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FIGURE 2.4. The lymphatic drainage of the stomach generally follows the blood supply, and the major
groups of lymph nodes are named after the major vessels (e.g., celiac, left gastric, splenic, and so on).
(Adapted from Barr H, Greenall MJ. Carcinoma of the stomach. In: Morris PJ, Wood WC, eds. Oxford
Textbook of Surgery. 2nd ed. Oxford, UK: Oxford University Press; 2000:1313–1328.)
Venous drainage essentially follows the arterial supply,
except on the lesser curvature aspect, where the venous
drainage collects into the coronary vein before the latter
drains into the portal vein.
Lymphatic Drainage
The lymphatic drainage of the stomach follows the blood
supply (Figure 2.4), using the lymph node stations defined
by the Japanese Research Society for Gastric Cancer, which
were designed to accurately define metastatic spread to
lymph nodes.
spread is so unpredictable, the numerical designation is
not as useful as might be expected.
The main lymphatic drainage of the stomach on the
lesser curvature is to the left gastric nodes, then onward to
the celiac nodes. The lesser curvature of the antrum drains
to the suprapyloric nodes, then to the common hepatic
nodes. Drainage of the gastric fundus is into the splenic
and left gastroepiploic nodes. The posterior aspect of the
stomach drains into nodes along the splenic artery, at the
root of the mesentery and in the retropancreatic area.
The nodes can be primary (N
drainage sites, depending on the location of the tumor.
The primary and secondary lymphatic drainage of tumors
in different regions of the stomach is shown in Table 2.1.
1
Unfortunately, however, because tumor
) or secondary (N2)
1
Nerve Supply
The nerve supply of the stomach consists of extrinsic,
enteric (intrinsic), and sensory innervation.
Extrinsic Nervous System
Extrinsic innervation is supplied by vagal and sympathetic
nerves; both systems playing a role in regulation of the
secretory and motor functions of the stomach. The role of
the vagus dominates.
AGAL INNERVATION OF THE STOMACH Figure 2.5
V
shows the subdiaphragmatic distribution of the vagus
nerve. The anterior and posterior vagal trunks are reconstituted over the distal esophagus. The left vagus nerve
emerges at the hiatus, anterior to the esophagus, as either
TABLE 2.1. Lymphatic Drainage of the Stomach
Drainage site N
Proximal third 1, 2, 3, 4 5, 6, 7, 8, 9, 10, 11
Middle third 3, 4, 5, 6, 12 1, 7, 8, 9, 10, 11
Distal third 3, 4, 5, 6 2, 7, 8, 11
1
N
2
A natomy .............................................................................................................................................. 39
FIGURE 2.5. The subdiaphragmatic distribution of the vagus nerves. (A) The anterior vagus, which
often emerges as more than one trunk from the hiatus, first gives the hepatic branches to the liver. It
then continues distally 1.0 cm from the lesser curvature to end on the anterior surface of the antrum.
The nerve of Latarjet provides the gastric branches from its left aspect to supply the anterior parietal
cell mass. (B) The posterior vagus nerve nearly always emerges as a single trunk from the hiatus
behind the esophagus and has divisions analogous to the anterior vagus but instead of the hepatic
branches it sends the celiac branches to the celiac axis. (Adapted from Jamieson GG, Debas HT, eds.
Rob & Smith’s Operative Surgery: Surgery of the Upper Gastrointestinal Tract. London: Chapman & Hall
Medical; 1994.)
a single trunk (70%) or multiple trunks (30%). The right
vagus nerve lies behind the esophagus as it emerges from
the hiatus and is nearly always a single trunk (94%). The
first branches of the vagus in the abdomen are extragastric,
including the hepatic branches (anterior vagus) and the
celiac branches (posterior vagus). The vagus nerves then
continue distally as the anterior and the posterior nerves of
Latarjet, otherwise called the long nerves to the antrum. On
reaching the antrum, the nerves of Latarjet become terminal branches that resemble a crow’s foot. From the left side
of the nerves of Latarjet, 12 to 20 gastric branches supply
the acid-secreting part of the stomach.
