HUMAN RESPIRATORY TRACT PHYSIOLOGY

5.2.1 Introduction

Industrial environments expose individuals to a plethora of airborne chem­ical compounds in rhe form of vapors, aerosols, or biphasic mixtures of both. These atmospheric contaminants primarily interface with two body surfaces: the respiratory tract and the skin. Between these two routes of systemic exposure to airborne chemicals (inhalation and transdermal ab­sorption) the respiratory tract has the larger surface area and a much greater percentage of this surface exposed to the ambient environment. Or­dinary work clothing generally restricts skin exposures to the arms, neck, and head, and special protective clothing ensembles further limit or totally eliminate skin exposures, but breathing exposes much of the airway to contaminants.

Inhaling potentially noxious airborne mixtures exposes respiratory tis­sue and the supporting vasculature to disease and injury. In addition, other organs can be injured due to transepithelial transport along the airway to the bloodstream and subsequent bulk transport throughout the body. Conse­quently, understanding the relationship between industrial ventilation and human health requires knowledge of how’ the respiratory tract interacts with the surrounding environment. It is the goal of this chapter to lay the ground­work for understanding how the human airway deals with potential air­borne threats.

5.2.2 Anatomical Overview

The human respiratory tract serves to deliver oxygen to the bloodstream and remove carbon dioxide. It accomplishes this by utilizing two large air bags (lungs) with extremely large internal surface areas to transport these gases be­tween the pulmonary airstream and capillaries. The lungs are situated inside a semirigid bony structure (rib cage), which is joined together by intercostal muscles and supported from below by a large sheet of muscle tissue (dia­phragm). These structures serve to physically protect the lungs and generate the forces required for inspiration and exhalation. Immediately surrounding the lungs are bags (pleura), which transfer force generated by the diaphragm and intercostal muscles to the lungs and are penetrated by numerous blood vessels.

The respiratory tract can be theoretically subdivided into distinct func­tional regions (Fig. 5.14). Dividing the respiratory tract into conducting and respiratory airways is perhaps the simplest division. Framed in this way, the respiratory tract consists of two airway regions: a series of tubes (nasal and oral cavities, pharynx, larynx, trachea, bronchi, and nonalveolated bronchi­oles) leading to a terminal region of essentially bag-like structures (respiratory bronchioles, alveoli), where gas is exchanged between the airway lumen and the surrounding capillaries.

A slightly more detailed airway organization suggested by the ICRP Task Group on Lung Dynamics1 divides the airway into five regions: nasal

And oral cavities, pharynx and larynx, tracheobronchial tree, bronchioles, and alveoli. This construct essentially refines the view of conducting airways into a portal region (extrathoracic airways) and conducting tubes (tracheo­bronchial tree). Extrathoracic airways comprise all airway structures proxi­mal to the larynx. Figure 5.14a shows this to include the nasal passages, nasopharynx, oral cavity, oropharynx, pharynx, and larynx. These struc­tures have the functions of removing gross contaminants from the inspired airstream, humidifying and warming inspired air, and primary recovery of whatever heat and humidity can be retained from expired air. The tracheo­bronchial tree consists of a straight tube (trachea) terminating in a series of bifurcating tubes, which subsequently terminate at the pulmonary airways. The trachea, bronchi, and nonrespiratory bronchioles have the functions of removing fine particulates from the inspired airstream and completing the conditioning (raising to body temperature and complete saturation) of in­spired air. Distal to the terminal bronchioles (the most distal nonrespiratory bronchioles) is the lung parenchyma, where gas exchange occurs in the respi­ratory bronchioles and alveoli.

