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The necessary function of gas exchange requires that the lung remain
exposed to the environment. Thus, the sterility of the lung is continuously
challenged by immense quantities of microorganisms and foreign material in
inhaled air, and by opportunistic pathogens within droplets that are
aspirated from the nonsterile upper respiratory tract. Despite this constant
challenge, the lung must remain sterile or at least minimally contaminated,
because excessive numbers of bacteria induce inflammation, which impedes
gas exchange in the lung. dditionally, because of the tremendous blood flow
through the lung, contamination of the lung by bacteria carries a significant
risk of bacteremia. Thus, the lung requires a multi-layeredsystem of defense
against infectious agents. The objective is to maintainthe sterility of the lung
without inducing inflammation, as inflammation is detrimental to gas
exchange. This is accomplished
by the following:
The mucus that lines the airways entraps particles and microbes, and is
propelled by coughing or by ciliary beating to the pharynx, where it is
Antibody and innate defense proteins kill microbes directly, prevent them
from colonizing mucosal surfaces, and/or opsonize the microbes to make
them more easily ingested by phagocytes.
Alveolar macrophages and newly recruited neutrophils that recognize
foreign invaders, particularly in the presence of opsonins, engulf and kill
these microbes without inducing inflammation.
If the infection cannot be contained by these mechanisms, inflammation is
triggered in an attempt to control the threat. In these situations, alveolar
macrophages and airway or alveolar epithelial cells produce cytokines and
other mediators that recruit neutrophils and more monocytes-macrophages
to the site of invasion. Inflammatory mediators also induce the production of
antibacterial proteins by epithelial cells of the airway surface and
submucosal glands. But this response has the potential to do harm:
inflammatory exudates impair gas exchange, leukocyte-derived enzymes
and oxygen radicals cause injury to lung tissue, and repair processes may
result in organization of alveolar exudates or fibrosis of alveolar septa that
permanently decreases lung compliance and thickens the blood-gas barrier.
The significance of these sequelae depends on the extent of lung
involvement.The tremendous reserve capacity of the lung means that many
animals have localized areas of pneumonia that are of no clinical
significance, yet mild changes present throughout the lung can seriously
compromise pulmonary function.

The inspired air may carry a variety of particulates, including infectious

agents, allergens, and inert particles. The site of particle deposition in the
respiratory tract depends on their size, density, and charge. Particles larger
than about 10 txm diameter are almost completely removed in the nasal
cavity, mainly by impaction at sites in the nasal turbinates where the airflow
changes direction. Particles that are 3-10 Ixm diameter are more likely to
impact the mucosa of the trachea and bronchi, where they can be cleared
by the mucociliary apparatus. In general, particles less than 5 txm have the
greatest potential to reach the deep lung (terminal bronchioles and alveoli),
although this is most common with smaller particles (1-2 txm).The velocity
of airflow declines precipitously in the terminal airways because the total
cross-sectional area increases; as a result, particle deposition in the
bronchioles and alveoli results from sedimentation, diffusion, and
electrostatic charge.
Coughing and mucociliary clearance are the major mechanismsfor
clearing of particles that become entrapped in the airways. Mucociliary
clearance of particles from distal airways requires 2-6 hours, and the
presence of innate defense proteins within the airway mucus, described in
more detail below, probably serves to limit bacterial growth during this time.
Mucociliary clearance may be as rapid as 10 mm/min in the trachea, but is
much less rapid in the bronchioles.The airways are covered by a lower
periciliary liquid layer (formerly known as the sol or hypophase) and a
superficial mucous layer. The mucous layer contains abundant glycoproteins
that are sticky and tend to trap a wide variety of particles that impact on the
airway surfaces. The quality of the periciliary liquid layer is also critical for
clearance of entrapped particulates, because the low viscosity of this fluid
permits the cilial of the epithelial cell to beat effectively. Additionally ,
clearance of sputum from the larger airways by coughing requires that the
periciliary liquid layer be fluid and abundant, allowing the superficial
mucous layer to be easily propelled. Finally, effective ciliary function is
necessary for mucociliary clearance, and requires coordinated unidirectional
ciliary beating at an adequate frequency of around 15 beats per second.The
regulation of this system is not well known. However, shear stress on the
epithelium both increases the ciliary beating frequency and promotes
epithelial secretion to maintain the quality of the liquid and mucous layer.
Nitric oxide, cyclic adenosine monophosphate, and cyclic guanosine
monophosphate are other regulators of ciliary beat frequency.When
entrapped particles reach the nasopharynx, they have the opportunity to
interact with the well-developed lymphoid tissue in the tonsils and
nasopharyngeal mucosa before reaching the pharynx and being swallowed.
Although this clearance of inhaled particles is normally beneficial, it is a
method for the spread of agents such as Mycobacterium boris and
Rhodococcus equi, and is important in the migration of helminth eggs and
larvae. Mucociliary clearance may be impaired by infection of the airway
epithelium with viruses, mycoplasmas, or Bordetella, exposure to cold air or
ammonia, quamous metaplasia due to chronic bacterial infection or toxin
exposure (cigarette smoke and environmental pollutants being the best-

