GASTROENTEROLOGY 2008;135:41– 60
GASTROENTEROLOGY
REVIEWS IN BASIC AND CLINICAL
GASTROENTEROLOGY
Gastric Mucosal Defense and Cytoprotection: Bench to Bedside
LOREN LAINE,* KOJI TAKEUCHI,‡ and ANDRZEJ TARNAWSKI§
*Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California; ‡Division
of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan; and
§
Gastroenterology Section, VA Long Beach Healthcare System and Division of Gastroenterology, University of California Irvine School of Medicine, Irvine, California
The gastric mucosa maintains structural integrity and
function despite continuous exposure to noxious fac-
tors, including 0.1 mol/L HCl and pepsin, that are
capable of digesting tissue. Under normal conditions,
mucosal integrity is maintained by defense mecha-
nisms, which include preepithelial factors (mucus-
bicarbonate-phospholipid “barrier”), an epithelial
“barrier” (surface epithelial cells connected by tight
junctions and generating bicarbonate, mucus, phos-
pholipids, trefoil peptides, prostaglandins (PGs), and
heat shock proteins), continuous cell renewal accom-
plished by proliferation of progenitor cells (regulated
by growth factors, PGE2 and survivin), continuous
blood flow through mucosal microvessels, an endo-
thelial “barrier,” sensory innervation, and generation
of PGs and nitric oxide. Mucosal injury may occur
when noxious factors “overwhelm” an intact mucosal
defense or when the mucosal defense is impaired. We
review basic components of gastric mucosal defense
and discuss conditions in which mucosal injury is
directly related to impairment in mucosal defense,
focusing on disorders with important clinical sequelae:
nonsteroidal anti-inflammatory drug (NSAID)-asso-
ciated injury, which is primarily related to inhibition
of cyclooxygenase (COX)-mediated PG synthesis, and
stress-related mucosal disease (SRMD), which occurs
with local ischemia. The annual incidence of NSAID-
associated upper gastrointestinal (GI) complications
such as bleeding is approximately 1%–1.5%; and re-
ductions in these complications have been demon-
strated with misoprostol, proton pump inhibitors
(PPIs) (only documented in high-risk patients), and
COX-2 selective inhibitors. Clinically significant
bleeding from SRMD is relatively uncommon with
modern intensive care. Pharmacologic therapy with
antisecretory drugs may be used in high-risk patients
(eg, mechanical ventilation >48 hours), although the
absolute risk reduction is small, and a decrease in
mortality is not documented.
BASIC AND CLINICAL
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David Metz, Section Editor
T he gastric mucosa is continuously exposed to many
noxious factors and substances. How the gastric
mucosa maintains structural integrity and resists auto-
digestion by substances such as 0.1 mol/L HCl and pep-
sin puzzled clinicians and investigators for more than
200 years. An early hypothesis proposed by Hunter in
1772 and supported by Virchow in 1853 was that con-
tinuous circulation of alkaline blood through the mu-
cosa neutralizes acid.1,2 Subsequent work demonstrated
that a large number of mucosal defense mechanisms
prevent mucosal damage and maintain mucosal integrity.
The discovery by Vane that the major mechanism by
which aspirin and other NSAIDs produce gastric damage
is inhibition of prostaglandin (PG) synthesis,3 and the
concept of cytoprotection developed in the late 1970s
and early 1980s by Robert et al4,5 sparked tremendous
interest in gastric mucosal defense.
Gastric mucosal injury may occur when noxious fac-
tors “overwhelm” an intact mucosal defense (eg,
Zollinger Ellison syndrome) or when the mucosal defen-
sive mechanisms are impaired. This review focuses on
conditions in which mucosal injury is directly related to
impairment in mucosal defense. Conditions in which the
inciting factor is an injurious agent (eg, acid, Helicobacter
pylori) are covered in other reviews in this series. We first
review the basic components and mechanisms that pro-
vide gastric mucosal defense and then discuss clinical
conditions that occur primarily because of impairment in
gastric mucosal defense. Finally, we will review the pre-
vention and treatment of 2 important clinical conditions
that result from impaired mucosal defense: NSAID-asso-
ciated injury and SRMD.
Abbreviations used in this paper: COX, cyclooxygenase; CRF, corti-
cotrophin-releasing factor; EGF, epidermal growth factor; NSAID, non-
steroidal anti-inflammatory drug; PGs, prostaglandins; PGI2, prostacy-
clin; PPIs, proton pump inhibitors; SRMD, stress-related mucosal
disease; TFFs, trefoil factor family peptides.
© 2008 by the AGA Institute
0016-5085/08/$34.00
doi:10.1053/j.gastro.2008.05.030
 42 LAINE, TAKEUCHI, AND TARNAWSKI
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Figure 1. Diagrammatic representation of gastric mucosal defense, modified and updated from Tarnawski.9
Gastric Mucosal Defense Mechanisms
Defense mechanisms permit the gastric mucosa to
withstand frequent exposure to damaging factors across
a wide range of pH, osmolality, and temperature.6 –12
These include local defense mechanisms and neurohor-
monal mechanisms described below (Figure 1).
Local Gastric Mucosal Defense Mechanisms
Mucus-bicarbonate-phospholipid “barrier.” The
mucus-bicarbonate-phospholipid “barrier” constitutes
the first line of mucosal defense.8,13–15 This barrier is
formed by mucus gel, bicarbonate, and surfactant phos-
GASTROENTEROLOGY Vol. 135, No. 1
pholipids, which cover the mucosal surface. This un-
stirred layer retains bicarbonate secreted by surface epi-
thelial cells to maintain a neutral microenvironment (pH
⬃7.0) at the surface epithelial cells and prevents penetra-
tion of pepsin and thus proteolytic digestion of the
surface epithelium.14,15 The mucus gel contains phospho-
lipids, and its luminal surface is coated with a film of
surfactant phospholipids with strong hydrophobic
properties.8,16
Mucus gel is secreted by apical expulsion from surface
epithelial cells and contains ⬃95% water and ⬃5% mucin
glycoproteins, products of mucin (MUC) genes. The gel-
July 2008
forming mucin units polymerize into large mucin mul-
timers essential for gel formation.14,15,17 The structure of
each of the gel-forming mucins, MUC2, MUC5AC,
MUC5B, and MUC6, has been elucidated.14,18 In the
stomach, MUC5AC is expressed in the surface epithelial
cells of cardia, fundus, and antrum; and MUC6 is ex-
pressed in the neck cells of the fundus and in antral
glands. Alternating layers of MUC5AC and MUC6 have
been demonstrated in the mucus layer in human gastric
mucosa.14,19 Mucus gel is cosecreted with low-molecular-
weight trefoil factor family peptides (TFFs).20,21 TFFs are
an integral part of the intracellular mucus secretory ves-
icles and may play a role in the intracellular assembly
and/or packaging of mucins.20 TFF2 increases the viscos-
ity of gastric mucin and stabilizes the gel network.22
Mucus secretion is stimulated by gastrointestinal hor-
mones, including gastrin and secretin, as well as PGE2
and cholinergic agents.7,14 Ulcerogenic substances such
as aspirin and bile salts cause dissipation of the mucus
gel and phospholipid layer, leading to acid back-diffusion
and mucosal injury.14,23
The secretion of HCO3⫺ into a stable, adherent mucus
gel layer creates a pH gradient at the epithelial surface in
the stomach and duodenum and provides the first line of
mucosal defense against luminal acid.14,15,24 pH gradient
studies provided experimental evidence for the existence
of the mucus-bicarbonate barrier in vivo and presence of
a nearly neutral pH at the epithelial surface.15 The surface
epithelium in acid-secreting gastric mucosa exports
HCO3⫺ at rates only 10% of the acid secretion rate.
Mucus gel minimizes luminal loss of HCO3⫺ sufficiently
to maintain a neutral pH at the apical cell surfaces.
Experimental studies show that Na⫹HCO3⫺ cotransport
at the basolateral membrane is the major mechanism for
import of HCO3⫺. Studies of rat and rabbit gastric mu-
cosa demonstrated expression of a Cl⫺/HCO3⫺ anion
exchanger in the apical membranes of gastric surface
epithelial cells.25 In the stomach, PGs stimulate HCO3⫺
secretion via EP1 receptors.26 Luminal acid, corticotro-
phin-releasing factor (CRF), melatonin, uroguanylin, and
orexin A also stimulate HCO3⫺ secretion.7,14
The mucus bicarbonate barrier is the only preepithelial
barrier between lumen and epithelium. When it is over-
whelmed or breaks down in disease, the next series of
protective mechanisms come into play, including intra-
cellular neutralization of acid, rapid epithelial repair, and
maintenance and distribution of mucosal blood flow.
