal neurons can respond to olfactory stimuli that can be of higher molecular weight including nonvolatile chemicals (Touhara and Vosshall, 2009). Vomeronasal receptors exist in two protein families, VN1R and VN2R. These receptors are similar to pheromone receptors. Pheromones are chemical signals that elicit specific physiological and behavioral responses in recipients of the same species. Similar to olfactory receptor genes several vomeronasal genes exist in rodents, with few in humans, that is, 2, 8, 163, and 226 members in human, dogs, rats, and mice, respectively. Humans have not been demonstrated to generate or respond to pheromones. Expressed only during fetal gestation, vomeronasal receptors are thought to be merely vestigial in humans.
In addition, the vomeronasal organ contains FPRs that are activated by bacterial or mitochondrial formylated peptides (Fleischer et al., 2009). These receptors were initially identified in leukocytes in which N-formyl-methionyl-leucyl-phenylalanine (fMLP) mediates chemotaxis and cell activation. In the mouse vomeronasal epithelium, FPRs are activated by fMLP and other compounds (including lipoxin A4 and cathelicidin antimicrobial peptide) indicating that vomeronasal cells are likely to perform olfactory functions associated with the identification of pathogens or of pathogenic states, thereby enhancing detection of infected cells or contaminated food.
Two evolutionary hypotheses have been proposed to explain the large interspecies difference in the number of chemosensory receptor genes. One states that humans have developed full trichromatic vision and therefore do not need as many chemosensory receptor genes for finding food, mates, or supportive environments. The other is that the number of chemosensory receptor genes has expanded in the rodent lineage because rodents probably need a higher level of olfaction to survive in heterogeneous environments. However, dogs known for a good sense of smell have a smaller number of functional chemosensory receptor genes than mice or rats. This suggests that the relationship between the number of olfactory receptor genes and the sense of smell may not be straightforward. Even more complexity is suggested in that humans can detect certain odors at concentrations equal to or even below those detected by dogs or mice. One reason for this may be that olfactory perception also involves the brain. With a better memory, humans may have better olfactory ability from the small number of genes, particularly in detecting fine differences in food flavors.
Irritant, Thermosensory, and Mechanosensory Functions
In addition to the detection of odor, the detection of irritant chemicals, cold and hot temperatures, or mechanical stress can be a protective mechanism that may limit exposure. The main nerve endings that perceive irritants, the chemical nociceptors also discern temperature and mechanical stress. Two protein families, the transient receptor potential (TRP) channels and the taste (TAS) receptors, perform these functions in the upper respiratory tract (Table 15-2).
Table 15-2Oronasal Irritant, Thermo-, and Mechanosensory Receptors ||Download (.pdf) Table 15-2 Oronasal Irritant, Thermo-, and Mechanosensory Receptors
|RECEPTOR PROTEIN FAMILY ||SYMBOL ||LIGAND |
|Transient receptor potential channels ||TRP || |
| Subfamily A (ANKTM1) ||TRPA ||Natural ingredients: allyl isothiocyanate (wasabi), cinamaldehyde, allicin and allyl sulfides (garlic), carvacrol, isovelleral, and polygodial |
| || ||Pain |
| || ||Cold (<17°C) |
| || ||Mechosenstory (Strech) |
| || ||Irritants (acrolein, isocyanates, tear gas, ozone, etc) |
| Subfamily C (Canonical) ||TRPC ||Mechanosensory |
| Subfamily M (Melastain) ||TRPM2 ||Hydrogen peroxide |
| || ||Heat (>38°C) |
| ||TRPM8 ||Menthol, eucaliptol |
| || ||Cold (<17°C) |
| Subfamily ML (Mucolipins) ||MCOLN ||Acid (low pH) |
| Subfamily P (Polycystic kidney disease) ||PKD ||Mechanosensory |
| || ||Acid (low pH) |
| Subfamily V (Vanilloid) ||TRPV1 ||Capascin, allicin, and allyl sulfides (garlic) |
| || ||Moderate heat (≥43°C) |
| ||TRPV2 ||High heat (>52°C) |
|Taste receptors ||TAS || |
| Subfamily 1R ||TAS1R ||Umami (glutamate) |
| || ||Irritants (acrolein, isocyanates, tear gas, ozone, etc) |
| Subfamily 2R ||TAS2R ||Bitter |
| || ||Irritants (acrolein, isocyanates, tear gas, ozone, etc) |
| Subfamily 3R ||TAS3R ||Umami (glutamate) |