characterized examples), inherited anomalies of ciliary structure or function,

or abnormal mucus production in human cystic fibrosis.
The mucus covering the airway mucosa contains a rich spectrum of
antimicrobial factors, which operate by several distinct mechanisms.
Some cause direct injury to pathogens, such as the [3-defensins, anionic
antimicrobial peptides, cathelicidins, lactoferrin, lysozyme, the complement
membrane attack complex, and lactoperoxidase. Lactoferrin binds iron and
makes it unavailable for use by many bacteria, while neutrophil gelatinaseassociated lipocalin- secreted by airway and alveolar epithelial cells in
addition to neutrophils binds bacterial siderophores that allow pathogens
to scavenge ferric iron. Other components, including immunoglobulin A and
polysaccharides within the mucus, block the attachment of bacteria to
mucosal surfaces. Finally, infectious agents may be opsonized by
imrnunoglobulin G, the complement component C3b, and surfactant
proteins A and D. Two families of antirnicrobial proteins, defensins and
collectins, deserve particular mention. The defensins are a family of 3-5
kDa, cationic, arginine-rich peptides that are present in neutrophil granules,
intestinal Paneth cells, and epithelial cells of the trachea and bronchi. Some
defensins are constitutively expressed, while others are rapidly induced by
proinflammatory cytokines, lipopolysaccharide, and other stimuli that
activate nuclear factor-rd3.The defensins are able to kill bacteria, fungi, and
enveloped viruses by forming pores within microbial membranes that are
rich in anionic phospholipids, and may also have roles in leukocyte
chemotaxis and wound healing. The collectins are a family of calciumdependent carbohydrate-binding lectin proteins that include the surfactant
proteins A and D. Both of these proteins are produced by type II
pneumocytes, and SP-A is also secreted by Clara cells in the bronchioles.
These pulmonary collectins agglutinate and opsonize bacteria, viruses, and
fungi, and also maintain suffactant homeostasis, have antioxidant activity,
and bind lipopolysaccharide to regulate inflammatory responses.
Alveolar macrophages are critical for defending the lung against particles
that are deposited in alveoli, and also play a key role in recycling and
removal of su~ctant. Their population is aintained by ongoing recruitment of
blood monocytes. Alveolar macrophages are decorated by a variety of cell
surface receptors that permit recognition of particles opsonized by antibody,
complement, or collectins. In addition, CD14, Toll-like receptors, mannose
receptors, and the scavenger receptor permit responses against bacteria
that have not been previously encountered by the host. Alveolar
macrophages phagocytose most opsonized particles within 2-4 hours,
although the ingestion of inert particles such as carbon and silicates is much
slower. Alveolar macrophages kill bacteria using reactive oxygen and
nitrogen species and enzymes within their lysosomes. In addition, these
cells are highly effective in promoting an inflammatory response by
secreting cytokines and chemotaaic cytokines that recruit and activate
neutrophils and macrophages. These newly recruited phagocytes are
important in the clearance of more severe bacterial infections of the lung.

Alveolar macrophages are integral to the immune response by presenting

antigen, secreting cytokines that modulate the response, and serving as
effector cells in delayed hypersensitivity reactions. However, compared to
other macrophage populations, alveolar macrophages are relatively poor
antigen-presenting cells.The actual physical removal of particulates from
alveoli is inefficient, in contrast to their removal when deposited on the
mucociliary blanket. Most particles phagocytosed by macrophages are either
inactivated or sequestered.Alveolar macrophages are mainly cleared
through the bronchioles on the mucociliary blanket.As the particulate load
increases, as occurs in the pneumoconioses, some particles penetrate into
the pulmonary interstitium by endocytosis across the type I pneumocytes,
where they enter the lymph and are phagocytosed by interstitial
macrophages. Particle-laden macrophages often cluster around bronchioles
and blood vessels, and some eventually find their way to the local lymph
nodes. In addition to the alveolar and interstitial macrophages, intravascular
macrophages are present in the lung of cats, horses, ruminants, and pigs.
These cells serve to remove infectious agents and other particles from the
blood, and thus serve an analogous role to Kupffer cells in the liver and
macrophages in splenic sinusoids.
Pulmonary immune responses are initiated when inhaled antigens are
taken up by dendritic cells, which inhabit the airway epithelium and migrate
to bronchial lymph nodes where the antigen is presented to lymphocytes.
Although bronchus-associated lymphoid tissue is often visible histologically,
this structure is not present in germ-flee animals of most species and may
represent a consequence of inflammation and antigenic stimulation. Finally,
T lymphocytes and natural killer cells constantly survey the pulmonary
milieu, and are probably most useful in defense against viruses, intracellular
bacterial pathogens, and fungi.
Thus, the lung is protected from inhaled bacteria by the filtering effect of
the nasal cavity, innate and acquired humoral defenses, mucodliary
clearance in the airways, alveolar macrophages, recruited neutrophils, and
T lymphocytes and natural killer cells. These defenses can be considered in
multiple layers, where most inhaled particles are removed in the nasal
cavity or neutralized by innate defense proteins in the airway mucus prior to
being cleared by the mucociliary apparatus. The small bronchioles seem to
be a site of particular vulnerability, being poorly served by either
mucociliary clearance or alveolar macrophages. Pathogens that reach the
alveoli may be phagocytosed and killed by alveolar macrophages,
particularly if the particles have been opsonized by complement or the
surfactant proteins A and D, or by antibody ifa previous encounter with the
agent has resulted in an immune response. Still greater threats invoke a
suppurative inflammatory response, which may be essential Nasal cavity
and sinuses to clear bacteria from the lung but also carry the risk of
compromised lung function and damage to the pulmonary tissue.