Surface epithelial cells. The next line of mucosal
defense is formed by a continuous layer of surface epi-
thelial cells (Figure 2), which secrete mucus and bicar-
bonate and generate PGs, heat shock proteins, TFFs, and
cathelicidins. Because of the presence of phospholipids
on their surfaces, these cells are hydrophobic, repelling
acid- and water-soluble damaging agents.8 Intercon-
nected by tight junctions, the surface epithelial cells form
a “barrier” preventing back diffusion of acid and pep-
GASTRIC MUCOSAL DEFENSE AND CYTOPROTECTION 43
GASTROENTEROLOGY
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sin.7,6,9,14 The surface epithelial cells are metabolically
and electrically coupled by gap junctions. Heat shock
proteins are generated by gastric epithelial cells in re-
sponse to stress, such as increased temperature, oxidative
stress, and cytotoxic agents.27–29 They prevent protein
denaturation and protect cells against injury. Activation
of heat shock protein response is one of the mucosal
protective mechanisms of the antacid hydrotalcite.30
Cathelicidin and ␤ defensins are cationic peptides that
play roles in the innate defensive system at mucosal
surfaces preventing bacterial colonization. They have
been demonstrated in gastric epithelial cells, and they
accelerate ulcer healing.31 Surface epithelial cells secrete
TFFs that regulate reepithelialization and exert mucosal
protective action.32
Continuous cell renewal from mucosal progenitor
cells. Continuous cell renewal from mucosal progenitor
cells maintains structural integrity of the mucosa. The
epithelium is continually renewed by a well-coordinated
and controlled proliferation of progenitor cells that en-
ables replacement of damaged or aged surface epithelial
cells. Complete replacement of the gastric surface epithe-
lium usually takes 3–7 days, whereas months are required
to replace the glandular cells. In gastric glands, a single
stem cell undergoes division to produce committed pro-
genitor cells, which further differentiate into an adult
epithelial cell type.33 The stem/progenitor cell niche is
made up of proliferating and differentiating epithelial
cells and surrounding mesenchymal cells.34 The latter
generate growth factors and thus promote mesenchymal
to epithelial cross talk and signaling to maintain the
niche progenitor cell survival. Restitution of the surface
epithelium after superficial injury occurs within minutes
by migration of preserved epithelial cells located in the
neck area of gastric glands.35,36 This migration precedes
and is independent of proliferation of progenitor cells,
which occurs later— hours after injury.36,37
Cell proliferation of progenitor cells is controlled by
growth factors. The major growth factor receptor ex-
pressed in gastric progenitor cells is epidermal growth
factor receptor (EGF-R),38 and the major mitogenic
growth factors that activate this receptor are transform-
ing growth factor ␣ (TGF-␣) and insulin-like growth
factor-1.39 PGE2 and gastrin transactivate EGF-R and
trigger the mitogen-activated protein kinase pathway
thereby stimulating cell proliferation and exerting a tro-
phic action on gastric mucosa.40 EGF peptide itself is
absent in normal gastric mucosa. However, it is present
in the gastric lumen, derived from salivary and esopha-
geal glands, and can stimulate progenitor cell prolifera-
tion in case of injury. An important new finding is the
expression of survivin, an antiapoptosis protein, in gas-
tric progenitor cells, which allows these cells to avoid
apoptosis and promotes mitosis (Figure 2C).41
Alkaline tide. “Alkaline tide” occurs because
stimulated parietal cells secreting hydrochloric acid
 44 LAINE, TAKEUCHI, AND TARNAWSKI GASTROENTEROLOGY Vol. 135, No. 1
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Figure 2. Structural elements of gastric mucosal defense. (A) Histology of upper part of human gastric mucosa visualizing surface epithelial cells
(SEC), foveoli (F), and upper gland area. (H&E staining; original magnification, ⫻50). Blood microvessels with erythrocytes in the lumen are present
in the lamina propria (arrows). (B) Scanning electromicrograph of human gastric mucosal luminal surface. The unstirred mucus gel layer is not seen
because of dissolution during fixation. Individual surface epithelial cells (SEC) are clearly visible as are lumina of the gastric pits (arrows). Reproduced
with permission from Tarnawski A, Krause WJ, Ivey KJ. The effect of glucagon on aspirin-induced gastric mucosal damage in man. Gastroenterology
1978;74:240 –245. (C) Immunostaining of human gastric mucosa with survivin (antiapoptosis protein) antibody. Survivin is strongly expressed
(brown-red staining) in the progenitor cells located in the foverolar/neck area (arrowheads). Reproduced with permission from Tarnawski et al.159 (D)
Vascular cast study of capillary blood vessels in the gastric mucosa. The remaining components of the mucosa were dissolved in concentrated NaOH
Reproduced with permission from Ichikawa et al.165 (E) Transmission electronmicrograph of normal human gastric mucosa. Surface epithelial cells
(SEC) contain prominent, dark mucus granules. Below the surface epithelial cells, a capillary blood vessel (CAP) with erythrocytes (E) in the lumen is
present in the lamina propia. N, nucleus of endothelial cell lining capillary vessel (original magnification, ⫻2000). Reproduced with permission from
Tarnawski et al.172 (F) Transmission electronmicrograph of a portion of human gastric capillary blood vessel. The structure of the capillary wall and
endothelial cell cytoplasm is normal with a characteristic fenestration (arrows) and presence of endothelial vesicles. BM, basement membrane; E,
erythrocytes in the capillary lumen; J, junction between 2 neighboring endothelial cells; CF, collagen fibers. Original magnification, ⫻17,400.
Reproduced with permission from Tarnawski et al.172

into the gastric gland lumen concurrently secrete bi-
carbonate into the interstitium and lumen of adjacent
capillary blood vessels (Figure 1). This bicarbonate is
transported upward to the base of the surface epithe-
lial cells and to the gastric lumen, where it contributes
to the unstirred layer of mucus and bicarbonate.
Mucosal microcirculation. Mucosal microcircu-
lation is essential for delivery of oxygen and nutrients
and removal of toxic substances. At the level of the
muscularis mucosae, most gastric arteries branch into
capillaries, which enter the lamina propria and travel
upward in proximity to gastric glandular epithelial
cells (Figures 1 and 2). At the base of surface epithelial
cells, capillaries converge into collecting venules.42
The endothelial cells lining the microvessels generate
potent vasodilators such as nitric oxide (NO) and pros-
tacyclin (PGI2), which protect the gastric mucosa
against injury and oppose the mucosal damaging ac-
tion of vasoconstrictors such as leukotriene C4, throm-
boxane A2, and endothelin. PGI2 and NO main-
tain viability of endothelial cells and prevent platelet
and leukocyte adherence to the microvascular endo-
July 2008 GASTRIC MUCOSAL DEFENSE AND CYTOPROTECTION 45

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Figure 3. Sensory innervation of gastric mucosa. Photomicrographs of rat gastric specimens immunostained with calcitonin gene-related peptide
(CGRP) antibody demonstrate the distribution of CGRP immunoreactivity reflecting sensory nerves. CGRP-immunoreactive fibers are present in the
submucosa, often close to the blood vessels (A; arrowheads). The nerve fibers form a dense plexus at the mucosal base (A; arrows). From this plexus,
sensory nerves enter the lamina propria and together with microvessels penetrate toward the mucosal surface (B; arrowheads), ending just beneath
the basement membrane of the surface epithelial cells. Through the acid sensing ion channels, these nerve endings sense luminal contents such as
acid and other irritants. Reproduced with permission from Tarnawski et al.48

thelial cells, thus preventing compromise of the
microcirculation.43
When the gastric mucosa is exposed to an irritant or
when acid back-diffusion occurs, a marked and rapid
increase in mucosal blood flow occurs. This increase
allows removal and/or dilution of the back-diffusing acid
and/or noxious agents. This response seems to be essen-
tial for mucosal defense because its abolition through
mechanical restriction of blood flow leads to hemor-
rhagic necrosis. This hyperemic response is mediated by
sensory afferent nerves (see below). The increased muco-
sal blood flow in response to acid secretion is mediated,
at least in part, by NO, generated by NO synthase. NO
plays a major role in mucosal defense by modulating the
mucosal circulation.43– 45 Endogenous and exogenous
NO protects gastric mucosa against injury by ethanol
and endothelin 1, whereas inhibition of NO synthase
(resulting in reduced NO generation) increases gastric
mucosal injury.9,43,45
Hydrogen sulfide is another endogenously generated
compound that exerts a strong mucosal protective action
similar to NO; it reduces tumor necrosis factor ␣
(TNF-␣) expression, decreases leukocyte adherence to
vascular endothelium, and inhibits NSAID-induced gas-
tric mucosal injury.46,47
Sensory innervation of gastric mucosa. Gastric
mucosa and submucosal vessels are innervated by pri-
mary afferent sensory neurons and nerves forming a
dense plexus at the mucosal base (Figure 3A).45,48,49,50 The
nerves fibers from this plexus enter the lamina propria
(accompanying capillary vessels) and end just beneath the
surface epithelial cells (Figure 3B). These nerve endings can
sense the luminal content and/or entry of acid into the
mucosa via acid-sensing channels. Activation of these nerves
directly affects the tone of submucosal arterioles, which
regulate mucosal blood flow.43 Stimulation of gastric sen-
sory nerves leads to the release of neurotransmitters such as
calcitonin gene-related peptide and substance P in the nerve
terminals located within or in close proximity to the large
submucosal vessels.45,48,49,50 Calcitonin gene-related peptide
exerts a mucosal protective action, most likely through
vasodilatation of submucosal vessels mediated by NO gen-
eration. Interference with any aspect of the sensory inner-
vation, such as ablation of the sensory afferent nerves with
chronic, large doses of capsaicin, impairs the hyperemic
response and thus diminishes resistance of the gastric mu-
cosa to injury.44,45,49,50
Continuous generation of PGE2 and PGI2.