TRP channels are ion channels that are permeable to cations, including calcium, magnesium, and sodium. In mammals, 28 genes encode the TRP ion channel proteins that are divided into six subfamilies including TRPA (ANKTM1), TRPC (canonical), TRPM (melastatin), mucolipins (TRPML also known as [aka] MCOLN), polycystic kidney disease (autosomal dominant) (PCK or TRPP), and TRPV (vanilloid) families. TRPA1 and TRPV1 are the major irritant receptors in the nasal passage and are primarily within the trigeminal nerve (Bessac and Jordt, 2008). TRPA1 is responsive to a variety of natural ingredients including allyl isothiocyanate (in mustard and wasabi), cinnamaldehyde (in cinnamon), allicin and allyl sulfides (in garlic and onion), carvacrol (in oregano), isovelleral (a fungal deterrent), and polygodial (in Dorrigo pepper). TRPA1 is also responsive to pain stimuli, cold (≤17°C), stretch, and a wide range of chemical irritants. TRPV1 is responsive to capsaicin (in chili pepper) or moderate heat (≥43°C), whereas TRPV2 is responsive to higher heat (≥52°C). TRPM8 is responsive to menthol (in peppermint and cigarettes) and cold (≤28°C). Lysosomal protein, mucolipins are involved in the late endocytic pathway and in the regulation of lysosomal exocytosis. TRPC proteins are mainly located in the central nervous system and to a lesser extent in peripheral tissues. PCK1, TRPV5, and TRPV6 are calcium entry channels mainly found in the kidney and intestine.
Other chemonsensory receptors are taste receptors (TAS), which are divided into two types (Chandrashekar et al., 2006). Taste buds determine salt, sour, sweet, umami (glutamates and nucleotides), and bitter. In the mouth, salt may be perceived by sodium ion channels, but this is controversial. Sour also may be perceived by hydrogen ion channels and possibly a TRP channel (polycystic kidney disease 2-like 1). Sweet and umami are perceived by type 1 receptors, which consist of three members (TAS1R1, TAS1R2, and TAS1R3). Taste variety is achieved by formation heterodimers of these proteins, for example, umami is detected by TAS1R1 and TAS1R3 heterodimers and through metabotropic glutamate receptors 1 and 4. Bitter taste is detected by type 2 receptors (TAS2Rs), which is a larger subfamily having over 35 members. Single solitary chemosensory cells (SCCs) are present in the nasal cavity and throughout the airways. In the mouse nose, SCCs contain both TAS1R and TAS2R, which can detect irritants and foreign substances that trigger trigeminally mediated protective airway reflexes.
At the beginning of the lower respiratory track is the larynx, which is responsible for speech (phonation). The conducting airways of the lower respiratory tract can be divided into proximal (trachea and bronchi) and distal regions (bronchioles). Conducting airways have a bifurcating structure, with successive airway generations containing about twice the number of bronchi progressively decreasing in internal diameter. In humans, this branching pattern is referred to as irregular dichotomous (because some branches have more or less than two daughters) and resembles the pattern of an oak tree. In laboratory animals, the branching pattern is more monopodial and resembles the pattern of a pine tree. Successive branching has two consequences—it increases total surface area of the airway epithelium, and it increases the cumulative cross-section diameter of the airways. Thus, airflow is faster in the larger diameter proximal airways, whereas airflow is slower in the smaller distal airways. The latter is somewhat counterintuitive because flow through a smaller diameter increases in many incidences (as in a weir), but flow is slower because the larger number of small airways have a much larger cumulative diameter. Thus, the bifurcations of proximal airways are flow dividers and as airway bending points they serve as sites of impaction for particles. Successively narrower diameters ultimately lead to very slow airflows and thereby favor the collection of gases and particles on airway walls by radial diffusion. Eventually a transition zone is reached where cartilaginous airways (bronchi) give way to noncartilaginous airways (bronchioles), which in turn give way to gas exchange regions, respiratory bronchioles, and alveoli. In the bronchiolar epithelium, mucus-producing cells and glands give way to bronchiolar secretoglobin cells (BSCs). The airflow is also altered by airway smooth muscle that surrounds the airways and is under autonomic innervation via the vagus nerve.