5.2.2.1 Extrathoracic Airway Anatomy

The most proximal regions of the extrathoracic airways are the nasal and oral cavities, which act as portals to and from the ambient environ­ment. Figure 5.14& shows how, during nasal breathing, inspired air enters at the two nares, passes through the nasal vestibules and turbinates, and ex­its at the nasopharynx. Total distance along the nasal passageway from the nares to the nasopharynx is approximately 10-14 cm. This narrow conduit (1-3 cm in width) divides into two paths by a septum extending from the nares to the distal edge of the turbinates. Though relatively short and nar­row, the nasal passageways have a large surface area ( =160 cm 2 compared with =69 cm2 for the trachea) because of the highly convoluted turbinate structure.

Inspired air enters the nasal passages via two nares (nostrils), whose cross­sectional area can be enlarged by circular muscles (dilator naris muscles). Im­mediately distal to the nares are the nasal vestibules, pyramidal openings lined by squamous epithelium with nasal hairs projecting from the epithelium. These hairs achieve coarse filtration of the inspired airstream. Inspired air passes out of the vestibules via the nasal valves, slit-like openings at the back of the vestibules (each valve having a cross-sectional area of =30 mm 2), and enters the turbinates.

The turbinate regions are 5-8 cm long and defined by bony projections (superior, middle, and inferior conchae) forming convoluted passages through this region of the nasal cavity. Corresponding openings (superior, middle, and inferior meatus) define three airway passages. Ciliated epithe — lia and mucus-secreting goblet cells generally line the luminal surfaces of the turbinate region, though olfactory tissues are found in the superior me­atus. Figure 5.15 shows how air traveling within the turbinates can easily pass between the different meatus. The tortuous passageways promote deposition of inspired particles as well as the exchange of heat and water

Nasal cavity nasopharynx oral cavity oropharynx Upper airway lower airway

Trachea

Mam bronchi smaller bronchi

(d)

N. V-wl

Ibu e

Ves

Nasal Turbinates

Frontal sinus sphenoid sinus concha nasalis superior superior meatus concha nasalis media medial meatus nasopharynx Concha nasalis inferior inferior meatus oral cavity Oropharynx tongue Hypopharynx

(b)

FIGURE 5.14 (a) Anatomical overview of the human respiratory tract. The larynx generally

Serves as the boundary between the upper (extrathoracic) and lower airways, (b) Anatomy of the upper airway.

Vapor between the airway wall and the inspiratory or expiratory air — str earns. Meatus cross-sectional areas correlate to airflow, the greatest quantity of air passing through the inferior meatus. Slower airflow within the superior meatus allows for greater residence times along these airway surfaces. Increased residence times enhance olfaction occurring at the ol­factory bulbs located along the superior surface of the superior meatus. Airstream mixing caused by eddy currents within the superior meatus fur­ther enhances olfaction.

The two (left and right) inspiratory nasal airstreams merge in the distal end of the turbinates before experiencing a 90° bend in the airway upon enter­ing the nasopharynx. The nasopharynx is roughly 5 cm long, has a volume of 12 cm2, and is lined with squamous epithelium, which appears to protect un­derlying tissue from gross mechanical injury. Any relatively large particles ( >3 |xm) successfully navigating the nasal passages will likely impinge upon the nasopharyngeal wall because of inertia. Ciliated columnar epithelium in­terspersed with mucus-secreting goblet cells appearing distal to the nasophar­ynx marks the start of the oropharynx.

Ambient air entering the oral cavity during oral breathing confronts a variety of surface structures. Inspired air initially passes between highly vas­cular lips and across the teeth, which can be viewed as a series of heat trans­fer fins. The tongue and buccal surfaces (both rough, highly vascular

Inferior M<

Middle Me

Superior IV

(c) 84 mm

(a) 33 mm

(b) 48 mm

FIGURE 5.15 Cross — section of human nasal turbinates at various positions aiong the airway. Dis­tances indicated are from the nares. The medial surface in each cross-section represents the nasal sep­tum. (Modified from Guilmette et al.2)

Surfaces) and the hard palate border the cavernous opening beyond the teeth. The soft palate defines the distal limit to the oral cavity, beyond which the airstream bends 90° to enter the oropharynx. Oral cavity dimensions vary greatly depending on tongue position and extension of the buccal sur­faces but a simple cylindrical model (8 cm length, 1.8 cm diameter) has been used to characterize the oral cavity.3 Inspired air passing our of the oral cav­ity enters the oropharynx.

