Overview of Protective Mechanisms
Many normal physiologic
functions necessary for breakdown and processing of ingested nutrients also
pose a potential risk to health. These include the normal mechanical forces
associated with gastrointestinal motility, extreme acidic content of the
stomach, the potent enzymes secreted by the pancreas and intestinal epithelium,
the caustic nature of bile salts, and the trillions of intraluminal
microorganisms. The digestive system must also have protection from ingested substances
that pose a risk to mucosal integrity and health. Even without gross disruption
of the integrity of the luminal organs, as occurs with penetrating wound injury
or disorders that lead to mucosal ulceration or perforation, there is a
constant potential for mucosal invasion at a cellular level.
The digestive system has incredibly complex and intricate immune
mechanisms that defend against microorganisms. These immune systems are
extensive and include both systems used by the rest of the body and systems
specific to the digestive tract, including intraepithelial lymphocytes;
specialized M cells; immunoglobulin A (IgA), the gut-associated immunoglobulin
submucosal immune cells; and cells outside the digestive system, known as
gut-associated lymphoid tissue (GALT) cells.
Epithelial lining cells of the digestive system have highly specific
structures designed to prevent back diffusion of intraluminal contents across
the epithelium. These include the ubiquitous secretion of mucus, specialized
apical surface characteristics, and cell-cell adhesion complexes such as tight
junctions. The intraluminal microorganisms pose a great threat, but they also
have a protective benefit (see Plate 1-54). There are also a host of nonimmune
defense mechanisms at play moment by moment to sustain the integrity of the
digestive system in the hostile environment of a “tube within a tube.” We will
summarize these other nonimmune defense mechanisms in this section, including
motility, secretion, and blood flow.
Motility plays an important role in protecting the digestive tract
from damage and in maintaining health. Propulsive contractions of the
muscularis propria occur in all luminal organs, including peristalsis,
migrating myoelectric complexes (phase III of the interdigestive motor
complex), and mass actions in the colon. Most contractions are not propulsive
but serve to mix the intraluminal contents and increase their exposure to the
luminal surface to facilitate digestion and absorption. In the composite
picture, however, the net sum of many propulsive contractions and fewer
retrograde contractions results in a net force propelling luminal contents in
an oral to anal direction. This prevents regurgitation and limits the
accumulation of microorganisms in the upper gastrointestinal tract. Tonic
contractions of the sphincters also help to maintain the correct flow of
luminal contents. The active mixing and propulsive contractions of the
muscularis mucosa and muscularis propria enhance digestion by increasing the
opportunity for luminal contents to be exposed to absorptive functions and brush-border enzymes and
enhancing the diffusion of nutrients in and enzymes out to the lumen by
reducing stasis, which could result in increased microorganism concentrations
and depth of the “unstirred water layer” (thus, potentially injurious
substances are exposed to chemical degradation before they can induce injury).
They also protect the mucosa by limiting the duration of exposure of mucosal
cells to potentially injurious agents, including organisms, medications, and
particulate material, that can have mechanically injurious properties.
Oral, pharyngeal, and upper esophageal sphincter relaxation works in an
intricately orchestrated way to propel liquids and solids away from the nasal
passages and larynx to protect against nasopharyngeal regurgitation and
pulmonary aspiration. The esophageal con- tractive force moves down the
esophagus in less than 10 seconds in a coordinated, single-ring–like
peristaltic sequence to propel the swallowed bolus into the stomach.
Peristalsis creates a stripping wave to propel the potentially dangerous
contents further away from the airway and below the check-valve function of the
lower esophageal sphincter. When the sphincter competence is interrupted, a
secondary (nonvoluntary) peristaltic contraction pushes regurgitated gastric
contents away from the airway and pharynx back into the stomach.
In the stomach, ingested materials are triturated or ground into smaller
particulate matter that can be acted upon more effectively by digestive
secretions. The pyloric sphincter
serves a “sieving function” that permits only small particles to pass. This
creates a soft chyme coated with mucus which can easily pass through to the
rest of the digestive tract. In so doing it not only optimizes the surface area
for digestion but further reduces the size of particulates to prevent larger
matter from interfering with digestion or becoming lodged in the lumen or
ileocecal sphincter.