YMPATHETIC
S
INNERVATION
The sympathetic innervation of the stomach is derived from the celiac ganglion and
is distributed on the adventitia of the arterial supply.
Enteric Nervous System
The enteric nervous system (ENS) is made up of the submucousal and myenteric ganglia, which contain the cell
bodies of the nerves whose long axons then form a rich
neuronal plexus. Preganglionic efferent vagal fibers terminate in these ganglia, from which emerge postganglionic
fibers that are distributed to target cells (i.e., smooth
muscle, epithelial), either directly or through interneurons. Neurotransmission at the ganglia is activated by the
release of acetylcholine, which acts on the cell bodies of
postganglionic neurons, which possess M3 receptors. It is
now believed that the majority of postganglionic neurons
are peptidergic, that is, they synthesize peptides in their
cell bodies, transport the peptides along their axons, and
release them in close proximity to the target cell. Part of
Figure 2.6 illustrates the mechanism for smooth muscle
relaxation and vagal release of gastrin. Postganglionic
neurons that mediate smooth muscle relaxation are predominantly vasoactive intestinal polypeptidergic (VIP),
while those responsible for gastrin release contain gastrinreleasing peptide (GRP). Immunohistochemical studies
show that the ENS is rich in neurons containing a variety
of peptides.
Sensory Nervous System
Unmyelinated sensory neurons, containing substance P
(SP) and calcitonin gene-related peptide (CGRP) provide
sensory innervation to the stomach. The cell bodies of
these sensory neurons, which are located in paravertebral
ganglia, also have axons that project into the posterior
horn of the spinal chord. When these cell bodies are
stimulated, SP and CGRP can be released simultaneously
in the spinal cord and the stomach. As is discussed later,
the sensory innervation of the stomach plays an important
role in mucosal defense and blood flow.
40 ..................................................................................................................... Stomach and Duodenum
FIGURE 2.6. Vagal regulation of gastric function. Preganglionic vagal fibers terminate in the submu-
cosal and myenteric ganglia of the stomach, where they are closely related to the postganglionic
fibers, which supply the target cells (smooth muscle and epithelial). The neurotransmitter in the
ganglia is acetylcholine. Relaxation of gastric smooth fibers is caused by the release of vasoactive
intestinal polypeptide (VIP) and nitric oxide (NO) at the neuromuscular junction. Postganglionic vagal
regulation of gastrin release is accomplished through postganglionic peptidergic fibers that release
gastrin-releasing peptide at the basal lateral surface of the G cell.
MICROSCOPIC ANATOMY
The gastric mucosa is lined with mucous cells. Gastric pits
in the mucosal surface provide openings for the gastric
glands, which extend down to the muscularis mucosa
(Figure 2.7). Five types of epithelial cells make up the
gastric gland: surface mucous cells and mucous neck cells,
both of which produce mucus and bicarbonate; parietal
(oxyntic) cells, which secrete H
+
and intrinsic factor; chief
cells, which produce pepsinogen; and endocrine cells, of
which the most important are the enterochromaffin-like
PHYSIOLOGY
The essentials of the physiology of the stomach are summarized in Table 2.2.
EXOCRINE SECRETION
Regulation of Acid Secretion
Acid secretion is regulated by neural, endocrine, and
paracrine mechanisms.
(ECL) cells. ECL cells make up 35% of the entire population of endocrine cells in the gastric gland, and they secrete
histamine, a final common mediator of gastric acid
secretion.
The stroma surrounding gastric glands make up the
lamina propria. In gastritis, the lamina propria is invaded
by inflammatory blood cells. The muscularis propria consists of three smooth muscle layers: the inner oblique,
the middle circular, and the outer longitudinal layers.
The stomach, unlike the esophagus, has a well-developed
serosa.
Neural Mechanisms
The vagus nerve plays a central role in both the stimulatory and inhibitory regulation of acid secretion.
