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What are two types of nasal cavity and sinus airway defense mechanisms?

Vibrissae and irritant receptors.


What are vibrissae? Where are they located? What are their functions? How do they perform them? When is their use limited?

As described in Chap. 2, the nasal cavities are lined with vibrissae
that are interspersed over the distal nasal turbinates, starting
at the keratinized epithelial layers that exist inside the nares
even before transition to the ciliated respiratory epithelium
(Fig. 10.1). With their large size and scattered spacing, these
hairs are suffi ciently strong to ensnare larger objects that might
be inhaled accidentally, such as small insects and large particles
of ash. Tactile stimulation of these hairs is often suffi cient to
induce sneeze, cough, or glandular secretions that collectively
act to consolidate and expel such foreign materials. However,
they fi lter few objects that are smaller than the size that can be
resolved with the unassisted human eye (~100 μm).


What do irritant receptors respond to? Where are they located? How do they send their signals? When stimulated, what do they cause to happen?

Less obvious are the delicate sensory nerve endings also
present throughout the upper nasal passages. Collectively,
these afferent fi bers serve as irritant receptors capable of
responding to both physical deformations, such as inhalation
of a gnat, and physico-chemical stimuli like smoke, mineral
dust, cold air, capsaicin, and ammonia vapors. Several classes
of receptors present in this region send myelinated or unmyelinated
fi bers to the CNS via the vagus, trigeminal, and perhaps
other cranial nerves. Additional details are presented in
Chap. 11 about their sensitivity thresholds and their relative rapidity of adaptations to continued stimulation. Activating
these receptors can induce bronchoconstriction, coughs, or
sneezes that physically propel foreign debris out of the nasal
passages. Receptor activation also stimulates serous or mucous
glandular secretions, hypo- or hyperventilation, apnea, and
potentially a full diving refl ex that is particularly prominent
in newborn infants and very young children (Chap. 39).


Explain how the responses of different individuals to the nasal and sinus airway defenses varies.

This combination of invoked responses in the nasal cavities
to foreign objects or noxious stimuli is typical of refl exes
that are present throughout the respiratory system. Virtually
every child and adult has experienced the consequences of
these responses, such as watery eyes, seasonal rhinitis, sinus
congestion, and even emesis that may occur within minutes
or hours of exposure to pollen, sawdust, animal dander, and
foul odors. Interestingly, natural or pathological variations in
the size and patency of the nasal vestibules will make individuals
more or less susceptible to these stimuli. For example,
deviations in the nasal turbinates or altered sinus drainage can
confound the abilities of these defensive reactions to clear the
offending stimuli, or drain the secretions they induce. Likewise,
there is enormous range in innate or acquired responsiveness
among otherwise healthy adults to the antigenicity
of certain biological materials such as tree pollens, soil
microbes, cats and other pets, or insect feces (see Chap. 21).


Describe the airway defense mechanisms that exist in the oropharynx.

Air streams inhaled through the nose or mouth eventually convergein the oropharynx. This makes the ventrolateral location there of the tonsils particularly important, often providing the respiratory system a fi rst opportunity to commence innate
immunity or the transition to adaptive immunity. These large,
bilateral depots of predominantly lymphoid cells are ideally
situated to sample all inspired gases. The tonsils are also continuously
exposed to the mixture of normal mouth fl ora, exogenous
microbes, and even refl uxed gastrointestinal fl uids that
bathe the oropharyngeal surfaces. Less conspicuous than the
tonsils are the lymphoid aggregates of variable sizes scattered
in the lamina propria beneath the oropharyngeal epithelium
and along the proximal and some distal airways (Fig. 10.2).
These lymphoid aggregates were introduced in Chap. 2 as the
mucosa-associated lymphoid tissues (MALT).


What are 5 airway defense mechanisms found in the upper airway? How are they categorized?

Inhaled gas or oropharyngeal aspirates that traverse the
epiglottis at the larynx and enter the trachea encounter a more
elaborate and comprehensive array of host defense barriers. In
conventional terms, these include purely physical processes
like impaction and sedimentation, as well as cell-mediated
mucociliary clearance, phagocytosis, and antigen presentation.
Each of these is summarized here in turn.


Describe impaction. How does it work? For which particles is it useful?

Impaction refl ects the tendency for particles suspended
in fl ight to remain on linear trajectories until an obstacle is
encountered. Not surprisingly, the constantly bifurcating
airways present such a barrier to deep lung penetration by
larger airborne objects that are being inspired at relatively
high velocities. Such inhaled particles collide with the apposing
airway wall of each Y-shaped branch point, becoming
entrapped there in the mucus layer that lines these airways
(Fig. 10.3). Modeling studies and experimental evidence suggest
that impaction is particularly effective at clearing inhaled
particles >5 μm diameter. The subsequent fate of impacted
particles is discussed below.


