In ammopharmacology, Vol. 10, No. 4–6, pp.

291– 302 (2002)

Ó VSP 2002.
Also available online - www.vsppub.com

Review

Mechanisms of peptic ulcer recurrence: role of

in ammation

TOSHIO WATANABE ¤ , KAZUHIDE HIGUCHI, TETSUYA TANIGAWA,

KAZUNARI TOMINAGA, YASUHIRO FUJIWARA and TETSUO ARAKAWA
Department of Gastroenterology, Osaka City University Medical School, 1-4-3 Asahimachi,
Abeno-ku, Osaka 545-8585, Japan

Received 1 October 2002; accepted 3 October 2002

Abstract—The mechanism of peptic ulcer recurrence is still unclear. Since ulcerogenic factors such
as Helicobacter pylori, non-steroidal anti-in ammatory drugs and stress can increase expression of
in ammatory cytokines in gastric mucosa, gastric mucosal in ammation may play key roles in ulcer
recurrence. In acetic acid-induced gastric ulcers, persistent inŽ ltration of neutrophils into scarred
mucosa, which is caused by prostaglandin deŽ ciency, affects future ulcer recurrence. In a rat model
of ulcer recurrence which we developed, in ammatory cytokines such as interleukin (IL)-1¯ are key
mediators of ulcer recurrence. In this model, IL-1¯ increases expression of adhesion molecules on
both leukocytes and endothelial cells, and cytokines, leading to neutrophil inŽ ltration into scarred
mucosa. Gastric acid also plays important roles in recurrence of gastric ulcer in this model. Acid
regulates in ammatory processes, including expression of adhesion molecules and in ammatory
cytokines during ulcer recurrence. This review focuses on recent advances in understanding of the
mechanisms underlying development of gastric ulcer recurrence.

Key words: Cytokines; ulcer; lymphocytes; prostaglandins; leucocyte antigens; Helicobacter pylori.

ABBREVIATIONS

NSAIDs non-steroidal anti-in ammatory drugs

TNF-® tumor necrosis factor-®
IL interleukin
LFA-1 lymphocyte function-associated antigen-1
ICAM-1 intercellular adhesion molecule-1
PG prostaglandin

¤
To whom correspondence should be addressed. E-mail: watanabet@med.osaka-cu.ac.jp
292 T. Watanabe et al.

1. INTRODUCTION
Peptic ulcers frequently recur. Clinical evidence has demonstrated that infec-
tion with Helicobacter pylori (H. pylori) and the intake of non-steroidal anti-
in ammatory drugs (NSAIDs) are major causes of peptic ulcer recurrence (Graham
et al., 1992; Marshall et al., 1988; Taha et al., 1994). However, the mechanisms of
ulcer recurrence are poorly understood due to lack of an appropriate animal model
of ulcer recurrence. Both H. pylori and NSAIDs cause neutrophil inŽ ltration into
gastric mucosa via induction of in ammatory responses including expression of in-
 ammatory cytokines, such as tumor necrosis factor-® (TNF-®) and interleukins
(ILs) (Appleyard et al., 1996; Fan et al., 1995; Mai et al., 1991; Takaishi et al.,
1999), and adhesion molecules on leukocytes and endothelial cells (Andrews et al.,
1994; Enders et al., 1995; Higuchi et al., 1997; Wallace et al., 1991, 1993; Yoshida
et al., 1993), resulting in gastric injury. Furthermore, recent animal studies have
demonstrated that neutophilic inŽ ltration and overexpression of TNF-® and adhe-
sion molecules also occurred in stress-induced gastric mucosal injury (Hamaguchi
et al., 2001) and other types of gastric injury (Watanabe et al., 2000). In amma-
tion in gastric mucosa may thus be responsible for gastric damage including peptic
ulcer recurrence. We developed a rat model of gastric ulcer recurrence induced by
IL-1¯ (Watanabe et al., 1997). This animal model is useful for investigating the
mechanisms of ulcer recurrence. This review focuses on the roles of neutrophils,
in ammatory cytokines, and adhesion molecules in ulcer recurrence.

2. INFLAMMATORY CYTOKINES AND ADHESION MOLECULES IN

GASTRIC DAMAGE
2.1. In ammatory cytokines
Cytokines such as ILs and TNF-®, which are produced by in ammatory cells, play
central roles in a variety of types of tissue injury. Clinical and experimental studies
have demonstrated that ulcerogenic factors such as H. pylori, NSAIDs and stress
can increase the expression of in ammatory cytokines in gastric mucosa.
Crabtree et al. (1991, 1993) have reported that the production of TNF-®, IL-6, or
IL-8 in gastric mucosal biopsy specimens from patients with H. pylori infection is
greater than that in specimens from persons not so infected, and that the amount
of IL-8 in active gastritis is closely correlated with the degree of epithelial surface
degeneration, as well as the magnitude of neutrophil inŽ ltration into gastric mucosa.
IL-8 is a chemotactic and activating factor for neutrophils (Lindley et al., 1988;
Matsushima et al., 1988). Since in gastric mucosa infected with H. pylori, gastric
epithelial cells themselves produce IL-8 (Crabtree et al., 1994), IL-8 may play a
crucial role in H. pylori-associated gastric injury. Noach et al. (1994) have reported
that the concentration of IL-1¯ is also increased in patients with H. pylori infection.
Both IL-1¯ and TNF-® play roles in many in ammatory processes. These two
cytokines can induce the production of IL-8 by many types of cells, including
 Ulcer recurrence and in ammation 293

