Respiratory Defense Mechanisms

Breathing exposes a large body surface area to attack by noxious materials or pathogens present in the ambient atmosphere. A complex series of defense mechanisms, including physical removal, chemical neutralization, and immu­nological response, protect against biological, chemical, or mechanical injury. Physically removing toxins or pathogens from the airstream by coughing, sneezing, movement along the mucociliary escalator, or phagocytosis in the al­veoli reduces exposure concentrations in vulnerable airway regions. Airborne toxins can be neutralized by endogenous NH3, while deposited materials are diluted, buffered, and neutralized by periciliary fluid and mucus gel. Immuno- globins and enzymes present in periciliary fluid and along alveolar surfaces can eliminate deposited pathogens that have not been physically removed. Vapor Phase Neutralization

In addition to typical atmospheric or metabolic constituents (N2, Oz, H20, and C02), breathing transports chemical species in the form of vapors and par­ticulates along the respiratory tract. While 02 and C02 gas exchange occurs solely in the lung parenchyma, air/blood exchange of other species can and does occur throughout the airway. The principal airway absorption sites of gases such as O. and S02 are largely determined by their waterrair partition coefficient (the concentration ratio at equilibrium) and water solubility.98 Highly water-soluble

Respiratory Defense Mechanisms

Chemical species with high watenair partition coefficients are generally absorbed in the extrathoracic airways, while less soluble species pass beyond the extratho — racic airways in relatively high concentrations (see Section 5.3).

Concentration gradients provide the driving force for gaseous chemical spe­cies diffusion between the luminal gas mixture and ASL. Factors that alter this gradient, such as local airstream concentration, chemical reactivity, lipid solubil­ity, and ASL metabolism, modulate local absorption or reentrainment into the airstream. Local airstream/ASL concentration gradients drive diffusion into or out of ASL along a given airway length. wo° As the inspiratory air passes along the airway and comes into contact with previously unexposed ASL, chemical species follow the concentration gradient and diffuse into ASL. The leading edge of the inspiratory wave becomes increasingly depleted of the diffusing species, increasing proximal ASL concentrations while reducing airstream concentra­tions downstream. Consequently, ASL absorption decreases in more distal air­ways. Reentrainment can occur during expiration if concentration gradients are reversed, i. e., tracheobronchial and extrathoracic ASL concentrations exceed those found in gases flowing outward from the lung parenchyma.

The rate at which an absorbed chemical species is removed from the ASL determines whether reentrainment occurs during a breathing cycle/1*1 Slow re­moval rates relative to the breathing cycle allow the concentrations in the ASL to be higher than in the expiratory airstream. Figure 5.26 shows processes that diminish the ASL concentration of absorbed chemical species. Metabolic pro­cesses or interactions with ions and other chemically reactive substances found

Respiratory Defense Mechanisms

Respiratory Defense Mechanisms


FIGURE 5.26 Various chemical and physical mechanisms which can affect ASL chemicaJ con­centration during breathing. Dilution due to transepithelial water exchange depends on the osmotic pressure gradient between periciliary and interstitial fluid.

Respiratory Defense Mechanisms

The nasal passages form an efficient filtration mechanism for inspired air, removing larger particulates ( >3 MM AD) before they can enter the tho­racic airways. The very largest inspired particles (roughly 10 fim MMAD and larger) impinge on nasal hairs (vibrissae) and are mechanically removed from the nasal cavity (e. g., by blowing one’s nose). Particle inertia generally causes the remaining larger particles to deposit along the nasal cavity surfaces by im­paction because of convoluted nasal geometry. A particle impacts an airway wall when the path length to the wall equals the lateral displacement, L, oc­curring while the particle moves at a velocity u along a streamline altering di­rection by an angle Q, which is given by

L = uutsinB (5 47)

‘ 8 ’ » ‘ ‘

Where terminal velocity, ut, is the particle velocity at which particle inertia is balanced by drag forces. For 1.0 jxm Ј d Ј 40 p. m,

Wf=i^(pp-pj> (5.48)

Where g is the gravitational constant, is the air viscosity, and pp and pa are the density of the particle and air, respectively. Larger particles that success­fully traverse the nasal passages typically impact the nasopharyngeal wall at the 90° turn beyond the distal edge of the nasal cavity.