Describe sedimentation. How does it work? For which particles is it useful?

Smaller airborne particles (alive or inert) tend to remain
suspended during rapid fl ight, despite the obstacles posed by
approaching airway walls. However, these particles still have
mass and respond to the effects of gravity, particularly as air
speed diminishes with deeper penetrations into the conducting
airways. For particles with diameters of 0.5-5 μm, sedimentation
is an important clearance mechanism that resembles the
way in which fi ne suspended particulates settle out of slowly
moving water (Fig. 10.3). Once smaller particles sediment out
and become entrapped in mucus, they also are expelled from the
lungs so that the alveolar parenchyma is spared their effects.


What happens to particles that aren't cleared by sedimentation or impaction? For which particles is this useful? Which particles can still end up making it into the parenchyma?

Particles <0.5 μm in diameter are not effectively cleared by
impaction or sedimentation. However, many of these become embedded in epithelial mucus by random Brownian motion
(termed “diffusion” by some authors), notably as airspeed slows
even more due to the high resistance to fl ow in the smallest
bronchioles. The net effects of impaction, sedimentation, and
such random Brownian collisions are to sterilize the inhaled air
of most objects down to the size of bacteria well before this gas
enters respiratory bronchioles. Nevertheless viruses, aerosolized
molecules like bacterial endotoxins, and organic vapors may
persist within the inspired airstream that challenge respiratory
system defensive functions within the alveolar parenchyma.


Describe mucociliary clearance in the upper airway. How does it work? Describe two syndromes that impair this process. What happens in them?

Most inhaled particulates become embedded in mucus secreted
by respiratory mucosa. However, adhesion does not in itself protect the lung until this hazardous material is degraded or expelled. A second cleansing process depends upon the ciliated
pseudo-stratifi ed epithelium (Fig. 10.4), by which mucusentrapped
material is expelled by the synchronized and retrograde
movement of cilia. The importance of ciliary function
to host defense is underscored by the autosomal recessive
disorder of primary ciliary dyskinesia (immotile-cilia syndrome)
found in one of 10,000-30,000 persons. Subjects with
impaired mucociliary clearance are prone to chronic cough,
rhinosinusitis, and recurrent infections of the lower respiratory
tract culminating in abnormal bronchial infl ammatory dilatation
termed bronchiectasis. Even under normal conditions, the viscosity
of normal mucus makes ciliary expulsion challenging, if not for the tearlike serous secretions of other epithelial cells creating
an aqueous or “sol” phase beneath the mucus. As will be discussed
in Chap. 38, the inability to secrete this serous subphase
results in the tenacious, airway-plugging mucus of patients with
cystic fi brosis (CF).


Describe the changes that occur in the epithelium as you go further down the airway, particularly when you get to terminal bronchioles.

As described in Chap. 2, the height and complexity of
the respiratory mucosa decrease as airway branching forms
progressively smaller bronchioles (Fig. 10.5). As this transition
occurs, epithelial cells shorten and their cilia also become
reduced in length and numbers. By the level of the deepest
bronchioles and terminal bronchioles, ciliated cells are rare,
seemingly replaced by shorter pear-shaped brush cells, each
with a tuft of 120-140 nonmotile microvilli on its narrowed
apex (Fig. 10.6). Little is known about the function of brush
cells, despite their intriguing appearance and consistent presence
in the smaller bronchioles of all mammalian lungs examined
to date. Some experts favor the view that they function
as chemosensory or sentinel cells, but further investigation is
needed to provide a defi nitive answer.
At about the same airway depth, goblet cells become
less numerous and are eventually replaced by apically domed
Clara cells that appear to have multiple phenotypes and functions
(Fig. 10.6).


Describe the functions of the various clara cells.

Many Clara cells are involved in production
of Clara cell secretory protein and lysozyme; together these proteins comprise a major part of bronchiolar lining fl uid. Clara cells also synthesize and recycle surfactant-associated proteins A and D, whose carbohydrate recognition domains bind to bacteria or viruses to promote phagocytosis by alveolar macrophages (see below). Some subsets of Clara cells are critical to host detoxifi cation of inhaled xenobiotics like lipopolysaccharide (LPS) endotoxin through their unique cytochrome P-450 mono-oxygenase, CYP4B1. Clara cells also play poorly defi ned roles in innate immunity and cytokine production.


What are alveolar macrophages like? Where are they found? What are their functions? What do they secrete? What do they recruit? How do those cells arrive?