VAGAL STIMULATION OF ACID SECRETION
Central Mechanisms The thought, sight, or smell of
food stimulates medullary nuclei and then the dorsal motor
nucleus (DMN) of the vagus nerve (Figure 2.8). The DMN
P hysiology .......................................................................................................................................... 41
A
B
FIGURE 2.7. (A and B) Microscopic structure of the gastric wall. The gastric glands are the functional
unit of the mucosa and communicate to the lumen by gastric pits. The luminal surface as well as the
neck of the glands is covered with mucous cells. The gastric glands themselves contain both epithelial
cells (e.g., parietal, chief) and endocrine cells (e.g., ECL cells). The muscular layer contains an outer longitudinal and an inner circular layer. Frequently, however, there are three layers, which include an
innermost oblique muscle layer. (Adapted with permission from Ito S. Functional gastric morphology.
In: Johnson LR, et al., eds. Physiology of the Gastrointestinal Tract. 2nd ed. Vol. 1. New York: Raven
Press; 1987.)
42 ..................................................................................................................... Stomach and Duodenum
TABLE 2.2. Essentials: Physiology of the Stomach
Motor function
Myogenic mechanisms
䊏
Gastric pacemaker: Located in greater curvature
䊏
Basal electrical rhythm (BER): 1 per 20 s
Neural mechanisms
䊏
Excitatory mechanisms: ACh, SP, 5-HT
䊏
Inhibitory neurotransmitters: VIP, NO (mediate receptive
relaxation)
Hormonal mechanisms
䊏
Stimulatory: Motilin
䊏
Inhibitory: CCK
Gastric emptying control
䊏
Liquids: Mainly proximal stomach
䊏
Solids: Mainly distal stomach
Secretory function
Exocrine
H+
䊏
Secreted by parietal cells
䊏
Stimulated by histamine, gastrin, ACh
䊏
Inhibited by somatostatin, intestinal peptides (CCK,
secretin, GIP)
Pepsinogen
䊏
Secreted by chief cells
䊏
Stimulated primarily by ACh
Mucus and bicarbonate
䊏
Secreted by mucous cells
䊏
Stimulated by prostaglandins, ACh, b-adrenergics
䊏
Inhibited by NSAIDs
Intrinsic factor
䊏
Secreted by parietal cell
䊏
Stimulated by histamine, ACh, gastrin
䊏
Binds vitamin B12for absorption in distal ileum
Endocrine/paracrine/neurocrine (see Table 2.4)
Abbreviations: ACh, acetylcholine; SP, substance P; CCK, cholecystokinin;
5-HT, 5-hydroxy tryptamine; GIP, gastric inhibitory peptide; H
ions; NO, nitric oxide; NSAIDs, nonsteroidal anti-inflammatory drugs; VIP,
vasoactive intestinal polypeptide.
+
, hydrogen
5. Vasovagal reflexes and short gastric reflexes are acti-
vated by gastric distension.
AGAL INHIBITORY
V
MECHANISMS
Vagal stimulation
results in the activation of several peptidergic inhibitory
pathways, including VIP, neuropeptide Y, CGRP, SP, and
galanin. The relative importance of these inhibitory peptidergic pathways has not been elucidated. Inhibitory vagal
regulation is more apparent on the G cell than on the
parietal cell. For example, basal and postprandial
hypergastrinemia develops following all types of vagotomy.
Postvagotomy hypergastrinemia is not fully explained
by the reduction of acid and the rise of luminal pH
postoperatively.
Humoral Mechanisms
S
TIMULATION OF ACID SECRETION
The key humoral
substances responsible for gastric acid secretion are histamine and gastrin.
is activated by release of thyrotropin-releasing hormone
(TRH) from neurons that project to the nucleus. DMN
activation, in turn, stimulates the afferent vagal fibers.
Peripheral Mechanisms Vagal stimulation of acid
secretion involves several peripheral mechanisms, as
described below and in Figure 2.9:
1. Release of acetylcholine (ACh) at nerve endings triggers direct vagal stimulation of the parietal cell. ACh binds
to M3 receptors on the parietal cell, resulting in a phospholipase C–activated rise in cytosolic calcium, elaboration of H
of H
+/K+
+
.
–ATPase on the apical surface, and secretion
2. Cholinergic stimulation of the ECL cell and release
of histamine stimulate the parietal cell by binding to the
histamine H
receptor.
2
3. Inhibition of somatostatin release from delta cells
results in “disinhibition” of the parietal, ECL, and G cells.