Finer particles ( < 3 pun), termed respirable particles, pass beyond the ex-

Trathoracic airways and enter the tracheobronchial tree. Impaction plays a sig­nificant role near the tracheal jet, but sedimentation predominates as the effects of rapid conduit expansion dampen in the distal trachea and beyond. Sedimentation occurs when gravitational forces exerted on a particle equal drag forces, i. e., when particle velocity falls to ut,. As mean inspiratory air — stream velocity gradually declines along the tracheobronchial tree, particle momentum diminishes and 0.5-3 p. m MMAD particles settle out of the air­flow and onto mucosal surfaces.

Mean airflow velocities approach zero as the inspired airstream enters the lung parenchyma, so particle momentum also approaches zero. Most of the particles reaching the parenchyma, however, are extremely fine (< 0.5/xm MMAD), and particle buoyancy counteracts gravitational forces. Temperature gradients do not exist between the airstream and airway wall because the inspired airstream has been warmed to body temperature and fully saturated before reaching the parenchyma.50,51 Consequently, diffusion driven by Brownian motion is the only deposition mechanism remaining for airborne particles. Diffusivity, Da can be described under these conditions by


Where k is the Boltzmann constant, T is the absolute temperature, is the air viscosity, and d is the particle diameter. Particle displacement, 5, is a function of residence time, t, and Dc such that

Respiratory Defense Mechanisms




Particle size, MMAD (urn)


FIGURE 5.28 Estimated overall airway deposition as a function of initial particle size and parti­cle hygroscopicity for particles with mass median aerodynamic diameters (MMAD) between 0.1 and 10 (jim.102 Geometric dispersion, a measure of particle size distribution, principally affects only smaller MMAD.

Respiratory Defense MechanismsConsequently, any breathing pattern which increases pulmonary residence times, such as breath-holding, increases fine particle deposition throughout the airway.

Where along the airway inspired particles deposit depends on particle mass, since the deposition mechanism depends on particle MMAD. Passage through the airway has no effect on nonhygroscopic particle mass (e. g., fly ash), and initial MMAD determines the deposition pattern (Fig. 5.28). In con­trast, hygroscopic particles (e. g., acid droplets) increase in mass when exposed to humid environments like the respiratory tract. Particle properties (e. g., chemical composition, ionic concentration, and particle surface area) and air — stream conditions (e. g., temperature, RH, and VE) which affect hygroscopic growth consequently play major roles in determining particle mass and depo­sition patterns (Fig. 5.29).

Acid Aerosol Neutralization

Sulfuric acid (H2S04) and ammonium bisulfate (NH4HS04) contribute im­portantly to ambient acid aerosols, particularly in geographic locations where sulfur-rich coal is used for power plant fuel, such as the eastern United States.103 Studies on animals and human subjects have shown that H2S04 and NH4HS04 alter mucociliary transport in a dose-dependent fashion104-106 and can adversely affect pulmonary function in humans.106 While this effect on clearance has generally been attributed to hydrogen ion concentration, [H+], the work of Schlesinger et al.107 suggests that, for equivalent inhaled [H+], H2S04 elicits a greater change than NH4HS04. If this observation is confirmed, it

Hygroscopic Particle Deposition Determined by Initial MMAD

(continuous RH protile, saturated saline, ag = 1.0′

{Q = 250 mL7min, f — 15 breachs/min)

Respiratory Defense Mechanisms

Airway generation (z)

Hygroscopic Particle Deposition Determined by Initial Ionic Concentration

{continuous RH profile, MMAD = 2.0 ^m)