Mucociliary Clearance and Antimicrobial Functions
In humans, the proximal airway and a portion of the nasal passage are covered by a pseudostratified respiratory epithelium that contains a number of specialized cells including ciliated, mucous, and basal cells (Fig. 15-2). These cells work together to form a mucous layer that traps and removes inhaled material via mucociliary clearance (Fahy and Dickey, 2010). The epithelial cells are covered by an upper mucus layer (a gel-like polymer network of high-molecular-weight mucins) and a lower periciliary liquid layer that separates the epithelial cell surface from the mucus layer. For mucociliary clearance in the airways to function optimally, regulation of ion transport, fluid, and mucus must be coordinated. To move fluid into the airway lumen, the large diameter airway epithelium can secrete chloride ion via chloride channels (Patel et al., 2009) and the cystic fibrosis transmembrane regulator (Chen et al., 2010). To move water out of the lumen or alveolus, sodium ion is absorbed via sodium channels. These ionic gradients permit water movement that can travel pericellulary or through specialized proteins called aquaporins.
Pseudo stratified respiratory epithelium lines the nasal cavity, trachea, and bronchi. The surface includes mainly ciliated epithelial cells that may or may not touch the basement membrane, (arrow) surface mucous (goblet) cell, and (arrowhead) basal cells. Photomicrograph modified from the Human Protein Atlas (www.proteinatlas.org) (Uhlen et al., 2010).
Ciliated cells have microtubule-based protrusions, cilia (Sanderson and Sleigh, 1981; Salathe, 2007). There are two general types of cilia: motile and primary. Motile cilia exert mechanical force through continuous motion to propel harmful inhaled material out of the nose and lung. Primary cilia often serve as sensory organelles. Motile cilia are ∼6 to 10 μm in length with a tubulin-based axoneme motor. The axoneme of each cilia consists of nine outer doublets of microtubules and a single central pair of microtubules (9 + 2 structure) formed by heterodimers of α and β tubulin. In motile cilium, dynein heavy chains on one microtubule interact with an adjacent microtubule that enables ciliary movement through energy generated by ATPase. Primary cilium lack dynein and have 9 + 0 structure.
Ciliary beat frequency is about 12 to 15 Hz, which can change in response to cholinergic (acetylcholine) or purinergic (adenosine or ATP) stimuli that changes in the phosphorylation state of ciliary targets, in intracellular [Ca2+] and in intracellular pH. In addition to controlling ciliary beat frequency, calcium is also involved in synchronizing the beat among cilia of a single cell and between cilia on different cells (Schmid and Salathe, 2011). Adenosine acts through the adenosine A2b receptor (ADORA2B) (Allen-Gipson et al., 2011). Motile cilia of the mammalian respiratory epithelium also exhibit both mechanosensory (via TRPV4) and chemosensory (via TAS2Rs) functions. TRPV4 channels respond to mechanical stress, heat, acidic pH, endogenous, and synthetic agonists, and activation leads to increases in intracellular calcium and ciliary beat frequency (Lorenzo et al., 2008). In response to bitter compounds, TAS2Rs also increase the intracellular calcium and stimulate ciliary beat frequency (Shah et al., 2009).
Mucus cells are full of lucid mucus granules. These granules increase in size as they move toward the apical cytoplasm, which produces a goblet shape and thus surface mucus cells are also called Goblet cells. Mucus consists mainly of water (95%) combined with salts, lipids, proteins, and mucin glycoproteins (Kesimer et al., 2009; Ali et al., 2011). Mucin glycoproteins provide the gel-like viscoelastic properties of mucus. Of the 20 identified membrane-associated or secretory mucin gene products, 16 have been identified in the airways (Leikauf, 2002b; Ali and Pearson, 2007). Of these proteins, mucin 5, subtypes A and C (MUC5AC), and MUC5B are the predominant mucins and to a lesser extent MUC2, 7, 8, 11, 13, 19, and 20 are produced by goblet cells on the surface epithelium and mucus cells from submucosal glands (Rose and Voynow, 2006). Membrane-associated mucins in the airways include MUC1, MUC4, and MUC16. Mucus cells can secrete antimicrobial proteins including bactericidal permeablility increasing (BPI) protein, BPI fold containing family A, member 1 (BPIF1A) (aka palate, lung, and nasal epithelium associated 1 [PLUNC1]) and BPIF3 (Bingle and Bingle, 2011).