4. Antral gastrin is released through stimulation of G
cells by GRP from GRP-containing postganglionic
neurons.
FIGURE 2.8. Central mechanisms of acid secretion control. Centrally located, the dorsal motor nucleus (DMN) of the vagus controls the stimulation of acid secretion. Neurons that project from
the medullary raphae nuclei activate the DMN through release
of thyrotropin-releasing hormone (TRH), which stimulates the
preganglionic vagal fibers to release acetylcholine at the ganglia
in the gastric wall. (Adapted with permission from Debas HT,
Carvajal SH. Vagal regulation of acid secretion and gastrin
release. Yale J Biol Med 1994;67:145–151.)
P hysiology .......................................................................................................................................... 43
FIGURE 2.9. Peripheral mechanisms of acid secretion. The parietal cells secrete hydrogen ions (H+)
when stimulated by histamine, gastrin, and acetylcholine (ACh). The main source of histamine, the
enterochromaffin-like (ECL) cell, secretes histamine in response to stimulation by both the vagus nerve
(ACh) and gastrin. Inhibitory regulation is accomplished chiefly by the release of somatostatin (SS) at
the level of either the ECL cell or the parietal cell. In the antrum, gastrin release is stimulated by
luminal food or by the vagus acting through the release of gastrin-releasing peptide (GRP). Inhibitory
control of the G cell is through the release of somatostatin from delta cells. Antral acidification
releases somatostatin from delta cells to shut off gastrin release. This constitutes the negative feedback regulation of gastrin release. (Adapted with permission from Debas HT, Carvajal SH. Vagal regulation of acid secretion and gastrin release. Yale J Biol Med 1994;67:145–151.)
Histamine Histamine has emerged as the common
final pathway for both vagal- and gastrin-stimulated acid
secretion, although both ACh and gastrin can act directly
on the parietal cell through the M3 and cholecystokinin-B
(CCK-B) receptors, respectively. Histamine is a paracrine
agent. It is now believed that the physiologically relevant
pool of histamine that lies within diffusion distance of the
parietal cell is the histamine contained within ECL cells.
The ECL cell contains receptors for ACh, gastrin, pituitary
adenylate cyclase activating peptide (PACAP), and somatostatin. Histamine released from ECL cells diffuses to the
parietal cell, binds to histamine H
receptors, and activates
2
the adenylate cyclase system to stimulate acid secretion.
Gastrin Gastrin, produced by G cells in the antrum
and proximal duodenum, is released by food and antral
distension. It is responsible for most or all of the gastric
phase of acid secretion and is synthesized in the cell as a
preprohormone. Posttranslational processing results in
production of several molecular sizes of the hormone; the
17-amino-acid C-terminal peptide (G-17) is the most
important stimulant of acid secretion.
As mentioned earlier, gastrin acts through the CCK-B
receptor, which is present on the parietal and ECL cells.
Although it can stimulate acid secretion in vitro from
isolated parietal cells, its acid secretory action in vivo is
probably mediated largely through histamine release from
the ECL cell.
In addition to its acid secretory effect, gastrin stimulates growth of the acid-secreting portion of the gastric
mucosa. The most important trophic action of gastrin is
on the parietal cell (which explains parietal cell hyperplasia in Zollinger-Ellison syndrome) and the ECL cell (which
explains ECL-cell hyperplasia and formation of carcinoid
tumors in chronic hypergastrinemic states). Gastrin has
no trophic effect on the antral mucosa.
The direct action of gastrin on the parietal cell through
the CCK-B receptor is mediated through the cyclic guanosine monophosphate (GMP) pathway.
NHIBITION OF ACID SECRETION Processes and sub-
I
stances that regulate the release of gastrin and somatostatin
are summarized in Table 2.3.
Inhibition of Gastrin Release Antral acidification, the
most important mechanism for turning off gastrin
secretion, releases somatostatin from antral D cells.
Somatostatin acts on the G cell to inhibit gastrin release.
44 ..................................................................................................................... Stomach and Duodenum
P hysiology .......................................................................................................................................... 45
Secretion of Somatostatin in Oxyntic Mucosa Somatostatin released from D cells in the oxyntic mucosa inhibits
acid secretion by directly acting on the parietal cell or indirectly by acting on the ECL cell to inhibit histamine release.