{Q = 250 ml /min* f = 15 breaths/min)

Respiratory Defense Mechanisms

Airway generation z)

FIGURE 5.29 Predicted effects of initial hygroscopic particle properties (initial diameter, ionic concentration) on the airway deposition profile.102 Larger initial particles are predicted (left) to deposit in the more proximal airways while fine particles reach pulmonary airways in much greater concentra­tions. Initially high ionic concentrations (saturated saline) are predicted (right) to deposit primarily in upper airways, probably due to their rapid growth during transit through the upper airway. More moder­ate growth rates represented by normal saline aerosol result in greater predicted deposition in the pul­monary airways. Airway generation — Irepresents the upper airway while the trachea is given as generation 0.

Would appear that the molecular form of the inhaled acid may play a significant role, perhaps through differences in hygroscopic growth and neutralization rate between H2S04 and NH4HSO4 particles.

For a given ambient concentration of acid aerosol, the dose of acid deliv­ered to the respiratory tract is in large measure determined by the pH and parti­cle size of the aerosol. Due to the efficiency of the upper airways (particularly the nasal passages) in filtering coarse (>3 |im) particles, submicrometrk acid aerosol particles pose the greatest risk to the lower airways. Ambient acid aero­sols are overwhelmingly submicrometric in size distribution at most relative hu­midities.108 Submicron acid particles therefore merit special attention in the attempt to understand the action of acid aerosols on airway health, particularly as they comprise a large proportion of acidic environments.108

Airstream neutralization of acid aerosols by NH3 present in the airway lumen reduces the health risk associated with acid particles by reducing the acid concentration prior to particle deposition.78’109 In addition, the liquid lining of the respiratory tract probably acts as a chemical buffer,110 further reducing the health hazard posed by inspired acid particles. Principal factors controlling airstream neutralization of acid aerosols, which is considered to be a diffusion-limited process, are particle surface area, [NH3]^, and particle residence time in the airstream.

Since NH3 is highly water-soluble and neutralization within the droplet occurs rapidly,111 the rate-limiting step in acid neutralization is normally NH3 transport to the air/droplet interface, which is dependent on [NH3]A and parti­cle surface area. At high [NH3]A, the rate of NH3 uptake across the air/droplet interface is given by


^ = —([NH^ — CfHqm), (5.51)

Ul f

Where Cs is the NH3 concentration in the acid droplet, Dg, is the airstream NH; diffusion coefficient, r is the droplet radius, H is the Henry’s law coefficient, and qNS is the activity coefficient of neutral undissociated species in solution in the droplet.112 Particle size of inhaled liquid aerosols does not remain constant within the airways, however. Water will condense on the surface of particles as they move distally along the airway because of local increases in relative humid — jty 85,i 13,1 L4 The resulting increase in particle radii due to hygroscopic growth will reduce NH3 concentration according to Eq. (5.49), while the increase in particle size will increase particle deposition.102’115 However, increasing the par­ticle radius results in greater particle surface area, which should increase NH. uptake, thereby opposing the reduction in particle [NH3].

Elevated inspiratory flow rates reduce airway [NH3] by diluting the endog­enous NH3. The effect of flow rate on [NH3j^ should be most apparent in the upper airway due to the large NH3 concentration difference between ambient air (as the diluent) and the upper airway (containing endogenous NH,), The di­luting effects of ventilation should be less evident in the large central airways and diminish steadily as the inspiratory wavefront moves distally along the air­way because air velocity declines as airway volume increases and NH3 is a highly soluble gas and most likely equilibrates rapidly with blood ammonia. As a result, flow-rate effects on [NH3]A should be negligible after approximately the eighth bronchial generation because the rapid increase in airway volume

Causes air velocity to decline and the airstream to become more diluted. Since the expiratory wavefront is anticipated to encounter uniform [NH3]A through­out the lower conducting airways, increased expiratory flow rates should have no effect on [NH3]a until the wavefront reaches the upper airway. With nasal expiration, there may be no longitudinal NH3 concentration gradient except at the nares, unless NH3 diffuses from the oral cavity into the oropharynx.