Arguably one of the most complex and fascinating physiologic activities
in the digestive system is the pattern of interdigestive motor complexes that
occurs after digestion of a meal. Initially, after the intense contractile
activity associated with mixing and propelling nutrients down the digestive
system there is a period of rest. Then, after a brief period of active, mixing
(segmental) contractility, the intestinal housekeeper passes from the
gastroesophageal junction to the distal ileum or ileocecal sphincter. This
sweeping wave of intense contractility provides a mechanism for clearing the
stomach and small intestine of any indigestible solids, microorganisms, and
waste products to prepare it for the next meal. In so doing, larger particles
such as sinew, indigestible food stems, large seeds, or such modern solids as
swallowed gum are retained in the stomach during digestion so that they do not
interfere with the body’s need to capitalize on all swallowed nutrients, until
the house-keeper wave propels them as waste into the colon. This cycle
continues in mammals such as dogs every 90 minutes in a strikingly regular way,
but it is less regular in humans. The
cycle is interrupted by eating and is initiated through the action of the
hormone motilin.
Secretions can both damage and protect the epithelium of the luminal
organs. Peristalsis and mixing contractions of the luminal organs can,
however, produce incredible forces against the mucosa. To reduce the impact of
these forces, epithelial cells and submucosal glands from the mouth to the anus
create a thin layer of slimy substances, including mucins, phospholipids, and
the trefoil-factor family of peptides, which lubricate the wall and reduce
friction. Mucus is synthesized in the Golgi apparatus of surface mucus cells
and submucosal cells and packaged into secretory granules that discharge their
contents from the apical surfaces of cells. Mucus-secreting cells can also
deliver their protective substance into the lumen by accumulating large
quantities of mucus in their cytoplasm and then exfoliating the entire cell into
the lumen.
Mucus not only provides a protective effect by lubrication but
establishes a diffusion barrier that creates a pH gradient above surface mucus
cells that face the lumen of the stomach or duodenum; it can contain
extraordinary concentrations of acid, to a pH of 1.0 to 1.5. Although the diffusion barrier of mucus alone is ineffective
against the diffusion of protons (hydrogen ions from hydrochloric acid), it can
effectively slow the diffusion of the much larger molecules of bicarbonate
secreted from the surface mucus cells and glands of the stomach. This creates a
pH gradient by slowing the diffusion of the much larger bicarbonate ions away
from the mucosa, where a much safer pH of 7.0 is seen at the cell surface; the gastric lumen pH of 1.0
to 1.5 is prevented from injuring the cell.
Secretion of fluids also provides a protective function. The secretion of
electrolytes and accompanying diffusion of water by salivary, gastric,
duodenal, pancreatic, and gallbladder epithelia dilute ingested nutrients to
facilitate digestion and transit. It also provides a means of diluting
potentially injurious chemicals and disperses them for processing by other
defense mechanisms. Secretion of high concentrations of hydrochloric acid by
gastric parietal cells creates a pH of 1.0 to 1.5. This solution protects the
body from potentially injurious organisms by effectively killing microorganisms
that are ingested or that grow in the oral or aerodigestive cavities. This
environment sterilizes intraluminal contents in the stomach and duodenum. When
acid secretion is decreased by medications or gastric atrophy, there is an
increased risk for infection and for small intestinal bacterial overgrowth. The
latter can lead to bile salt deconjugation and competition for nutrients, most
notably vitamins such as B12. Digestive enzyme and bile salt secretion also
reduces the survival of all but the most resistant microorganisms.
Each of these nonimmune defense mechanisms depends on rich mucosal blood flow to occur. When this blood flow
is reduced by the ‘mucosal steal’ that occurs as a result of hypotension or
sympathetic over-load, the risk for mucosal injury is increased. Regulatory
messengers that enhance mucosal protective mechanisms, including blood flow,
such as prostaglandins, are also critical for maintaining mucosal health.