Intestinal Inhibitory Mechanisms (Enterogastrones)
The introduction of fat or acid into the duodenum elicits
the release of various inhibitory substances, some known
and some unknown. Some of the known inhibitory peptides released from the intestine include CCK, secretin, VIP,
somatostatin, and enteroglucagon. Infusion of glucose into
the intestine also releases gastric inhibitory peptide (GIP).
Regulation of Pepsinogen Secretion
Pepsinogen is a proenzyme secreted mainly by the chief
cells in the gastric mucosa. Seven types of pepsinogen have
been classified into two groups. Pepsinogen I (PGI) contains PG1 through PG5 and is the dominant form in the
oxyntic mucosa. PGI is not found in the cardia, antrum,
or duodenum. PGII, containing PG6 and PG7, on the
other hand, is found in all parts of the stomach and in the
Brunner’s glands of the duodenum. Both PGI and PGII are
present in the serum but only PGI is excreted in the urine
as “uropepsin.”
Pepsinogen is converted by acid into the active enzyme
pepsin. The pH optimum for PGI is 1.5 to 2.0 and for PGII
3.2. Once pepsin is generated, it autocatalyzes the conversion of pepsinogen into pepsin. The initial digestion of
proteins is the primary function of pepsin. Pepsin
hydrolyzes proteins to generate smaller protein fragments
and some free amino acids. Protein digestion into amino
acids is completed in the intestine mainly by pancreatic
enzymes.
Primary regulation of pepsin secretion in vivo is under
cholinergic control. Vagal stimulation and gastric distension release ACh, which activates chief cells by acting on
M3 cholinergic receptors, utilizing calcium as the intracellular messenger. Histamine also leads to the release of
pepsinogen into the gastric lumen. Whether this release
represents true stimulation of the chief cell or a “wash-out
phenomenon” has been debated for a long time. Gastrin
and secretin also stimulate pepsinogen secretion, but stimulation of pepsinogen by hormones is not as important as
that by cholinergic mechanisms.
Regulation of Mucus and
Bicarbonate Secretion
Both mucus and bicarbonate are secreted by surface cells
of the gastric mucosa. Mucus is secreted continuously by
exocytosis mostly from mucous surface and mucous neck
cells, and is stimulated by several agonists, including ACh,
b-adrenergic agents, and prostaglandins. The mucus
forms an aqueous gel on the surface of the epithelial cells.
Bicarbonate secretion is stimulated by prostaglandins.
Compared with the amount of acid the gastric mucosa
secretes, bicarbonate secretion is small, at most 10% of
total acid output. Nevertheless, bicarbonate plays a critical
protective role in the gastric mucosa because it is trapped
beneath the “unstirred” mucous gel layer close to the
surface of the mucosa. In this strategic location, the small
amount of bicarbonate secreted plays a significant role in
neutralizing acid at the luminal surface of gastric cells.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
eliminate the synthesis of prostaglandins, thereby inhibiting the production of both mucus and bicarbonate. Acidification of the duodenal bulb mucosa also results in
increased synthesis and release of both mucus and
bicarbonate—a mechanism believed to be important in
preventing duodenal ulceration.
Regulation of Secretion of Intrinsic Factor
Intrinsic factor (IF) is secreted by the parietal cells of the
stomach, stimulated by the same agents that stimulate acid
secretion. It is then transported bound to R-protein of salivary origin. In the small intestine, IF is released from the
binding protein by pancreatic proteases. Once released, IF
binds vitamin B
12
. The complex is carried into the ileal cell,
and vitamin B
12
is then released into plasma. In other
words, IF is a necessary carrier glycoprotein for the
absorption of vitamin B
12
in the ileum. Failure of IF secretion leads to megaloblastic anemia. Conditions that
contribute to such failure include atrophic gastritis, in
which the parietal cell mass is critically small or nonexistent, and total gastrectomy and proximal gastrectomy,
which remove the entire parietal cell mass. Following total
and proximal gastrectomy, therefore, patients must receive
parenteral vitamin B
12
monthly.