Continuous generation of PGE2 and PGI2 by the mu-
cosa is crucial for the maintenance of mucosal integ-
 46 LAINE, TAKEUCHI, AND TARNAWSKI
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rity and protection against ulcerogenic and necrotizing
agents.9 –12,44,51–53 Almost all of the mucosal defense
mechanisms are stimulated and/or facilitated by PGs.
PGs inhibit acid secretion; stimulate mucus, bicarbon-
ate, and phospholipid secretion; increase mucosal
blood flow; and accelerate epithelial restitution and
mucosal healing.9 –12,44,51–54
PGs also inhibit mast cell activation and leukocyte and
platelet adherence to the vascular endothelium.9 –12,51–53
The importance of PGE2 and PGI2 in gastric mucosal
defense is demonstrated by the fact that immunoneutral-
izing antibodies to these PGs cause development of gas-
tric and duodenal ulcers in rabbits and dogs55,56 identical
to those produced by NSAIDs that inhibit PG generation.
Endogenous and exogenous E-type PGs and their an-
alogs exert biologic actions via EP receptors 1– 4.57 The
mucosal protective action of PGs is mainly mediated via
EP-1 receptors, which also increase bicarbonate secretion
and mucosal blood flow in damaged mucosa and de-
crease gastric motility.58 – 60 EP-3 and EP-4 receptors af-
fect acid and mucus secretion, respectively.61,62
Neurohormonal Regulation of Gastric
Mucosal Defense
In addition to local mucosal factors, gastric mu-
cosal defense is regulated, at least in part, by the central
nervous system and hormonal factors.10,44,50,63–70 Central
vagal activation increases mucus gel and surface cell
intracellular pH in rat stomach,63 and central CRF sig-
naling pathways are involved in the endocrine and vis-
ceral responses to stress.64,65 Peripheral CRF-related
mechanisms also contribute to stress-induced changes in
gut motility and mucosal function. The CRF2 receptor is
present in the human stomach in which it plays a pro-
tective role by inhibiting apoptosis.64 Peripheral injection
of CRF or urocortin inhibits gastric emptying and mo-
tility through interaction with CRF2 receptors. Con-
versely, CRF receptor antagonists given peripherally pre-
vent acute restraint and stress-induced delayed gastric
emptying. These findings provide evidence that activa-
tion of peripheral CRF receptors and mast cells are im-
portant mechanisms involved in stress-related alterations
of gut physiology.10 –12,44,51,63– 65 Also, activation of central
opioid receptors enhances gastric mucosal defense.66
Various peptides including gastrin 17, cholecystokinin,
thyrotropin-releasing hormone, bombesin, CRF, EGF,
peptide YY, neurokinin A analogs, and intragastric pep-
tone exert gastroprotection that is abolished by afferent
nerve denervation, blockade of calcitonin gene-related
peptide receptors, and inhibition of NO synthase.44,67
Ghrelin, a peptide hormone produced by gastric A-like
cells in rodents and P/D1 cells in humans, regulates
growth hormone secretion at the hypothalamic and pi-
tuitary level and elicits orexigenic (appetite stimulating)
action.70 Ghrelin also may exert peripheral actions such
as gastric mucosal protective and healing action by en-
GASTROENTEROLOGY Vol. 135, No. 1
hancement of gastric mucosal blood flow via stimulation
of NO production and calcitonin gene-related peptide
release from sensory afferent nerves.70
Adrenal glucocorticoids also play an important, facili-
tating role in gastric mucosal defense.68,69,71–73 An acute
rise of corticosterone during stress is a potent gastropro-
tective component of the hormonal response to stress.71
Pretreatment with glucocorticoid at pharmacologic doses
causes a long-lasting decrease of stress-induced cortico-
sterone rise and increased gastric ulcerogenic responses
to different models of stress, whereas corticosterone re-
placement reduces gastric lesions in rats.72 Administra-
tion of a specific glucocorticoid receptor antagonist (RU-
38486) increases the severity of stress-induced erosions,
further supporting a gastroprotective role of glucocorti-
coids during stress.71 The protective action of glucocor-
ticoids is assumed to occur via their maintenance of
glucose homeostasis, gastric blood flow, and mucus se-
cretion and their attenuation of enhanced gastric motil-
ity and microvascular permeability.73
Gastric Mucosal Injury Because of
Impaired Mucosal Defense
The most important conditions in clinical prac-
tice that are initiated by impairment of gastric mucosal
defense are NSAID-related injury and SRMD. Other fac-
tors that reduce gastric mucosal defense include aging
and portal hypertension.
NSAID-Related Gastric Injury
NSAIDs are the most widely used medications in
the United States.74,75 Eleven percent of the US adult
population use an NSAID regularly (nearly every day for
a month or more),75 and a much larger number use
NSAIDs intermittently.74
Traditional, nonselective NSAIDs induce predictable
gastric mucosal injury. Initial early injury with agents
such as aspirin may occur because of a topical effect.
Most nonselective NSAIDs are weakly acidic. In gastric
juice, they are relatively nonionized and lipophilic, allow-
ing them to move across cell membranes into the interior
of cells.76 The neutral pH within the cell causes conver-
sion to the ionized form of the NSAID, leading to accu-
mulation within the cell and local injury. Within 10
minutes of a single dose of 650 mg of aspirin, the gastric
potential difference is decreased, and 25% of surface ep-
ithelial cells show damage on light and electron micro-
scopic examination.77 On endoscopic examination, sub-
epithelial hemorrhages develop within 15–30 minutes.
Virtually 100% of subjects given aspirin 650 mg once
develop gastric subepithelial hemorrhages, and virtually
all subjects given aspirin 650 mg 4 times in 24 hours
develop gastric erosions—primarily in the antrum.76 Sub-
epithelial hemorrhages and erosions are confined to the
mucosa and therefore do not cause clinically severe GI
complications such as major bleeding or perforation.
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Table 1. Upper GI Complications and Clinical Events From Traditional NSAID Arms of GI Outcome Studies ⱖ6 Months
Duration Without GI Protective Cotherapy
MUCOSA CLASS
(n ⫽ 4439)87 (n ⫽ 3981)88,89
Type of arthritis Rheumatoid Osteoarthritis (73%);
rheumatoid (27%)
NSAID 10 specified Ibuprofen 800 mg 3 times
NSAIDs daily; diclofenac 75 mg
twice daily
Low-dose aspirin Not stated 22%
Median follow-up 6 mo 9 mo
Upper GI complications 1.5 1.0
(annualized incidence) (%)
Upper GI clinical events 2.7 2.8
(annualized incidence) (%)
NOTE. Upper GI complications include bleeding, perforation, or obstruction. Clinical events include complications plus uncomplicated symptom-
atic ulcers.