These include alveolar macrophages that can be found
patrolling the lumens of airways, inspecting the alveolar surfaces,
migrating through septal interstitia, and adhering to
the walls of blood and lymphatic vessels (Fig. 10.7). Some
scientists divide these lung cells into specifi c subpopulations
based upon their intrapulmonary locations. In any case, they
appear phenotypically similar: large, aggressive, and highly
mobile phagocytes that probably are a self-replicating population
within the lung.
Alveolar macrophages function as initiators of infl ammation
and innate immunity by their abilities as professional
phagocytes. Through their secretion of key proinfl ammatory
cytokines including TNF-α, IL-1β, and IL-8, these macrophages
also initiate the recruitment and activation of additional leukocytes
to the lung. Such recruited cells include circulating
monocytes and polymorphonuclear neutrophils (PMNs) that respond to chemotactic gradients by migrating from the blood
through tissue barriers into the airspaces (Fig. 10.8).


What is BALF? How is it studied? What differences exist between the BALF of a healthy individual and one with pneumonia?

Lung macrophage functions have been studied extensively
since the development of diagnostic bronchoscopy
as performed clinically using fl exible bronchoscopes. During
such a procedure, a small volume (100-150 mL) of sterile saline is sequentially instilled and then withdrawn yielding
a suitable sample of bronchoalveolar lavage fl uid (BALF)
that represents alveolar epithelial cell lining fl uid (Chap. 18).
The BALF recovered from patients with pneumonia differs
strikingly in its cell counts and cytokine concentrations versus
fl uid lavaged from healthy subjects.


What is the cellularity of BALF normally like? Explain how the mobility of alveolar macrophages can lead to emphysema.

In a healthy nonsmoking adult, >95% of host cells in BALF
are macrophages, but this cellular diff erential quickly
increases in PMNs and lymphocytes during a lung infection
or other disease process. Macrophage mobility up and
down airways when stimulated by foreign materials has
important consequences. A commonly cited example is
their role in degrading adjacent lung tissue as they engulf
and attempt to destroy the large burden of ash and other
products in cigarette smoke that become entrapped in
mucus of the upper and middle airways. Their secretions
of proteases, including collagenase and elastase, can be
extraordinarily eff ective against microbial pathogens and
components of tobacco smoke, but the enzymes also
degrade the alveolar architecture to cause emphysema,
currently irreversible (Chaps. 20 and 22).


What cells express SP-A and SP-D? What do these molecules do? What can they be compared to? How does each they bind together (what shape do they form)? What kinds of molecules does each bind? What happens in mice when each is deleted?

Epithelial type 2 cells and bronchiolar Clara cells constitutively express surfactant-associated proteins SP-A and SP-D within the distal airways. Both are pattern-recognition molecules of the collectin (collagenous Ca2+-dependent lectins) family that opsonize pathogens with their C-terminal carbohydrate recognition domains (CRD).

Thus, SP-A and SP-D are thought to be the lung’s innate immune equivalents of multivalent IgG and IgM antibodies of adaptive immunity.

SP-A monomers (~34 kDa) trimerize along their linear central and N-terminal domains with their clustered globular CRDs displayed outwardly; six such trimers join into octadecameric (6 × trimers) super molecules whose shape has been compared to a bouquet of tulips (Fig. 10.9).

The CRD of SP-A is considered
suffi ciently hydrophobic to bind lipophilic membranes
including the lipid A component of gram-negative bacteria.

The CRDs of SP-D are more hydrophilic and bind surface
glycoconjugates, including those on pathogens and the mannose receptors of host leukocytes.

Secreted SP-D monomers(~43 kDa) also form axial trimers along their N-termini that organize into multimers, with dodecamers most common (4 ×trimers) (Fig. 10.9). The CRDs of SP-D extend outward like wheel rims, maximizing their display and binding of simple
and complex carbohydrates. Thus they promote binding of microbes by macrophages.

In mice, deletion of SP-A primarily affects surfactant assembly, but SP-D deletions lead to ineffectual intrapulmonary responses to airway challenges of
respiratory viral and bacterial pathogens.


Describe the recruitment of circulating monocytes into the lung parenchyma? How does it happen? Describe the different steps.

Circulating monocytes are normally present in the lungs only as they occur in pulmonary capillary blood. However, their numbers can increase greatly within minutes or hours of an inhaled or bloodborne threat to lung function. Once activated by chemotactic stimuli such as IL-1β or gram-negative bacterial LPS, they adhere to endothelial surfaces in large numbers, termed margination due to their alignment along vessel walls as seen histologically (Fig. 10.10). Within hours they move through blood vessel walls by diapedesis, presumably
fi nding or making passageways that are not readily
apparent in a quiescent lung. It is unresolved whether these recruited monocytes mature into antigen presenting dendritic cells that are found in the lung during infl ammation, since the dendritic phenotype is not particularly abundant in the healthy lung. Blood monocytes probably also replenish the alveolar macrophage population, since both cell types share developmental affi nities to the same myeloid precursor
stem cells.