ENDOCRINE/PARACRINE/
NEUROCRINE SECRETION
The discussion of the exocrine secretion of the stomach
indicated that an integration of humoral and neural
mechanisms regulate acid secretion. This section briefly
discusses each of the important humoral agents. As a
TABLE 2.3. Regulation of Gastrin and Somatostatin (SS)
Release
Stimulation Inhibition
Gastrin Proteins, amino acids Somatostatin
GRP (vagus) Antral acidification (SS)
Antral distension Galanin
Antral alkalization
Somatostatin Antral acidification Acetylcholine
CCK Vagal stimulation
PACAP
VIP
Abbreviations: CCK, cholecystokinin; GRP, gastrin-releasing peptide; PACAP,
pituitary adenylate cyclase-activating peptide; VIP, vasoactive intestinal
polypeptide.
46 ..................................................................................................................... Stomach and Duodenum
preamble, notice that humoral agents may be released
from endocrine cells or neurons. Endocrine cells may
release their secretory products (e.g., peptides, amines)
directly into the bloodstream or into the interstitial space.
Humoral agents released into the bloodstream and carried
by it to their target site are called hormones. Gastrin is a
good example of a hormone. Substances secreted into the
interstitial space diffuse through the interstitial fluid to
reach their target are known as paracrine agents. Both histamine and somatostatin are examples of paracrine agents.
Neurocrine agents are usually secreted at the nerve terminal and cross a short synaptic gap to reach their receptors
on target cells. ACh and GRP are examples. The major
humoral secretory products of the stomach are listed in
Table 2.4.
Although somatostatin is classified here as a paracrine
agent, it is also both a hormone and a neurocrine agent.
Released into the bloodstream following antral acidification and intestinal perfusion with fat, somatostatin is also
present in the enteric nervous system as shown by
immunohistology. Whether its role as a hormone or neurocrine agent is important in gastric physiology is as yet
unknown.
Most gastrointestinal peptides are neurocrine agents.
In the stomach, CGRP and substance P are found in smalldiameter sensory neurons and in the enteric nervous
system. CGRP appears to play an important role in gastric
mucosal defense and blood flow as well as in motility. Pituitary adenylate cyclase-activating peptide (PACAP) and
VIP belong to the secretin family of peptides. Both are
present in postganglionic neurons in the stomach, and
both play a role in regulating the ECL and the D cells.
Galanin, another peptide released from postganglionic
nerve endings in the stomach, appears to be an inhibitor
of the ECL cell and the G cell.
DEFENSE MECHANISMS OF THE
GASTRODUODENAL MUCOSA
The gastric mucosa is continually exposed to acid, with
luminal pH often approaching 1.0. Because this degree of
acidity is one million times greater than that within the
interstitial or intracellular spaces of the gastric mucosa,
how does the gastric mucosa protect itself from peptic
damage in this acidic environment? How does it prevent
acidification of the gastric mucosa and submucosa? The
development of peptic ulceration is explained as a disruption of the balance between the aggressive factors (acid
and pepsin) and the defensive factors (to be described
below), in which the equilibrium is tilted in favor of the
former. Even after the discovery of Helicobacter pylori as
an important cause of peptic ulcer, the imperative that
gastric acid must be present to cause ulceration has not
TABLE 2.4. Major Humoral Products of the Stomach
Humoral agent Cell of origin Target (receptor) Action
Endocrine
Gastrin G cell ECL cell (CCK-B) ≠ histamine release
Parietal cell (CCK-B) ≠ mucosal growth
Paracrine
Histamine ECL cell Parietal cell ≠ H
+
secretion
(histamine, H-2)
Somatostatin D cell ECL cell (SS-2) Ø histamine release
G cell (SS-2) Ø gastrin release
Neurocrine
Acetylcholine Vagal efferents ECL cell (M3) ≠ histamine release
Parietal cell (M3) ≠ H
+
secretion
Smooth muscle (M1) Contraction
PACAP ENS ECL cell ≠ histamine release
VIP ENS Blood vessel ≠ blood flow
Smooth muscle Relaxation
GRP ENS G cell ≠ gastrin release
CGRP, SP Vagal afferents D cell ≠ somatostatin release
ENS Blood vessel ≠ blood flow
Galanin ENS G cell Ø gastrin release
ECL cell Ø histamine release
Other local agents
Prostaglandins Endothelial cells Mucous cell ≠ mucus, ≠ HCO
3
Parietal cell Ø H+secretion
Nitric oxide ENS Smooth muscle Relaxation
Abbreviations: CCK-B, cholecystokinin-B; CGRP, calcitonin gene-related peptide; ECL, enterochromaffin-like; ENS, enteric
nervous system; GRP, gastrin-releasing peptide; PACAP, pituitary adenylate cyclase-activating peptide; SS, somatostatin;
VIP, vasoactive intestinal polypeptide.