The pharynx (nasopharynx, oropharynx, and hypopharynx) serves to pass air between the airway portals (nasal and oral cavities) and the thoracic airways (tracheobronchial tree, alveoli). It terminates at the epiglottis, a valve that prevents swallowed food and liquids from entering the lower airways. Be­yond the epiglottis lies the larynx, which serves as a conduit for air passing in and out of the lower airways and as a tone-producing structure. Both pharyn­geal and laryngeal surfaces are lined with columnar ciliated epithelium and goblet cells, except for the squamous epithelium lining the nasopharynx and a small area on the vocal folds of the larynx.

5.2.2.2 Central and Pulmonary Airway Anatomy

Inspired air passing out of the larynx forms a jet as it enters the trachea, the largest conducting tube in the airway. The most proximal tube in the tra­cheobronchial tree (generation zero in the Weibel “A” model),4 the trachea has an approximate diameter of 1.8 cm and extends in adults roughly 12 cm from the distal edge of the larynx to the carina. Columnar ciliated epithelium and goblet cells are the primary cell types lining the tracheal lumen. Negative pressures within the tracheal lumen during strenuous inspiration can produce significant radial pressure gradients that would, if possible, collapse the tra­chea. Tracheal patency during strenuous breathing is ensured by a series of in­complete cartilaginous rings supported by fibroelastic and smooth muscle tissues extending along the length of the trachea.

The trachea terminates at the carina, the site at which the main bron­chi bifurcate. Bronchial tube diameters and generally lengths decrease dis­tally from the carina with successive bifurcations. The right and left main bronchi have diameters of approximately 1.2 cm and lengths of 4.76 cm, decreasing to diameters of approximately 0.13 cm and lengths of 0.46 cm in the smallest bronchi (generation 10). Cartilage occurring in airway walls down to the tenth generation of bifurcations assists bronchial smooth mus­cle in maintaining bronchial patency during strenuous breathing. Bronchi­oles (generations 11-18) lack cartilage and rely entirely on smooth muscle for maintaining luminal patency during breathing. Alveolar ducts (genera tions 19-23) and alveoli (generation 24) lack any cartilage or smooth mus­cle and maintain patency by a balance between tensile forces generated by gases present within the alveolar lumen and alveolar fluid surface tension. Surfactants present in alveolar fluid prevent surface tension from collaps­ing the alveoli (atelectasis).

The estimated number of tubes in each airway generation depends on the bifurcation model used in describing the tracheobronchial tree. Though bronchial bifurcations are asymmetric, symmetric models, exemplified by Weibel,"’ or asymmetric models, such as one suggested by Horsfield, h can

Each serve to represent airway branching. Recent studies have also suggested a fractal pattern to the bifurcations.7’8 Whatever the overall bifurcation pat­tern, the general structure can be most easily summarized by the Wei be 1 “A” model,4 in which successive bronchial generations are more numerous, shorter, and have smaller individual cross-sectional areas than more proxi­mal generations. According to the Weibel “A” model, the number of branches in generation z is

N(z) = 2Z (5.32)

And the mean diameter of airways in generation z, d(z), is given by

D(z) = d02~*/3 (5.33)

Where d0 = tracheal diameter (Table 5.5). Consequently, overall cross­sectional area increases exponentially as a function of distance from the nares, producing a predicted alveolar surface area of 43-80 m2. Respira­tion (exchanging 02 for C02) depends on this large exchange surface to provide sufficient gas exchange capacity during strenuous activity to ac­commodate demands by active muscles for greater volumes of 02 and the need to remove excess C02.