The pseudostratified epithelium also contains a basal cell with an apical membrane that does not make contact with the airway lumen (Evans et al., 2001). These cells have desmosomal and hemidesmosomal attachments to other columnar cells and thereby anchor the respiratory epithelium. Positioned on basal lamina, basal cells can also interact with neurons, basement membrane, underlying mesenchymal cells, lymphocytes, and dendritic cells. Moreover, they can divide and differentiate into ciliated, goblet, or BC cells (Rock and Hogan, 2011).
Serous cells contain and secrete a less viscous fluid, and are also enriched in antimicrobial proteins including lysozyme and lactotransferin. In addition to surface epithelial cells, mucus and serous cells are contained in the submucosal glands limited mainly to the cartilaginous airways. The glands contain multiple branching tubules arranged with the proximal tubules contain mucus cells and the distal ascini contain serous cells. Submucosal glands secrete MUC5B, and MUC8, with MUC5B being predominate in submucosal glands, whereas surface mucus cells secrete mainly MUC5AC. Submucosal glands are contained in the cartilaginous airways (bronchi) in humans, but are minimal in rodents (especially mice). Serous cells contain the antimicrobial protein, BPIF2 (aka SPLUNC2). Secretory leukocyte proteinase inhibitor (SLPI) is a serine proteinase inhibitor that is produced locally in the lung by cells of the submucosal bronchial glands and by nonciliated epithelial cells. The main function of SLPI is the inhibition of neutrophil elastase and other proteinases, and may also have antimicrobial functions. Neutrophil elastase (ELANE) enhances SLPI mRNA levels while decreasing SLPI protein release in airway epithelial cells. In addition, glucocorticoids (which are used to treat airway inflammation) increase both constitutive and ELANE-induced SLPI mRNA levels (Abbinante-Nissen et al., 1993; Sallenave, 2010). Other submucosal gland/nonciliated epithelial cell antiproteinase/antimicrobial proteins include peptidase 3, skin-derived (aka elafin), and whey acidic protein-type (WAF) 4-disulfide core domain 2.
Another airway secretory cell is the bronchiolar secretoglobin cell (BSC), previously called the Clara cell (Winkelmann and Noack, 2010). BSCs have an extensive endoplasmic reticulum and secretory granules containing secretoglobins including SCGB1A1 (aka CCSP or CC10). The roles of secretoglobins are not fully understood, but in the lung, SCGB1A1 can inhibit phospholipase A2 and limit inflammation. In humans, BSCs are found mainly in the distal airways and can act as tissue stem cells (Rock and Hogan, 2011). In mouse, BSCs are found throughout the airways and can become ciliated cells (Rawlins et al., 2009) or mucus-producing cells (Chen et al., 2009) and can express chitinases following inflammation (Homer et al., 2006).
Neuroendocrine cells are contained in neuroepithelial bodies or separately in the proximal airways (Van Lommel, 2001) and contact can stimulate underlying sensory nerve fibers. They synthesize, store, and release bioactive substances including 5-hydroxytryptamine (aka serotonin), calcitonin-related polypeptide α (aka calcitonin), and gastrin-releasing peptide (aka bombesin). These cells express cholinergic receptor, nicotinic, α polypeptide 7 (Chrna7) and release serotonin in response to nicotine. Serotonin can also be released following hypoxia or mechanical strain. The release of these bioactive substances can redistribute pulmonary blood flow, and alter bronchomotor tone and immune responses (Cutz et al., 2007). Pulmonary neuroendocrine cells and neuroepithelial bodies in the fetal and neonatal lung modulate airway development and these cells are linked to specific types of lung cancer.
The gas exchange region consists of terminal bronchioles, respiratory bronchioles, alveolar ducts, alveoli, blood vessels, and lung interstitium (Fig. 15-3). Human lung has five lobes: the superior and inferior left lobes and the superior, middle, and inferior right lobes. In rat, mouse, and hamster, the left lung consists of a single lobe and the right lung is divided into four lobes: cranial, middle, caudal, and ancillary. A ventilatory unit is defined as an anatomical region that includes all alveolar ducts and alveoli distal to each bronchiolar–alveolar duct junction (Mercer and Crapo, 1991). Gas exchange occurs in the alveoli, which comprise −85% of the total parenchymal lung volume. Adult human lungs contain an estimated 300 to 500 million alveoli. The ratio of total capillary surface to total alveolar surface is slightly less than one. Capillaries, blood plasma, and formed blood elements are separated from the air space by a thin layer of tissue formed by epithelial, interstitial, and endothelial components.