FIGURE 2.10. Defense mechanisms of the gastroduodenal mucosa. The luminal components include
secretion of bicarbonate beneath the “unstirred” mucous gel layer applied to the apical surface. The
mucosal components include the phospholipid bilayer of the apical membrane, the tight junctions,
and the ability of the gastric mucosa to both secrete prostaglandins and undergo rapid epithelial
regeneration. The submucosal components include the rich blood flow, which brings defense factors
and disposes of noxious agents, as well as the sensory neurons, which are mainly responsible for cytoprotection of the mucosa.
changed. The old adage, “no acid, no ulcer,” therefore, still
holds. Not all patients who develop duodenal ulcer are
acid hypersecretors. With H. pylori, inappropriate acid
secretion occurs in the basal state because acid inhibitory
mechanisms are deranged.
The term defense mechanisms is used here to describe
all the elements that operate to prevent acid-peptic
damage to the gastroduodenal mucosa. These mechanisms, described as gastric and duodenal, are depicted in
Figure 2.10.
Defense Mechanisms of the
Gastric Mucosa
Luminal Factors
The secretion of mucus from the mucous surface and neck
cells and the formation of a continuous mucous gel layer
that closely adheres to the mucosa has already been discussed. Between this gel layer and the apical surfaces of the
mucosal cells is a small quantity of fluid that constitutes
the “unstirred” layer, into which the surface mucous cells
secrete bicarbonate. The mucous gel layer and the
unstirred layer containing bicarbonate are important
luminal defense factors.
Mucosal Factors
IGHT JUNCTIONS In contrast to the leaky tight
T
junctions of intestinal epithelium, the gastric epithelium
contains “tight” tight junctions that are resistant to back
diffusion of acid from the gastric lumen.
ROSTAGLANDINS
P
The generation of prostaglandins
by gastric mucosa is an important regulator of mucus and
bicarbonate secretion. Small doses of exogenous 16,16dimethyl prostaglandin E2 (PGE2) have been shown to
protect the gastric mucosa against gross damage from subsequent application of injurious agents such as strong acid,
strong alkali, alcohol, or heat. This phenomenon has been
described as “cytoprotection.” The means by which PGE2
confers cytoprotection is unknown, but it may involve as
yet undescribed mechanisms beyond mucus and bicarbonate production.
Several types of prostaglandins are generated from
arachidonic acid. Prostaglandins of the E type are potent
inhibitors of acid secretion by acting on a G protein–
coupled EP3 receptor. NSAID therapy abolishes the
generation of prostaglandins from arachidonic acid by
inhibiting Cox I. Recently, NSAID-type drugs that are
selective Cox II inhibitors have been developed in the hope
of preventing interference with the generation of
prostaglandins by Cox I.
APICAL CELL MEMBRANE The gastric surface is coated
by a phospholipid layer, similar to the surfactant found in
the lung. The phospholipid bilayer lacks proteins capable
of transporting protons and hence is acid resistant.
P hysiology .......................................................................................................................................... 47
EGENERATIVE CAPACITY OF GASTRIC EPITHELIAL CELLS
R
The entire gastric mucosa is renewed every 3 to 5 days by
the twin processes of cell regeneration and cell desquamation. The rapid regenerative capacity of the mucosa is
48 ..................................................................................................................... Stomach and Duodenum
important in the process of healing erosions and ulcers.
Inhibition of this cellular regenerative capacity of the
gastroduodenal mucosa may explain, at least in part, why
steroids aggravate peptic ulceration.