5.2.2.3 Airway Wall Anatomy

Airway cross-sections have the nominal anatomy shown in Fig. 5.16. Air­way surface liquid (ASL), primarily composed of mucus gel and water, sur­rounds the airway lumen with a thickness thought to vary from 5 to 10 mm. ASL lies on the apical surface of airway epithelial cells (mostly columnar cili­ated epithelium). This layer of cells, roughly two to three cells thick in proxi­mal airways and eventually thinning to a single cell thickness in distal airw^ays, rests along a basement membrane on its basal surface. Connective tissue (col­lagen fibers, basement membranes, elastin, and water) lies between the base­ment membrane and airway smooth muscle. Edema occurs when the volume of water within the connective tissue increases considerably. Interspersed within the smooth muscle are respiratory supply vessels (capillaries, arterio­venous anastomoses), nerves, and lymphatic vessels.

Certain respiratory diseases (e. g., asthma and emphysema) alter air­way dimensions, thereby modifying airflow patterns and adversely affect­ing gas exchange and particle deposition. Emphysema breaks down alveolar walls, enlarging alveolar sac volume but significantly reducing overall alveolar surface area. Assuming a constant gas exchange flux, re­ducing alveolar surface area decreases gas exchange and diminishes the body’s ability to obtain oxygen from the inspired airstream. In addition, eliminating alveolar walls reduces the number of alveoli and shortens over­all path length. A shorter path may allow larger inhaled particles to reach and deposit in the pulmonary airways, potentially leading to adverse clini­cal consequences. Diseases that reduce bronchial diameter (asthma, chronic bronchitis, and cystic fibrosis) increase airstream velocity in oc­cluded airway regions, increasing heat and water vapor exchange and par­ticle impaction while reducing sedimentation in the affected bronchi. This results in a greater volume of fine inhaled particles [<3.0 jxm mean mass aerodynamic diameter (MMAD)] passing to more distal (and potentially

TABLE 5.S Representative Conducting Airway Dimensions Based on the Weibel “A” Model Reynolds number Minute ventilation Cross- Equivalen Airway Sectional T Segment Area Diameter Length 8 16 30 Airway region (cm) (cm) (cm) L/min L/min L/min

Nasal vestibule	1.3	67	0.9	1515	3029	5679
Nasal cavity	2.4	0.61	1.8	1664	3327	6238
Nasal turbinates	2.3	0.44	1.3	2306	4612	8648
Nasal turbinates	2.6	0.36	4.4	2819	563 7	10570
Nasal turbinates	3	1.18	0.6	860	1720	3225
Proximal nasopharynx	3.9	2.03	2	500	1000	1875
Distal nasopharynx	2.9	1.45	3	700	1400	2624
Proximal oropharynx	2.8	1.26	1.7	805	1611	3020
Distal oropharynx	3	1.3	1.3	781	1561	2927
Proximal hypopharynx	2.3	1.5	2.4	676	1353	2537
Distal hypopharynx	1.9	1.3	1.3	781	1561	2927
Larynx	1.8	1.5	1.1	676	1353	2537
Proximal trachea	2.1	1.6	2.7	634	1268	2378
Distal trachea	2.8	1.9	9.3	534	1068	2003
Bronchii gen. 1	3.4	1.47	4.8	345	689	1292
Bronchii gen. 2	3.9	1.11	1.9	227	454	851
Bronchii gen. 3	3.9	0.79	0.8	161	323	605
Bronchii gen. 4	3.9	0.56	1.3	114	229	429
Bronchii gen. 5	4	0.4	1.1	80	159	299
Bronchii gen. 6	4.3	0.29	0.9	54	107	202
Bronchii gen. 7	4.7	0.22	0.8	37	75	140
Bronchii gen. 8	5.4	0.16	0.6	24	47	89
Bronchii gen. 9	6.7	0.13	0.5	15	31	58
Bronchii gen. 10	8	0,1	0.5	10	20	37
Bronchii gen. ! 1	19.6	0.11	0.4	4.4	8,9	17
Bronchii gen. 12	28.8	0.1	0.3	2.8	5.5	Hi
Bronchii gen. 13	44.5	0.08	0.3	1.4	2.9	5,4
Bronchii gen. 14	69.4	0.07	0.2	0.8	1.6	3
Bronchii gen. 15	113	0.07	0.2	0.5	1	1,9
Bronchii gen. 16	180	0.06	0.2	0.3	0.5	I
Bronchii gen. 17	300	0.05	0.1	0.1	0.3	0,5