Although direct topical injury may occur, the major
mechanism via which NSAIDs cause ulcers and GI com-
plications is thought to be systemic: inhibition of COX-
mediated PG synthesis, as discussed below. Clinical in-
formation supports the primacy of a systemic NSAID
effect in induction of gastric injury. NSAIDs given by the
rectal, intravenous, and intramuscular routes increase the
risk of ulcers and ulcer complications.78
Gastroduodenal ulcers identified at endoscopy are
common in patients taking nonselective NSAIDs regu-
larly, with a prevalence of ⬃15%–30%76 and a 6-month
incidence in double-blind trials as high as ⬃45%.79 Gas-
tric ulcers are approximately 4 times more common than
duodenal ulcers in patients taking NSAIDs79,80: the inci-
dence of gastric ulcers in a pooled analysis of 3– 6 month
randomized trials of traditional NSAIDs was 19% vs 5%
for duodenal ulcers.80
Continued use of nonselective NSAIDs after ulcer for-
mation decreases healing rates even with concomitant
antisecretory therapy: 8-week gastric ulcer healing rates
with histamine H2-receptor antagonist (H2RA) therapy
were 95% with discontinuation vs 63% with continuation
of NSAIDs.81 Whether COX-2 selective NSAIDs also de-
crease healing has been a question of interest. Induction
of gastric ulcers in animal models is associated with a
marked rise in local COX-2 expression, and selective
COX-2 inhibitors delay healing of these experimental
ulcers similarly to nonselective NSAIDs.82– 84 To study
this issue, patients with NSAID-associated gastric ulcers
were randomly assigned to celecoxib 200 mg twice daily
or placebo in a double-blind trial.85 All received famoti-
dine 40 mg daily and had endoscopy at 4 and 8 weeks. A
significantly lower healing rate was seen with celecoxib
(66% vs 80%, respectively; P ⫽ .015), indicating that
COX-2 selective inhibitors delay ulcer healing in ulcers
and supporting the concept that the PGs produced by
the up-regulated COX-2 are important for ulcer healing.
The major clinical concern regarding NSAID use is
their induction of upper GI clinical events, composed of
GASTRIC MUCOSAL DEFENSE AND CYTOPROTECTION 47
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VIGOR TARGET
(n ⫽ 4029)90 (n ⫽ 9127)91
Rheumatoid Osteoarthritis
Naproxen 500 mg Ibuprofen 800 mg three times
twice daily daily; naproxen 500 mg
twice daily
Exclusion criterion 24%
9 mo 12 mo
1.4 1.3
4.5 2.8
complicated events (bleeding, perforation, or obstruc-
tion) and uncomplicated events (eg, symptomatic ulcer
identified on endoscopy done for abdominal pain). The
risk of upper GI complications in observational popula-
tion studies in NSAID users is approximately 4-fold
higher than in people not taking NSAIDs.86 Four large
prospective GI outcome studies of ⱖ6 months assessed
upper GI complications and overall upper GI clinical
events in arthritis patients taking traditional NSAIDs
without GI-protective cotherapy (Table 1).87–91 Annual-
ized incidences of upper GI complications were 1%–1.5%,
and annualized incidences of all upper GI clinical events
were 2.7%– 4.5%.
Pathogenesis of NSAID-Induced Gastric Injury:
Prostaglandin Synthesis and the Role of COX-1 and
COX-2 in Gastric Mucosal Defense. COX-1 and COX-2
are key enzymes in the biosynthesis of PGs. COX-1 is
constitutively expressed in many tissues,92–94 whereas
COX-2 has little or no expression in most tissues but is
rapidly induced in response to growth factors and cyto-
kines.95,96 The COX-1-mediated PG synthesis is mainly
responsible for maintaining gastric mucosal integrity at
baseline. The traditional NSAIDs such as indomethacin
or ibuprofen are dual, nonselective inhibitors of both
COX-1 and COX-2. They cause damage in the stomach
with a marked decrease in the gastric mucosal PGE2
content.97,98 Gastric injury was assumed to be related to
inhibition of gastric mucosal PG production by COX-1.
This contention was further supported by the fact that
COX-2 selective NSAIDs, which do not inhibit COX-1 at
therapeutic doses, do not affect the mucosal PG produc-
tion and do not produce gross gastric injury in experi-
mental models. However, a selective COX-1 inhibitor
(SC-560) also does not cause gross damage in the stom-
ach, despite inhibiting PG production in the gastric mu-
cosa.99 –101 In contrast, the combined administration of
COX-1 selective and COX-2 selective inhibitors induces
mucosal damage. These data challenge the contention
 48 LAINE, TAKEUCHI, AND TARNAWSKI
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that only COX-1 plays a “housekeeping” role in the
stomach.
Selective inhibition of COX-1 induces a PG deficiency
but up-regulates COX-2 expression.100,101 This conten-
tion is supported by the fact that gastric mucosal PGE2
content in a rat model is markedly decreased by indo-
methacin and SC-560, yet the values are partially restored
8 hours after SC-560 but not indomethacin, a time suf-
ficient for COX-2 induction.100,101 In addition, combined
treatment with SC-560 and rofecoxib induces gross gas-
tric injury, but the damage is prevented by administra-
tion of PGE2 4 hours after the selective COX inhibitors.
Furthermore, a selective COX-2 inhibitor by itself in-
duces damage in the rat stomach when the expression of
COX-2 is up-regulated in the gastric mucosa by adrenal-
ectomy, adjuvant-induced arthritis, or the administration
of COX-1 inhibitors.101–103 Thus, both COX-1 and
COX-2 may play a role in PG synthesis and maintenance
of gastric mucosal integrity. COX-2 plays a “back-up”
role by alleviating PG deficiency in situations in which
COX-1-induced PG synthesis has been decreased.
Wallace et al99 found that neutrophil adherence to
gastric mesenteric venules was increased by indometha-
cin and celecoxib but not by SC-560, whereas gastric
mucosal blood flow was decreased by indomethacin and
SC-560 but not celecoxib. These data indicate that
NSAID-induced reduction in gastric mucosal blood flow
is due to COX-1 inhibition, whereas NSAID-induced neu-
trophil adherence to vascular endothelium is due to
COX-2 inhibition. Thus, reduction in mucosal blood
flow alone with COX-1 inhibition is insufficient to cause
gross gastric damage. In line with the finding that COX-1
is responsible for maintaining mucosal blood flow, SC-
560 by itself, but not rofecoxib, increased microvascular
permeability in the stomach, similarly to indometha-
cin.100,104 However, both COX-1 and COX-2 may be re-
quired for enhancement of neutrophil migration in the
gastric mucosa. Neither SC-560 nor rofecoxib alone af-
fect myeloperoxidase activity in the gastric mucosa, yet
together they increase myeloperoxidase activity to levels
comparable with those induced by indomethacin.100,104 –107
This may reflect the combination of COX-1-mediated mu-
cosal blood flow and COX-2-mediated neutrophil adher-
ence to vascular endothelium.
Several investigators, using a variety of experimental
models, have also demonstrated a role of motility in
gastric mucosal defense. Normal gastric motility, me-
diated by COX-1-induced PG synthesis, may be in-
volved in maintaining normal gastric mucosal blood
flow.100,104,108,109 A marked increase in gastric motility
is reported after treatment with the selective COX-1
inhibitor SC-560 but not the selective COX-2 inhibitor
rofecoxib, although the duration of hypermotility is
shorter than that induced by nonselective COX inhib-
itors.101 High amplitude contractions may result in a
temporal restriction of blood flow to the mucosa with
GASTROENTEROLOGY Vol. 135, No. 1
resulting hypoxia and decreased mucosal defense.104
Inhibition of COX-1 but not COX-2 also increases acid
secretion in the damaged stomach.110
In summary, the likely sequence of events in NSAID-
induced gastric injury is inhibition of PG synthesis and
induction of gastric hypermotility, followed by microvas-
cular disturbances and neutrophil activation (Figure 4).
Gastric hypermotility and microvascular disturbances are
associated with a PG deficiency caused by COX-1 inhibi-
tion. However, the inhibition of COX-1 up-regulates the
expression of COX-2, and the PGs produced by COX-2
suppress the neutrophil-endothelial interaction caused
by the vascular disturbances because of COX-1 inhibi-
tion. These sequential events related to COX-1 and
COX-2 inhibition may explain why gastric damage occurs
only when both COX isozymes are inhibited and indicate
a “housekeeping” role of COX-1 as well as COX-2 in the
stomach.