Centriacinar region (ventilatory unit) of the lung. An airway (AW) and a blood vessel (BV) (arteriole) are in close proximity to the terminal bronchiole (TB). The terminal bronchiole leads to the bronchiole–alveolar duct junction (BADJ) the alveolar duct (AD). A number of the (arrows) alveolar septal tips close to the BADJ are thickened after a brief (four-hour) exposure to asbestos fibers, indicating localization of fiber deposition. Other inhalants, such as ozone, produce lesions in the same locations. (Photograph courtesy of Dr Kent E. Pinkerton, University of California, Davis.)
The alveolar epithelium consists of two cells, the alveolar type I and type II cell (Fig. 15-4). Alveolar type I cells cover −95% of the alveolar surface and therefore are susceptible to damage by noxious agents that penetrate to the alveolus (Williams, 2003). Alveolar type I cells have an attenuated cytoplasm to enhance gas exchange. Alveolar type II cells are cuboidal and have abundant perinuclear cytoplasm, extensive secretory capacity, and contain secretory vesicles called lamellar bodies (Whitsett et al., 2010). They produce surfactant, a mixture of lipids, and four surfactant associated proteins and can undergo mitotic division and replace damaged type I cells (Rock and Hogan, 2011). Surfactant protein B and C are amphipathic and aide in spreading secreted lipids which form a monolayer that reduces surface tension. Surfactant protein A1, A2, and D are members of the subfamily of C-type lectins called collectins, which defend against pathogens. Surfactant protein A1 and A2 do not alter lipid structure but do bind lipopolysaccharides (LPS) and various microbial pathogens, enhancing their clearance from the lung. Surfactant protein D is also necessary in the suppression of pulmonary inflammation and in host defense against viral, fungal, and bacterial pathogens. Like surfactant protein B and C, surfactant protein D does influence the structural form of pulmonary surfactant. Surfactant protein D also influences alveolar surfactant pool sizes and reuptake. The shape of type I and type II cells is independent of alveolar size and is remarkably similar in different species. A typical rat alveolus (14,000 μm2 surface area) contains two type I cells and three type II cells, whereas a human alveolus with a surface area of 300,000 μm2 contains −30 type I cells and −50 type II cells (Pinkerton et al., 1991).
Alveolar region of the lung. The (A) alveolus is separated by the thin air-to-blood tissue barrier of the alveolar septal wall, which is composed of flat alveolar type I cells and occasional rounded (II) alveolar type II cells. A small interstitial space separates the epithelium and endothelium that form the (C) capillary wall. During lung injury the interstitial space enlarges and interferes with gas exchange. (Photograph courtesy of Dr Kent E. Pinkerton, University of California, Davis.)
The mesenchymal interstitial cell population consists of fibroblasts and myofibroblasts that produce collagen and elastin as well as other cell matrix components and various effector molecules. Pericytes, monocytes, and lymphocytes also reside in the interstitium, as do macrophages before they enter the alveoli. Endothelial cells have a thin cytoplasm and cover about one-fourth of the area covered by type I cells.
The principal function of the lung is gas exchange, which consists of ventilation, perfusion, and diffusion. The lung is superbly equipped to handle its main task: bringing essential oxygen to the organs and tissues of the body and eliminating its most abundant waste product, CO2 (Weibel, 1983).
During inhalation, fresh air is moved into the lung through the upper respiratory tract and conducting airways and into the terminal respiratory units when the thoracic cage enlarges and the diaphragm moves downward; the lung passively follows this expansion. The thoracic cage enlarges by the constriction of external intercostal and internal intercondral muscles, which elevate the sternum and ribs and thus increase the width of the thoracic cavity. When the parenchyma of the lung expands during inhalation, force is transferred to the airways (especially the small diameter distal airways), which increases the airway diameter and diminishes obstruction to airflow. After diffusion of oxygen into the blood and that of CO2 from the blood into the alveolar spaces, the air (now enriched in CO2) is expelled by exhalation. Relaxation of the chest wall and diaphragm diminishes the internal volume of the thoracic cage, the elastic fibers of the lung parenchyma recoil, and air is expelled from the alveolar zone through the airways. Any interference with the elastic properties of the lung, for example, the alteration of elastic fibers that occurs in emphysema, adversely affects ventilation, as do the decrease in the diameters of, or blockage of, the conducting airways, as in asthma.