Note that turbulent flow (Reynolds number > 3000 is predicted only in the exfrathoracie airways at flow rates < 30 L/min.

And hydrostatic pressure.19 Estimates of daily mucus production range from 7-12 mL/day in healthy individuals to > 100 mL/day in cystic fibro­sis patients.

Airway Epithelial Cell Types

Conducting airway passages are generally composed of ciliated pseudostratified cuboidal columnar epithelial cells interspersed with basal, brush, and secretory cells (goblet, serous, Clara). Cilia found on ciliated epithelial cell apical surfaces (along the lumen) provide motive force for propelling mucus gel along the airway. Extrathoracic airway surfaces are lined with ciliated epithelium, except for squamous epithe­lium covering the nasal vestibule, nasopharynx, oral cavity, orophar­ynx, and portions of the larynx. Squamous epithelium protects airway surfaces against mechanical impact or shear in areas where relatively large inspired particles usually impact. Also, nasal olfactory surfaces are not lined with ciliated epithelium but covered instead by special sensory cells. These specialized olfactory receptor cells react with in­haled odorant molecules, generating neural signals sent to the olfactory bulbs of the brain that produce a sense of smell. All tracheobronchial surfaces are lined with ciliated epithelium down to the pulmonary air­ways. Proximal airway epithelium is thickest and progressively flattens and chins toward the lung parenchyma, gradually transitioning into al­veolar endothelium.

Secreting cells found along the conducting airways include nonciliated goblet and serous cells. Goblet cells produce glycoproteins that form droplets or sheets of mucus gel floating on periciliary fluid. Serous cell exudates are believed to include periciliary fluid, various proteins and peptides (including lysozyme and lactoferrin), and protease inhibitors. Periciliary fluid also de­rives from interstitial fluid transudate. Glycosaminoglycans, lipids, serum proteins, and ions found in ASL appear to originate from all surface epithelial cells and submucosal glands (serous and mucous). The quantity of submu­cosal glands decreases in more distal airways and are absent from pulmonary airways.

Microvilli, approximately 2 jim long, give a “brush-like” appearance as they project from the apical surface of brush cells. These cells contribute to fluid regulation along the luminal surface by absorbing excess periciliary fluid either secreted by neighboring serous cells or transported from distal airways by the mucociliary elevator. Basal cells are progenitors of the other epithelial cells and are the most actively mitotic epithelial cells. Lymphocytes also ap­pear in ASL as either migratory or basal cells.

Pulmonary airways are lined with specialized cells generally not found in the conducting airways. Alveolar epithelium, composed of thin sheet-like cells separated from pulmonary capillaries by only a basement membrane, permits easy exchange of gases between alveolar sacs and blood (Fig. 5.17). Secretory Clara and Type 11 pneumonocyte cells produce surfactant, lipids, and protease inhibitors within the pulmonary airways. Macrophages are scavenger cells that remove microorganisms and particulates depositing along alveolar surfaces.