Potential Prostaglandin-Independent Mecha-
nisms of NSAID-Induced Gastric Injury. NSAIDs may
induce tissue and cell injury by mechanisms independent
of prostaglandin inhibition, related to the inhibition of
oxidative phosphorylation in mitochondria, inhibition of
kinases (phosphorylating enzymes), and/or activation of
apoptosis.111 A potential role for leukotrienes in NSAID-
induced gastric injury also has been postulated. With the
decrease in arachidonic acid metabolism via the COX
pathway in NSAID users, arachidonic acid metabolism
may be shifted to the alternative 5-lipoxygenase pathway,
with a resultant increase in leukotriene production. This
suggestion was supported by experimental studies docu-
menting that licofelone, an inhibitor of COX-1, COX-2,
and 5-lipoxygenase, did not increase gastric mucosal in-
jury. A randomized 4-week endoscopic trial in 121
healthy volunteers revealed no gastric ulcers with placebo
or licofelone (vs 20% with naproxen); the gastric mucosa
was normal in 90% of subjects receiving placebo and 91%
of those receiving licofelone, compared with 37% of those
given naproxen.112
Potential Lessening of Gastric Mucosal Injury
With Aspirin. Interestingly, aspirin may provide some
protection against COX-mediated gastric injury in exper-
imental studies. Unlike other NSAIDs, acetylation of
COX-2 by aspirin leads to generation of 15(R)15-epili-
poxin A4, termed aspirin-triggered lipoxin. 15(R)15-epili-
poxin A4 and analogs exert protective actions on the
gastric mucosa by inhibiting neutrophil chemotaxis, re-
ducing neutrophil-mediated tissue injury and epithelial
apoptosis, and mediating adaptation of the gastric mu-
cosa to long-term aspirin administration. High-dose as-
pirin in rats induces COX-2 expression and lipoxin A4
production in the gastric mucosa,113 and coadministra-
tion of aspirin and a selective COX-2 inhibitor resulted in
substantially more severe gastric injury than that pro-
duced with either agent alone. In human volunteers,
low-dose aspirin increases urinary excretion of lipoxin A4,
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Figure 4. Current hypotheses
for roles of COX-1 and COX-2 in
the pathogenic mechanism of
NSAID-induced gastric damage.
The motility hypothesis suggests
that gastric motility plays an im-
portant role in NSAID damage.
NSAIDs induce vagal-depen-
dent gastric hypermotility via in-
hibition in COX-1-mediated
prostaglandin (PG) production
and CNS actions. Subsequent
microvascular disturbances lead
sequentially to neutrophil-endo-
thelial interaction and oxyradical
production. Inhibition of COX-1
leads to up-regulation of COX-2
expression. PG production me-
diated by COX-2, which may
suppress the neutrophil-endo-
thelial interaction, is also de-
creased by COX-2 selective or
nonselective NSAIDs. The neu-
trophil-endothelial interaction
plays a major role in the neutro-
phil hypothesis, which suggests
that NSAIDs activate the neutro-
phil through alteration of arachi-
donic acid metabolites (eg,
PGs), enhancing neutrophil-en-
dothelial cell adhesion.

whereas production of lipoxin A4 is inhibited by a COX-2
selective inhibitor.113,114 The latter effect has been sug-
gested as a potential explanation for the more than
additive effect of COX-2 selective inhibitors plus low-
dose aspirin in causing mucosal injury.115 In addition,
aspirin is reported to not increase basal gastric motil-
ity.104,108 The clinical relevance of these observations is
uncertain because aspirin in full anti-inflammatory doses
is not “safer” than other NSAIDs.
SRMD
SRMD occurs in critically ill patients: not all pa-
tients in an intensive care setting but only those who are
extremely ill, eg, severe trauma, burns ⬎one third of the
body surface area, major intracranial disease, major sur-
gery, and severe medical illness. Prospective assessment of
2252 medical-surgical intensive care unit (ICU) patients
revealed only 2 independent risk factors for clinically
important stress bleeding: mechanical ventilation for
ⱖ48 hours (odds ratio [OR], 15.6) and coagulopathy
(OR, 4.3).116 These data were generated primarily in pa-
tients with cardiovascular surgery and medical illness; the
results may not be generalizable to patients with central
nervous system disease, trauma, burns, or transplanta-
tion because these groups were not well represented in
the population. In a subsequent multivariable analysis of
1200 ICU patients on mechanical ventilation receiving
prophylactic therapy, maximum serum creatinine during
ICU stay was the sole patient characteristic identified as
a significant predictor of clinically important bleeding
(relative risk [RR], 1.16; 95% confidence interval [95% CI]:
1.02–1.32).117
Endoscopic studies generally indicate that approxi-
mately 75%–100% of critically ill patients have gross
gastric lesions visible when endoscopy is performed
within the first 1–3 days of illness; the proportion is
probably closer to 100% in patients who are extremely
ill as defined above.118 –120 An exception to this finding
was reported in a study of 40 patients with intracranial
disease requiring neurosurgery and mechanical venti-
lation ⬎48 hours121: less than half of patients under-
going endoscopy within 12 hours of admission had
erosions or subepithelial hemorrhage, although the
 50 LAINE, TAKEUCHI, AND TARNAWSKI
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proportion increased to ⬎50% at 5 days in those with
no stress prophlyaxis. Lesions are generally diffuse
subepithelial hemorrhage and erosions and occur more
commonly in the proximal stomach.119,122 Bleeding
from these mucosal lesions tends to be slow; if massive
bleeding occurs, it suggests that an ulcer (ie, extension
below the mucosa) has developed.
Overt bleeding (eg, bloody nasogastric aspirate, he-
matemesis, melena) is reported in ⬃20% of critically ill
patients; pooled results from placebo/no therapy control
groups of 10 randomized controlled trials in metaanaly-
ses of prophylactic therapy performed from 1980 to
1998120,121,123–132 reveal an incidence of 17%. However,
the most relevant outcome to consider is clinically sig-
nificant bleeding. Clinically significant or clinically im-
portant bleeding has been variably defined to include
overt bleeding combined with transfusion, hemodynamic
instability, and/or the need for intervention and is now
suggested to occur in ⱕ5% of patients.122 Pooled analysis
of placebo control groups in the randomized trials from
metaanalyses cited above reveals an 8% incidence of clin-
ically significant bleeding. The mortality in patients with
stress-related bleeding is high, related primarily to the
underlying illness. Although stress-related bleeding has
been calculated to increase hospital stay and mortality,
studies of prophylactic therapy have not revealed that
decreased bleeding translates into decreased mortality.133
The incidence of SRMD-associated clinically significant
bleeding appears to have markedly decreased in the past
few decades, most likely because of better care of critically
ill patients.122,134
Pathogenesis of SRMD. Stress-related gastric
mucosal injury appears to be related to local ischemia,
although progression to significant mucosal injury re-
quires acid as well. Critically ill patients who develop
acute gastric mucosal lesions have a significant decrease
in gastric mucosal blood volume compared with controls,
whereas patients without acute gastric lesions do not.135
Studies in the rat model136 reveal a significant correla-
tion between blood pressure during hypotension and
gastric mucosal blood flow. Leung et al reported that a
threshold level of hypotension to 40% of baseline was
required for lesions to form.136 Similar to reports in
endoscopic studies, gross gastric lesions develop in a
significantly greater area of the body than the antrum in
the rat model.
A rat model of hemorrhagic shock and retransfusion-
induced gastric injury reveals that histologic mucosal
damage occurs even without acid, although it increases
with intragastric instillation of acid in a dose-dependent
fashion.137 In addition, reperfusion after ischemia in-
creased histologic injury as compared with ischemia
alone, although increasing the duration of ischemia
(from 20 to 30 minutes) increased gastric histologic le-
sions to the same extent as a similar period of retransfu-
sion (10 minutes after 20 minutes ischemia). In the
GASTROENTEROLOGY Vol. 135, No. 1
absence of acid, gross gastric lesions were minimal, in-
volving 4% of the body and 3% of the antrum surface
area. However, intragastric instillation of acid markedly
increased the gross lesions in dose-dependent fashion to
53% and 45% of the body and antral surface areas, respec-
tively, with 0.1 mol/L HCl. Oxygen-free radicals appear to
play a role in the induction of ischemia-reperfusion his-
tologic injury (which is prevented by allopurinol) but not
injury because of ischemia alone (not prevented by allo-
purinol). Ritchie also suggested that bile salts, along with
ischemia and acid, were required to induce acute gastric
mucosal injury.138
Ischemia/reperfusion increases COX-2 messenger RNA
levels in the rat gastric mucosa,139 and hypoxia increases
the expression of the COX-2 gene in human vascular
endothelial cells in vitro.140 Ischemia/reperfusion-in-
duced gastric damage is also aggravated by administra-
tion of selective COX-2 inhibitors and dexamethasone at
a dose that inhibits COX-2 expression.139 COX-2 expres-
sion is therefore assumed to be up-regulated as one of the
protective mechanisms when the stomach is exposed to
stress such as ischemia/reperfusion.