Lung function changes with age and disease and can be measured with a spirometer (Fig. 15-5). The total lung capacity (TLC) is the total volume of air in an inflated human lung, 4 to 5 L (women) and 6 to 7 L (men) (American Thoracic Society [ATS], 1991). After a maximum expiration, the lung retains 1.1 L (women) and 1.2 L (men), which is the residual volume (RV). The functional residual capacity and residual volume cannot be measured with spirometry and are determined by several other methods including nitrogen washout, in which the concentration of nitrogen is measured in expired air following inhalation of 100% oxygen. The vital capacity is the air volume moved into and out of the lung during maximal inspiratory and expiratory movement and typical is 3.1 L (women) and 4.8 L (men). Only a small fraction of the VC, the tidal volume (TV), is typically moved into and out of the lung during quiet breathing. In resting humans, the TV measures −0.5 L with each breath. The respiratory frequency, or the number of breaths per minute, is 12 to 20 (thus the resting ventilation is about 6–8 L/min). During exercise, both the TV and the respiratory rate can increase markedly. The amount of air moved into and out of the human lung may increase from 12 to 15 L/min to 40 to 60 L/min with light and moderate exercise, respectively. Increased ventilation in a polluted atmosphere increases the deposition of inhaled toxic material. Thus, susceptible individuals, particularly children and the elderly, should not exercise during episodes of heavy air pollution.
A spirometer reading of lung volumes. The total lung capacity is the total volume of air in an inflated human lung. After a maximum expiration, the lung retains a small volume of air, which is the residual volume. The air volume moved into and out of the lung during maximal inspiratory and expiratory movement, which is called the vital capacity. The tidal volume is typically moved into and out of the lung during each breathe. The functional residual capacity and residual volume cannot be measured with spirometer.
Lung function changes with age and disease and can be measured by a forced expiratory maneuver with a spirometer. In this test, an individual first inhales maximally and then exhales as rapidly as possible. The volume of air expired in one second, called the forced expiratory volume 1 second (FEV1), and the total amount expired, forced vital capacity (FVC), and the ratio of FEV1/FVC, are good measures of the recoil capacity and airway obstruction of the lung. In a healthy individual the FEV1/FVC = −80%. In chronic obstructive pulmonary disease (COPD), the parenchyma recoil is compromised, small airways close during exhalation obstructing airflow, and more air is trapped in the lung (Fletcher and Peto, 1977). Although the FVC may stay the same or may even increase slightly, narrowed small airways slow airflow at low lung volumes and thereby decrease FEV1. Thus, the FEV1/FVC is also decreased and airflow is considered obstructed when FEV1/FVC is >70% of predicted value (based on sex, height, and age). The decreased FVC is accompanied by an increase in RV. If part of the lung collapses, becomes filled with edema fluid, or is restricted due to altered lung collagen (fibrosis), FEV1, and FVC are equally reduced.
The lung receives the entire output from the right ventricle, −75 mL of blood per heartbeat. Blood with high CO2 and low O2 travels to the lung via the pulmonary artery and leaves the lung with high O2 and low CO2 via the pulmonary vein. The bronchi also have independent circulation with O2-enriched blood supplied by an artery. Substantial amounts of toxic chemicals carried in the blood can be delivered to the lung. A chemical placed onto or deposited under the skin (subcutaneous injection) or introduced directly into a peripheral vein (intravenous injection) travels through the venous system to the right ventricle and then comes into contact with the pulmonary capillary bed before distribution to other organs or tissues in the body.
Gas exchange takes place across the entire alveolar surface. Contact with an airborne toxic chemical thus occurs over a surface of −140 m2. This surface area is second only to the small intestine (−250 m2) and is considerably larger than the skin (−2 m2), two other organs that are in direct contact with the outside world. A variety of abnormal processes may severely compromise the unhindered diffusion of oxygen to the erythrocytes. Acute events may include collection of liquid in the alveolar or interstitial space and disruption of pulmonary surfactant system. Chronic toxicity can impair diffusion due to abnormal alveolar architecture or abnormal formation and deposition of extracellular substances such as collagen in the interstitium.