Lnrravascular blood pressure drops as a function of arterial and arteriole diameter to such an extent that capillary walls can consist of a single layer of endothelial cells. Capillaries, with diameters of 6-8 ^.m, transport blood close enough (roughly 20—30 jini) to cells throughout the body to allow gas (O, and COj), heat, nutrient and waste, and water exchange between blood and cells via diffusion. Interstitial tissue containing collagen fibers, basement mem­branes, elastin, and water supports capillary endothelial cells and provides ad­ditional tensile strength. Capillaries merge to form venules, which in turn merge to form veins. These low-pressure components of the cardiovascular system—capillaries, venules, and veins—transport deoxygenated blood from the capillaries to the right atrium of the heart via the largest vein, the inferior vena cava.

Blood supplying conducting airway tissues derives from large bron­chial arteries branching off either the aorta or intercostal arteries. These vessels also supply blood to the visceral pleura, regional nerves and lymph nodes, and vascular walls of the pulmonary arteries and veins. Bronchial artery branches follow the conducting airways and provide blood to the bronchial walls down to the respiratory bronchioles. Smaller arterial branches form anastomoses along the peribronchial surface (Fig. 5.18). Arterioles originating from the peribronchial anastomoses penetrate the bronchial smooth muscle and form relatively straight, thin bronchial cap­illaries and submucosal anastomoses. Conducting airway luminal cells

Bronchial

Artery

FIGURE 5.18 Vasculature structure along a portion of bronchial muscle. Airway epithelia are not shown In this figure but lie between the submucosal venules and the airway lumen. Modified from Deffe — bach et al.20

Bronchial Vein

Bronchial Muscle

(ciliated epithelium, serous, and goblet cells) are supplied with nutrients, oxygen, water, and heat via these submucosal anastomoses.

Respiratory bronchioles and alveoli are supplied with deoxygenated blood from the right ventricle of the heart by the pulmonary arteries, rive lo­bar arterial branches follow the bronchi, and subsequent bronchopulmonary arterial branches run adjacent to smaller airways to the level of the respiratory bronchioles. Dense coiled capillary networks beyond this point distribute deoxygenated blood to capillaries and return oxygenated blood to the venules arising from the respiratory bronchiolar, alveolar, and alveolar duct capillary beds. Pulmonary capillaries directly attach to lung connective tissue, reducing diffusive resistance to gas exchange.

Vessels linking bronchial arteries directly with pulmonary alveolar mi­crovessels are commonly found in neonates but apparently decrease in fre­quency with age. There is also evidence of direct communication between bronchial arteries and pulmonary veins. Venous blood originating from ex — trapulmonary airways (proximal to approximately generation 3 bronchi) drains into the right atrium via the azygos and hemiazygos veins. Intrapul — monary bronchial venous flow, returning blood to the heart from bronchi distal to the third generation, drains into the pulmonary circulation, which subsequently drains into the left atrium either directly or via the pulmo­nary vein.

Airway surfaces, like skin, are continually exposed to the ambient envi­ronment. In contrast to skin submucosal vessels, however, which shed excess heat by vasodilating when heated and conserve heat by vasoconstricting when chilled, it is unclear how the airway vasculature responds to temperature ex­tremes. Inspiring cold air poses two challenges to conducting airway tissues: the risk of tissue injury should inadequate heat reach the airway surface and excessive body heat loss due to increasing the radial temperature gradient. Va­sodilation would protect airway tissue but increase heat loss, while vasocon­striction would produce the opposite effect.

Nasal vasculature may offer some insight into this question, though re­search to date has been equivocal. Nasal turbinate vessels can be classified as either capacitance vessels or resistive vessels. Capacitance vessels appear to va­sodilate in response to infection23 while resistance vessels appear to respond to cold stimuli by vasoconstriction.-2 Buccal vascular structures also respond to thermal stimuli but appear to respond principally to cutaneous stimuli.23 How pharyngeal and tracheobronchial submucosal vessels react to thermal stimuli is not known, though cold-induced asthma is believed to result from broncho — spasms caused by susceptible bronchial smooth muscle responding to expo­sure to cold dry air.24’25 This asthmatic response suggests an inadequate vascular response to surface cooling.

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