Reduced local mucosal NO generation and increased
endothelin-1 (a potent vasoconstrictor) also appear to
play an important role in the mechanisms of
SRMD.141,142 Endogenous NO plays a dual role in isch-
emia/reperfusion-induced gastric injury: constitutive NO
synthase/NO is protective, whereas inducible NO syn-
thase/NO is proulcerogenic.143,144 The gene expression of
inducible NO synthase is markedly up-regulated in the
stomach following ischemia/reperfusion, accompanied
by a significant increase in the mucosal NO content,
supporting a pathogenic role.145
Hemorrhagic shock in an animal model has been re-
ported to increase gastric mucosal permeability with in-
creased back diffusion of hydrogen ions,146 presumably
allowing for greater mucosal injury in the presence of
intraluminal gastric acid. This increase in back diffusion
has also been reported in critically ill patients.146 Gastric
mucosal acidosis can be assessed in critically ill patients
with gastric tonometry. The intramucosal pH, which is
calculated from intraluminal gastric juice pCO2 and ar-
terial HCO3⫺, is used as a measure of mucosal ischemia
and is reported to be a significant risk factor for major
bleeding from stress ulceration and mortality.147
Critically ill patients may have a decrease in gastric
mucosal blood flow through systemic hypotension, but,
in addition, patients may have splanchnic hypoperfusion
even when systemic hemodynamics are relatively main-
tained.122,148 Normotensive critically ill septic patients on
mechanical ventilation were reported to have a 50%– 60%
reduction in mucosal blood flow measured by reflectance
spectrophotometry compared with controls.122 In addi-
tion, induction of an isolated increase in splanchnic
blood flow in critically ill patients, in the absence of any
significant changes in systemic measurements of hemo-
July 2008
dynamics and oxygen delivery, was noted to increase
gastric intramucosal pH.149
Of interest, mild stress prevents gastric lesions that
occur in response to severe stress. This effect is mediated
by PGs derived from both COX-1 and COX-2, probably
in both the brain and the stomach, and the effect is
functionally associated with prevention of the decrease in
body temperature that occurs during severe stress.150
Phospholipase A2 plays a role, triggering central PG pro-
duction by COX-1 and COX-2, and thyrotropin-releasing
hormone also may be involved in the protective action of
mild stress.
Aging gastropathy
Experimental studies indicate that the aging gas-
tric mucosa has impaired mucosal defense, eg, decreased
mucus and bicarbonate secretion and reduced prosta-
glandin generation.151,152 Cryer et al demonstrated that
aging reduces gastric and duodenal PG concentrations in
humans.153 Other studies showed that aging gastric mu-
cosa has reduced NO synthase activity and impaired
sensory nerve response to luminal acid.152,154 –156 Further-
more, in experimental models, aging increases the sus-
ceptibility of gastric mucosa to injury by a variety of
damaging agents, such as NSAIDs, ethanol, and hyper-
tonic solutions,152,156,157 and impairs healing of both
acute injury and chronic gastric ulcers.151,155,158
A recent study159 of aging rats demonstrated that gas-
tric mucosal blood flow is decreased by 60% with hypoxia
and atrophy of glandular cells. In addition, expression of
multifunctional phosphatase and tensin homolog de-
leted on chromosome 10 (PTEN) and activated
caspases-3 and -9 was increased, whereas survivin was
reduced, all resulting in increased apoptosis. Further-
more, this study demonstrated increased susceptibility of
aging gastric mucosa to ethanol injury and that down-
regulation of elevated PTEN in gastric mucosa of aging
rats completely reverses this increased susceptibility. This
study also demonstrated increased PTEN expression and
reduced survivin in aging human gastric mucosa. These
experimental observations may explain at least in part the
well-described increase in NSAID-associated ulcers and
ulcer complications with increasing age.
Portal hypertensive gastropathy
Experimental studies indicate that the gastric mu-
cosa of individuals with portal hypertension has im-
paired mucosal defense, reduced oxygenation, increased
susceptibility to injury, and impaired healing,160 –169 sim-
ilar to that of the aging mucosa. Capillary endothelial
abnormalities in portal hypertensive gastropathy result
in a 3.5-fold reduction in mucosal capillary lumen diam-
eter168 causing diminished capillary blood flow and re-
duced mucosal oxygenation.167,168 Also, activation of the
TNF-␣ gene and overexpression of endothelial NO syn-
thase occurs with increased formation of toxic peroxyni-
GASTRIC MUCOSAL DEFENSE AND CYTOPROTECTION 51
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trate.164 Furthermore, a dramatic 10-fold reduction of
gastric angiogenesis occurs in response to alcohol injury
in portal hypertensive gastric mucosa.165 The relative
contribution of this impairment in gastric mucosal de-
fense to the blood loss seen in some patients with portal
hypertensive gastropathy has not been defined.
Reduction of Upper GI Injury and
Clinical Events
Cytoprotection
Cytoprotection is defined as an ability of pharma-
cologic agents, originally PGs, to prevent gastric and
intestinal mucosal injury produced by a variety of ulcero-
genic agents (eg, aspirin, indomethacin, bile acids) and by
necrotizing agents (eg, boiling water, absolute alcohol,
0.6 mol/L HCl, 0.2 mol/L NaOH).4,5 Andre Robert and
colleagues demonstrated that pretreatment of rats with a
minute amount (0.1 to 1 ␮g/kg) of 16,16 dimethyl PGE2
given orally or subcutaneously 15–30 minutes prior to
intragastric instillation of 100% alcohol or boiling water
completely prevents severe gastric mucosal necrosis from
occurring.4 This remarkable protection is accomplished
by mechanisms other than reduction of the gastric acid
secretion, as indicated by the fact that certain PGs protect
the gastric mucosa in nonantisecretory doses and that
even elimination of luminal acid with antisecretory
agents does not prevent necrosis.4 This novel concept
sparked a dramatic expansion in research. The cytopro-
tective action of PGs was found to apply to the human
gastric and duodenal mucosa170 –172 as well as other organ
systems (eg, liver, pancreas, kidney, blood vessels, and
heart).170 Endoscopic studies with assessment of mucosal
appearance, histology, and ultrastructure demonstrated
that 16,16 dimethyl PGE2 effectively protects the human
gastric and duodenal mucosa against injury produced by
concentrated (40%– 60%) alcohol.171,172
Since the first demonstration of cytoprotection by PGs,
other agents also have been shown to be cytoprotective.
They include sulfhydryl agents; growth factors; and pep-
tides such as EGF, TGF-␣, TFFs, gastrin, cholecystokinin,
thyrotropin-releasing hormone, bombesin, CRF, peptide
YY, neurokinin A, somatostatin, leptin, ghrelin, NO, hy-
drogen sulfide, agonists of adenosine and agonists of
proteinase activated receptor-1, and topically active anti-
ulcer drugs such as sucralfate, aluminum-containing ant-
acids, and rebamipide.19,173 Aluminum-containing antac-
ids (eg, hydrotalcite) have been shown to exert a potent
mucosal protective action against a variety of injurious
factors including ethanol, NSAIDs, pepsin, bile acids,
stress, and ischemia/reperfusion.174,175 These actions are
due to activation of PG synthesis; binding to and inacti-
vation of pepsin, lysolecithin, bile acids and H pylori
toxins; activation of heat shock proteins; and activation
of genes encoding EGF, basic fibroblast growth factor,
and their receptors.174 –176 Other topically active antiulcer
drugs may have similar modes of action.
 52 LAINE, TAKEUCHI, AND TARNAWSKI
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Table 2. Metaanalyses of Randomized Controlled
Endoscopic Trials for Prevention of
NSAID-Associated Ulcers
Gastric ulcer Duodenal ulcers
Misoprostol Cotherapy 0.26 (0.17⫺0.39) 0.47 (0.33⫺0.69)
H2 receptor antagonist 0.73 (0.50⫺1.09) 0.36 (0.18⫺0.74)
(standard dose)
cotherapy
H2 receptor antagonist 0.44 (0.26⫺0.74) 0.26 (0.11⫺0.65)
(double dose)
cotherapy
Proton pump inhibitor 0.40 (0.32⫺0.51) 0.19 (0.09⫺0.37)
cotherapy
COX-2 selective inhibitor 0.21 (0.18⫺0.25) 0.34 (0.25⫺0.45)
NOTE. Relative risk (95% CI) of traditional NSAIDS ⫹ medical co-
therapy or of COX-2 selective inhibitors vs traditional NSAIDs alone
(80,178).