M
UCOSAL RESTITUTION The gastric mucosa has a
remarkable ability to establish epithelial integrity following
mucosal damage. This process, known as mucosal restitu-
tion, is a rapid process of cell migration from the edges of
the defect to cover it. The process is completed within
minutes and cannot be explained by cell proliferation. The
mechanisms underlying restitution are unknown but
involve proteins of the basal lamina (e.g., laminin) and
matrix receptors on epithelial cells.
Sensory Neurons and Calcitonin
Gene-Related Peptide
The major sensory neurons in the stomach are smalldiameter C-fibers containing CGRP and SP. Capsaicin, the
sensory neurotoxin present in pepper, and other noxious
agents are capable of releasing CGRP from sensory
neurons in the stomach. CGRP, thus released, has been
shown to protect against ulceration and to promote restitution. The mechanisms for the protective action of CGRP
and CGRP-containing neurons may involve stimulation of
blood flow, inhibition of acid secretion, release of somatostatin, and inhibition of motility.
Blood Flow
Not only does the gastric mucosa have rich blood flow, but
the blood flow increases during stimulation of gastric acid
secretion. The important role sensory neurons play in
mucosal protection and the powerful vasodilatory effects
of CGRP have been mentioned. Conditions that decrease
gastric blood flow, such as hemorrhagic shock and sepsis,
predispose to erosive gastritis and ulceration.
Postmucosal Factors
Circulating agents such as growth factors and antibodies
probably also contribute to the protection of gastric
mucosa from offending toxins and bacteria.
Duodenal Defense Mechanisms
The first few centimeters of the duodenal mucosa are frequently exposed to low pH levels and must be appropriately protected from acid and pepsin,particularly since the
duodenal tight junctions are significantly leakier than
those of the gastric mucosa. Three protective mechanisms
appear to be important, as described below.
Mucosal Bicarbonate Secretion
The mucosa of the proximal duodenum secretes appreciable amounts of bicarbonate in response to luminal acidi-
fication. This response is diminished in patients with duodenal ulcer and in individuals with H. pylori infection.
Mucosal Dissipation of Acid
Unlike the stomach, the duodenum has a large capacity to
dissipate acid across its mucosa. This probably is the result
of paracellular pathways and the leaky tight junctions in
the duodenal mucosa.
Pancreatic Bicarbonate Secretion
Acidification of the duodenal mucosa provokes rapid
secretion of pancreatic bicarbonate. In this regard, the
duodenum acts like a titrimeter, causing equivalent bicarbonate secretion from the pancreas to the acid load it
receives. Duodenal acidification stimulates pancreatic
secretion mainly through the release of secretin and CCK
from the duodenum.
MOTOR FUNCTION OF THE STOMACH
Control of Gastric Motility
Myogenic, neural, and humoral mechanisms regulate
gastric motility. The essential features of gastric motor
function are listed in Table 2.5.
Myogenic Mechanisms
Myogenic mechanisms provide the most important
control of stomach functions. The smooth muscle fibers
of the stomach exhibit a basal electrical rhythm (BER) that
oscillates every 20 seconds. The BER is controlled by a
“pacemaker”located on the greater curvature aspect of the
proximal stomach. It is believed that the pacemaker is
made up of a concentration of interstitial cells of Cajal.
The BER spreads from the pacemaker distally toward the
TABLE 2.5. Essentials: Gastric Motor Function
Regulation of gastric motility
Myogenic mechanisms
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Gastric pacemaker: Greater curvature, proximal stomach
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Basal electric rhythm (BER)
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Action potential: Coordinated by BER
Neural mechanisms
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Excitatory neurotransmitters: ACh, SP, neurokinin A
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Inhibitory neurotransmitters: VIP, NO
Hormonal mechanism
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Motilin: Accelerates gastric emptying
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CCK: Inhibits gastric emptying
Gastric emptying
Liquids controlled by proximal stomach
Solids controlled by antropyloric segment
Abbreviations: ACh, acetylcholine; CCK, cholecystokinin; NO, nitric oxide;
SP, substance P; VIP, vasoactive intestinal polypeptide.
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