Despite our limited knowledge of [NH3]A distribution and control, there are at least two mathematical models80’112 that attempt to predict the neutral­ization of inhaled acid aerosols. Cocks and McElroy112 base their model on acid particle growth by predicting equilibrium particle size as a function of initial particle diameter and relative humidity (RH). Molecular diffusion is a major de­terminant of particle growth in the Cocks and McElroy112 model, particularly for submicrometric particles, because their size approaches the mean free path of water vapor. Neutralization of acid particles was determined as a function of time and constant [NH3]A at parenchymal conditions. Cocks and McElroy112 did not account for higher levels of ammonia in the upper airways, which sug­gests that the bulk of neutralization will occur in the upper airway, at lower RH and temperature than in the parenchyma. The effect of a longitudinal intra-air­way [NHj]a gradient on neutralization was also not considered.

Larson80 developed a model of acid aerosol neutralization that accounts for RH and temperature gradients along the airway. The longitudinal gradi­ents used in the model were taken from the model of Martonen and Miller156, which did not account for airway geometry or ventilation. Two fixed intra-air­way [NH3|A gradients, reflecting oral and nasal breathing, were modeled and both assumed linear concentration gradients along the airway (with a step change at the oropharynx during nasal breathing). Dilution due to increased flow rate was not modeled, nor is it clear whether the [NH3]A gradients changed during exhalation. Neither Cocks and McElroy112 nor Larson80 ac­counted for gas-phase NH3 transport (except at the particle surface) or the possible effect a reduction in oral wall pH, caused by exposure to acid aerosol, would have on segmental control of [NH3]A.

Both models predict that two factors would decrease [H+] in the particle: (1) hygroscopic growth of the particle, which is thought to be capable of reducing particle [H2S04] from 15.3 M to 0.22 M; and (2) particle neutralization due to [NH3]A, which is potentially more significant but likely to be more variable within an exposed population. Without neutralization, highly acidic submicrometric par­ticles (pH = 0.66) were predicted to be deposited onto distal airway tissues.80 To refine our understanding of the potential for acid neutralization to mitigate ad­verse health effects, the assumptions regarding NH3 concentration appear to be critical for any mathematical description of acid aerosol effects. Cocks and McElroy112 demonstrated the importance of NH3 concentration estimates, with complete neutralization of submicron droplets at 500 jxg/m’ NH3 but less than 15% neutralization at 50 (xg/m3 NH3. Since measured oral NH3 concentration vary over a wide range, 144-1536 ng/m3,78,93 model predictions would improve if the factors controlling NH3 production and [NH3]A were known.

Mucociliary Escalator

Bacterial and viral inoculants deposited onto airway mucus are normally inactivated by immunoglobins and macrophages117 while being physically

Removed by the mucociliary escalator (mucociliary clearance).17’77 Deposi­tion and adherence of particulates onto airway mucus also prevents aspi­rated pollutants,108’118 viral particles,77’119 and infected epithelial cells shed from the airway wall77 from reaching the alveoli.17’22,119 Airway mucus also plays an important role in buffering and chemically neutralizing inhaled pol­lutant gases.120 In addition, mucus serves to protect the airway epithelium against injury caused by rapid fluctuations in airstream temperature, T„ and humidity, Ca.66

Disruption of these defense mechanisms can lead to bacterial colonization or viral infection. Mucus temperature is important in controlling respiratory infections because decreasing Tm below central body core temperature not only impairs ciliary movement,73’76 but also enhances viral replication,11 greatly increasing the likelihood of respiratory infection. Drying of airway mucus also increases the possibility of respiratory infection by reducing mucus thickness and impairing mucociliary clearance.121,122