Increased production of endogenous PG by mild irri-
tants (eg, 20% ethanol, capsaicin) may induce adaptive
cytoprotection and thereby decrease injury from more
severe irritants administered subsequently.5 This action is
mediated through EP-1 receptors and is blocked by COX
inhibition with indomethacin and by an EP-1 receptor
antagonist.177
Reduction of NSAID-Associated Injury and
Clinical Events
Strategies designed to decrease upper GI tract
injury because of NSAIDs target either the decrease in
mucosal defense related to NSAID-induced inhibition of
PG production (eg, misoprostol cotherapy, COX-2 selec-
tive inhibitors) or the acid that is required to cause gross
injury in the presence of an impaired mucosal defense
(eg, H2RAs, PPIs).
Medical Cotherapy. Misoprostol. Misoprostol is a
synthetic PGE1 analog designed to help overcome the
NSAID-induced deficiency of PGs in the gastric mu-
cosa. Misoprostol also has antisecretory properties. A
metaanalysis of randomized controlled trials found
that misoprostol significantly decreases NSAID-associ-
ated gastric and duodenal ulcers vs placebo (Table 2);
efficacy increases with increasing daily doses from 400
to 800 ␮g.178 Misoprostol is superior to H2RAs for
prevention of gastric but not duodenal ulcers.178 A GI
outcomes study in 8848 rheumatoid arthritis patients
followed for up to 6 months revealed a significant
decrease in complicated ulcers (RR, 0.49; 95% CI: 0.27–
0.89; number needed to treat [NNT], 263) and overall
clinical events (RR, 0.46; 95% CI: 0.29 – 0.73; NNT,
139).87 In the United States, misoprostol represents
only 2% of medical cotherapy prescriptions for NSAID
users179; this low rate may be due to misoprostol’s GI
adverse effects, such as diarrhea and abdominal dis-
comfort,178 and the need for multiple daily doses.
Histamine H2-receptor antagonists. Standard doses of
H2RAs are not significantly better than placebo for re-
GASTROENTEROLOGY Vol. 135, No. 1
duction of NSAID-induced gastric ulcers but do decrease
duodenal ulcers (Table 2).178 Double-dose H2RA therapy
does significantly decrease NSAID gastric ulcers.178 Ran-
domized controlled outcome trials to assess clinical
events with H2RAs have not been performed.
PPIs. PPIs significantly decrease NSAID-induced
gastric and duodenal ulcers vs placebo (Table 2).178 A
randomized comparison after healing of NSAID ulcers
(or ⬎10 erosions) revealed significantly lower 6-month
ulcer incidences for omeprazole 20 mg daily than raniti-
dine 150 mg twice daily: gastric ulcers, 5% vs 16%; duo-
denal ulcers, 0.5% vs 4%, respectively.180 PPIs are superior
to misoprostol in prevention of NSAID duodenal ulcers,
but, when used at high dose (200 ␮g 4 times daily),
misoprostol was superior to PPI therapy for prevention
of gastric ulcers in a randomized trial.178,181
No randomized controlled trial of PPIs for upper GI
clinical events in a general population of NSAID users
has been performed. However, trials in high-risk patients
hospitalized with NSAID-associated bleeding ulcers are
available. After ulcer healing, Chan et al182 resumed
NSAID therapy with naproxen 500 mg twice daily in 150
such patients with H pylori infection and randomly as-
signed them to maintenance PPI therapy or H pylori
eradication therapy. At 6 months, the rate of recurrent
ulcer bleeding was significantly lower in the PPI group
(4% vs 19%, respectively). A randomized placebo-con-
trolled trial demonstrated that PPI therapy decreased
recurrent ulcer complications (bleeding) in low-dose as-
pirin users who had presented with ulcer complications
(2% vs 15%, respectively, at median follow-up of 12
months).183
COX-2 Selective Inhibitors. Endoscopic random-
ized controlled trials reveal that COX-2 selective inhibitors
(coxibs) significantly decrease gastroduodenal ulcers as
compared with nonselective NSAIDs (Table 2).80 Ulcer rates
were significantly decreased with all 5 coxibs (celecoxib,
rofecoxib, valdecoxib, etoricoxib, lumiracoxib) and when
coxibs were tested against any of the most commonly used
NSAIDs (ibuprofen, naproxen, or diclofenac).
Large randomized controlled outcome trials demon-
strate a significant reduction in upper GI complications
and overall upper GI clinical events with coxibs vs tradi-
tional NSAIDs (Table 3): a recent metaanalysis revealed a
RR of 0.39 (95% CI: 0.31– 0.50) for upper GI complica-
tions with a 0.4% absolute risk reduction. Interestingly,
when diclofenac is the comparator traditional NSAID,
outcome studies have shown a significant benefit in over-
all upper GI events but not complicated events.80,88,89,184
This may be due to the lack of effective antiplatelet
activity in most patients taking diclofenac.
Medical Cotherapy vs COX-2 Selective
Inhibitor to Prevent UGI Complications
A traditional NSAID plus PPI has been compared
with celecoxib in patients presenting with NSAID-asso-
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Table 3. Upper GI Complications and Clinical Events From Randomized Outcome Trials of COX-2 Selective Inhibitors vs
Traditional NSAIDs
CLASS VIGOR TARGET SUCCESS MEDAL
(n ⫽ 3981)88,89 (n ⫽ 4029)90 (n ⫽ 9127)91 (n ⫽ 13,274)204 (n ⫽ 34,701)184
Type of arthritis Osteoarthritis (73%); Rheumatoid Osteoarthritis Osteoarthritis Osteoarthritis (72%);
rheumatoid (27%) rheumatoid (28%)
COX-2 selective inhibitor Celecoxib 400 mg Rofecoxib 50 mg Lumiracoxib 400 Celecoxib 100, Etoricoxib 60, 90
twice daily daily mg daily 200 mg twice mg daily
daily
Traditional NSAID Ibuprofen 800 mg 3 Naproxen 500 mg Ibuprofen 800 mg Naproxen 500 mg Diclofenac 50 mg 3
times daily; twice daily 3 times daily; twice daily, times daily, 75
diclofenac 75 mg naproxen 500 diclofenac 50 mg twice daily
twice daily mg twice daily mg twice daily
Low-dose aspirin use 22% Exclusion criterion 24% 7% 33%
PPI use Exclusion criterion Exclusion criterion Exclusion criterion Exclusion criterion 40%
Median follow-up 9 mo 9 mo 12 mo 12 wk Mean, 18 mo
Upper GI complications
RR (95% CI) 0.77 (0.41⫺1.46) 0.43 (0.24⫺0.78) 0.34 (0.22⫺0.52) 0.14 (0.03⫺0.69) 0.91 (0.67⫺1.24)
NNT — 128 (1 yr) 120 (1 yr) 714 (12 wk) —
Upper GI clinical events
RR (95% CI) 0.66 (0.45⫺0.98) 0.46 (0.33⫺0.64) 0.46 (0.36⫺0.60) 0.50 (0.26⫺0.96) 0.69 (0.57⫺0.83)
NNT 111 (1 yr) 41 (1 yr) 64 (1 yr) 476 (12 wk) 333 (1 yr)

NOTE. Clinical events include complications plus uncomplicated symptomatic ulcers.

PPI, proton pump inihibitor; NNT, number-needed-to-treat (at specific time period based on individual study).

ciated gastroduodenal ulcer bleeding in 2, 6-month ran-
domized controlled trials.185,186 Differences in recurrent
ulcer complications between the 2 groups were not sig-
nificant: celecoxib rates were 1.5% and 2.6%, respectively,
lower than the traditional NSAID plus PPI. Most impor-
tantly, the rates of recurrent ulcer complications were
unacceptably high in both groups. Chan et al found
recurrent ulcer bleeding in 4.9% and 6.4%, respectively, of
patients in the 2 treatment arms at 6 months, with an
additional 19% and 26%, respectively, having endoscopic
ulcers identified.185,187 These results suggest that very
high-risk patients should receive a coxib plus a PPI. A
recent randomized controlled trial in patients presenting
with NSAD-associated ulcer bleeding assessed this strat-
egy by comparing celecoxib alone vs celecoxib plus PPI
after ulcer healing.188 The incidence of recurrent ulcer
bleeding at 1 year was 9% with celecoxib alone vs 0% with
combined therapy.
Summary. Misoprostol, PPIs, and COX-2 selec-
tive inhibitors all significantly decrease the risk of ulcers
and ulcer complications associated with NSAID use.