Describe how circulating PMNs enter the lung parenchyma. What do both PMNs and macrophages do to attack microbes? How do PMNs differ from macrophages?

Recruited PMNs follow a similar path and time course
of migration into the alveolar zone during infl ammatory
situations, and they can quickly become the numerically
dominant cell type recovered in BALF during severe pneumonia
(Fig. 10.11).
Once within the alveoli, PMNs rapidly attack most biological
substrates, which they phagocytize whole or can degrade
extracellularly with secreted proteases. Like macrophages,
PMNs interact with substrates that have been opsonized by SP-A,
SP-D, and respiratory mucosal antibodies like IgG and IgA. Also
like macrophages, these activated PMNs utilize NADPH oxidase
and myeloperoxidase to produce reactive oxygen species
(ROS). During such a respiratory burst, PMNs release ROS
including superoxide anion (•O2
- ), hydroxyl radical (•OH),
and hypochlorite ion (OCl- ). During infl ammation, PMNs and
macrophages upregulate their expression of inducible nitric
oxide synthase (iNOS) that catalyzes formation of nitric oxide
(NO), the predominant reactive nitrogen species (RNS). In
addition to its role as a neuromodulator, NO is potently microbicidal.
Furthermore, NO and •O2
- combine spontaneously in
vivo to produce peroxynitrite anion (ONOO- ), arguably the
most active oxidant in terms of the damage it causes to cells and
their macromolecules.

Unlike macrophages, mature PMNs do not replicate and
can be relatively short-lived at sights of active infection like
pneumonia. In patients with advanced forms of acute lung
injury and ARDS, the PMNs that are recovered in BALF frequently
show signs of apoptosis. PMNs are frequently seen in
lung tissues within alveolar macrophages that have phagocytized
these now exhausted leukocytes (Fig. 10.12).


Briefly explain adaptive immunity in the lungs.

Fixed or circulating lymphocytes in the lung, such as
the MALT mentioned above, offer multiple opportunities for infl ammation and innate immunity to progress toward adaptive immunity. While usually rarer than macrophages, such luminal and MALT lymphocytes secrete pathogen-specific IgG and IgA into the serous phase of airway and alveolar fl uids. Experimental studies indicate that activated alveolar macrophages and probably most other leukocytes routinely utilize the lymphatic drainage of the lungs and thorax to access axial lymph nodes and spleen. There, they encounter the full array of effector and helper cells to which they can present antigen and other pathogen-generated substrates to initiate antibody production, memory, and suppression as when exposures to foreign antigen occur in the GI tract, skin, and blood.


Describe what happens to many natural and synthetic materials that can be suspended in air? What are some examples? What are the results? What are some examples of solids that are non-degradable biologically? What treatments exist for when this gets into the lungs?

Many natural and synthetic materials can be suspended in air as a dust, aerosol, or fume. These may enter the airways in large amounts and challenge mechanisms that have evolved to protect the lungs. Some, like chlorine and cyanide gases and even distilled water, are injurious to the alveolar epithelium but have short half-lives. Thus patients either succumb to acute lung injury (ALI) abruptly, or survive with scarring or loss of functional parenchyma.

At least as common are the many sources of organic and inorganic solids for which there is no biological degradative pathway. Among these are ground minerals containing silica, talc, coal, and asbestos, and paint aerosols containing titanium, lead, or cadmium (Fig. 10.13). Even a casual observer of mills, mines, construction sites, and road repair knows that
many workers are exposed with insuffi cient respiratory protection. The accumulated burden in the lungs of unprotected workers is measured in the tens of grams, particularly if they engaged in such professions for several decades.

Regrettably, there is little available therapy to eliminate
this foreign material. Innovative approaches like sequential single-lung lavage to clear paint aerosols have achieved mixed success. Much of the inhaled burden becomes inaccessible even to this strategy, once walled off by leukocytes and fi broblasts into granulomas, fi brotic plaque, and the like. Thus, an appropriate closing note for this chapter is to remind physicians-in-training that often the only treatment for such patients is prevention. A complete patient history documenting exposure to such risks often provides the best opportunity to intervene. Advice from a physician that
includes suggestions for modifying personal behavior and improving workplace safety standards can prevent an existing threat from worsening.