Strategies to decrease NSAID-induced GI complications
should be employed in patients at increased risk for GI
clinical events: older age (eg, ⬎65 years); prior upper GI
clinical event; concomitant use of corticosteroid, antico-
agulant, or antithrombotic (eg, aspirin). Patients at very
high-risk for ulcer complications, such as those with
prior ulcer complications or multiple GI risk factors,
should receive a coxib plus a PPI.
Reduction in SRMD
A variety of agents have been used in an attempt
to decrease SRMD-related bleeding. Similar to NSAID
protective cotherapy, these agents enhance mucosal de-
fense (eg, sucralfate, misoprostol) or decrease the effects
of gastric acid (eg, antacids, H2RAs, PPIs). Antacids were
among the earliest medications used. Metaanalysis of
randomized controlled trials failed to show a significant
decrease in overt or clinically important bleeding, and the
frequent large volumes required were inconvenient and
potentially could increase risk of aspiration.123 Intrave-
nous administration of H2RAs significantly decreased
overt bleeding (OR, 0.58; 95% CI: 0.42– 0.79) and clini-
cally important bleeding (OR, 0.44; 95% CI: 0.22– 0.88) as
compared with placebo or no therapy.123 Metaanalysis of
sucralfate vs placebo/no therapy showed a decrease in
overt bleeding (OR, 0.58; 95% CI: 0.34 – 0.99), although
limited data show no decrease in clinically important
bleeding.123,189
The randomized trials done in the 1970s to the 1990s
were small and of variable methodologic quality with
variable definitions of bleeding, and metaanalysis of these
diverse and heterogeneous trials is no substitute for a
randomized controlled trial of proper sample size. A
landmark multicenter Canadian double-blind random-
ized trial comparing ranitidine and sucralfate in 1200
patients was published in 1998. Medical-surgical ICU
patients requiring mechanical ventilation ⱖ48 hours
were randomly assigned to ranitidine 50 mg intrave-
nously every 8 hours or sucralfate 1 g every 6 hours via
nasogastric tube.190 Clinically important bleeding was
significantly lower with ranitidine (1.7% vs 3.8%, respec-
tively [RR, 0.44; 95% CI: 0.21– 0.92]) with no difference in
mortality (23.5% vs 22.8%, respectively [RR, 1.03; 95% CI:
0.84 –1.26]) (Figure 5).
 54 LAINE, TAKEUCHI, AND TARNAWSKI
GASTROENTEROLOGY
BASIC AND CLINICAL
REVIEWS IN
Figure 5. Results of a double-blind randomized trial of ranitidine intra-
venously vs. sucralfate via nasogastric tube in 1200 intensive care unit
patients requiring mechanical ventilation ⱖ48 hours.162
An additional concern with stress prophylaxis relates
to the development of ventilator-associated pneumonia,
a common and serious problem in critically ill patients.
Gastric colonization with gram-negative bacilli is sug-
gested to play a causal role, and an increase in gastric pH
increases gastric colonization.191 However, an association
of gastric organisms with ventilator-assisted pneumonia
is not identified in all studies.192–194 Furthermore, meta-
analyses of randomized controlled trials failed to show a
significant increase in pneumonia with H2RAs (RR, 1.25;
95% CI: 0.78 –2.00) or sucralfate (RR, 2.11; 95% CI: 0.82–
5.44) vs placebo/no therapy, although there was a trend
to more pneumonias with H2RAs than sucralfate (RR,
1.19; 95% CI: 0.98 –1.44).123 However, methodologic de-
ficiencies and small sample sizes made a large prospective
randomized trial necessary to confirm or refute these
findings. The large multicenter trial mentioned above
carefully assessed ventilator-associated pneumonia and
found no significant difference (19.1% vs 16.2%, respec-
tively [RR, 1.18; 95% CI: 0.92–1.51]).190 These results are
very similar to those of the earlier metaanalysis and do
not rule out a small RR increase with antisecretory ther-
apy compared with sucralfate.
Based on the results of the large trial, intravenous
H2RAs have generally been recommended for preventive
therapy in high-risk patients. However, some authors
have suggested, because the rate of clinically important
bleeding is very low and the benefit of therapy uncertain
in recent studies, that prophylaxis is unnecessary.189,195–197
In addition, if nosocomial pneumonia is increased with
antisecretory therapy, this may offset some or all of the
benefit because of the decrease in bleeding. Furthermore,
early enteral nutrition is suggested to decrease the risk of
stress-related bleeding, although it also increases gastric pH
and colonization as well as gastric volume.197,198 In the
multicenter Canadian trial, enteral nutrition was a signifi-
cant independent predictor of decreased bleeding risk (RR,
0.30; 95% CI: 0.13– 0.67).117 However, regardless of whether
GASTROENTEROLOGY Vol. 135, No. 1
patients were receiving enteral nutrition in that study, rani-
tidine was still associated with a significant decrease in
bleeding.
PPIs have been used increasingly for stress prophylaxis,
despite very limited trial data supporting their use in past
years. A recent large double-blind randomized trial com-
pared PPI (immediate-release suspension via nasogastric
tube) and constant infusion H2RA in 359 patients who
required mechanical ventilation for ⱖ48 hours and had 1
additional risk factor.199 Significantly fewer patients had
overt bleeding with the PPI (19% vs 32%, respectively), but
there was no significant difference in persistent bleeding
(3.9% vs 5.5%, respectively), transfusion-requiring bleed-
ing (2.8% vs 2.8%, respectively), nosocomial pneumonia
(11.2% vs 9.4%, respectively), or death (15.2% vs 11.6%,
respectively); bleeding was not the cause of death in any
patient.
Limited information is available for use of misopros-
tol. No placebo-controlled trials of misoprostol for pre-
vention of stress-induced ulcers are available, but trials
with antacid and H2RA controls show no significant
differences in outcomes assessed.200 –202
Summary. Preventive cotherapy aimed at decreas-
ing SRMD bleeding should not be used in all patients in
the ICU but only in those at high risk for stress bleeding,
eg, severe trauma, burns ⬎ one third of the body surface
area, major intracranial disease, severe illness requiring
mechanical ventilation ⬎48 hours. Intravenous H2RAs
or PPIs via nasogastric tube are appropriate therapies,
although the absolute risk reduction with these agents in
modern ICUs is likely small. If the rate of clinically
important bleeding is 5% or less, then a 50% RR reduc-
tion with prophylactic therapy means that 40 patients or
more will need to be treated to prevent 1 additional
episode of clinically important bleeding—and little or no
benefit in mortality can be expected.203
Future Directions
In the clinical arena, knowledge regarding gas-
tric mucosal defense mechanisms has led to the devel-
opment of current and potential future therapies to
reduce NSAID gastrointestinal injury, including miso-
prostol, coxibs, NO-NSAIDs, H2S-NSAIDs, and phos-
phatidylcholine-NSAIDs. Future pharmacogenomic
studies may help better stratify patients for their risk
of NSAID complications (eg, polymorphisms influenc-
ing drug metabolism and COX activity). Gastric mu-
cosal defense mechanisms also may be applicable to
the esophagus, intestine, and extraintestinal tissues.
For example, a PGE2 analog effectively protects liver,
pancreas, myocardium, and other tissues from injury.
Other important areas for future research include bac-
terial-epithelial interactions through toll-like and
other receptors; epithelial/endothelial cell interactions
with matrix through integrins, focal adhesion proteins,
and cytoskeletal elements; and mucosal immune re-
July 2008
sponse. Future studies will allow a better recognition
of cellular and subcellular defensive mechanisms, such
as ATP-ase pumps; K⫹ and Ca⫹⫹ channels in cell mem-
branes; mitochondrial membrane potential and perme-
ability; activation of pro- and antiapoptotic pathways,
including PI-3K and survivin prosurvival signaling and
PTEN-induced proapoptotic signaling; intracellular
pH, hypoxia, and oxygen cellular sensing mechanisms;
and nuclear transport of transcription factors by im-
portins, as well as genetic regulation of these mecha-
nisms. Finally, optical devices such as confocal endo-
microscopy, optical coherence tomography, Mauna-
Kea probe, and multiphoton microscopy will allow
real-time assessment of cellular structures and molec-
ular imaging of specific targets involved in human
gastric mucosal defense.
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Received January 23, 2008. Accepted May 5, 2008.
Address requests for reprints to: Loren Laine, Room 12-137, L. A.
County and U.S.C. Medical Center, 1200 N State St, Los Angeles,
California 90033. e-mail: llaine@usc.edu.; fax: (323) 226-7573
Supported in part by a VA Merit Review (to A.T.).