endothelial cells (Sica et al., 1990), macrophages (Philip and Epstein, 1986; Strieter
et al., 1990) and gastric epithelial cells (Beales and Calam, 1997) and a strong
correlation was found between the productions of IL-1¯ and IL-8 (Noach et al.,
1994).
NSAIDs such as indomethacin and aspirin induce neutrophil inŽ ltration, leading
to gastric mucosal injury (Wallace et al., 1990; Yoshida et al., 1995). There is
evidence that increased production of TNF-® is closely associated with such injury
(Appleyard et al., 1996; Santucci et al., 1995). Administration of indomethacin to
rats resulted in elevation of plasma TNF-® levels within 30 min (Appleyard et al.,
1996), and pretreatment with anti-TNF-® antisera or pentoxifylline, an inhibitor
of TNF-® synthesis, reduced gastric injury caused by indomethacin. Santucci
et al. (1995) demonstrated that pretreatment with IL-2 and lipopolysaccharide,
which increased TNF release, enhanced neutrophil margination and gastric mucosal
injury, but that administration of dexamethasone, pentoxifylline and G-CSF, which
inhibited TNF release, provided almost total protection against such injury.
TNF-® is also involved in stress-induced gastric injury. We recently reported
that water-immersion and restraint stress induced TNF-® expression in rat gastric
mucosa, accompanied by increase in neutrophil inŽ ltration, and that pretreatment
with anti-TNF-® antibody and anti-neutrophil serum prevented stress-induced
gastric injury (Hamaguchi et al., 2001). The cytokine network may thus participate
in in ammatory responses to various ulcerogenic factors, resulting in enhancement
of in ammation and injury in gastric mucosa.

2.2. Adhesion molecules

Migration of leukocytes into extravascular spaces is the result of interactions

between circulating leukocytes and endothelial cells (Butcher, 1991; Springer,
1990). These interactions are mediated by adhesion molecules on the surfaces
of both leukocytes and endothelial cells. The Ž rst step of leukocyte-endothelial
adhesion is mediated by the selectins and their counter-receptors. The selectins
lead relatively loose tethering of leukocytes to endothelium that results in the
in vivo phenomenon of rolling. These initial events in adhesion are followed
by up-regulation and/ or activation of other adhesion molecules of leukocytes
such as leukocytic ¯2 integrins, lymphocyte function-associated antigen (LFA)-1
(CD11a/ CD18) and Mac-1 (CD11b/CD18), and up-regulation of expression of
adhesion molecules of endothelial cells such as intercellular adhesion molecule
(ICAM)-1 (CD54), allowing for much stronger adhesion (Ž rm adhesion) (Diamond
et al., 1990; Marlim and Springer, 1987). The Ž nal stage of the cascade is
actual transmigration across the endothelium, a process in which immunoglobulin
superfamily members are thought to participate. In ammatory cytokines play
important roles in each step of this process. For example, IL-1¯ and TNF-® can
enhance the expression of LFA-1 and ICAM-1 (Pober et al., 1986; Pohlman et al.,
1986), and IL-8 induces expression of Mac-1 on neutrophils. Adhesion molecules
294 T. Watanabe et al.

are now thought to be responsible for inŽ ltration of leukocytes into gastric mucosa
in H. pylori- and NSAID-associated gastric injury.
We demonstrated that in patients with H. pylori infection, ICAM-1 expression was
prominent in most vessels, and that LFA-1 and Mac-1 were strongly expressed in
in ammatory cells inŽ ltrating gastric mucosa, but that after successful eradication
of H. pylori, the expression of these molecules markedly decreased (Higuchi et al.,
1997). Yoshida et al. (1993) demonstrated that treatment with a water extract of
H. pylori induced expression of CD 11b (Mac-1) on neutrophils within several
minutes, and that neutrophils strongly adhere to human endothelial cells. This
Ž nding is supported by a subsequent study by Enders et al. (1995), who reported that
expression of CD 11b, but not CD 11c, is up-regulated by water-soluble membrane
protein from H. pylori.
Neutrophil adherence to the vascular endothelium is a crucial event in the
pathogenesis of NSAID-induced gastric mucosal injury. The interaction between
neutrophils and endothelial cells is mediated by adhesion molecules. Wallace
et al. have reported that pretreatment with monoclonal antibodies directed against
ICAM-1, CD18, P-selectin, or E-selectin reduced gastric mucosal injury induced by
indomethacin in rabbits (Wallace et al., 1991) and in rats (Wallace et al., 1993).
Andrews et al. (1994) have examined the in vivo expression of adhesion molecules
such as ICAM-1 and LFA-1 after treatment with NSAIDs. Indomethacin increased
the numbers of vessels stained for ICAM-1 30 min after administration, at which
time appreciable mucosal injury was not evident. Increase in number of cells
stained for LFA-1 was observed 60 min after administration. These Ž ndings
suggest that the increase in ICAM-1 expression induced by indomethacin may
contribute to inŽ ltration of LFA-1 positive leukocytes. Since plasma TNF-® levels
increase prior to the increase of adhesion molecules, TNF-® may play a role in
the increased expression of adhesion molecules at sites of gastric injury caused
by NSAIDs. Recently, we found that anti-TNF-® antibody inhibited increase
in ICAM-1 expression and neutrophil inŽ ltration in stress-induced gastric injury
(Hamaguchi et al., 2001). In a variety of types of gastric injury, in ammatory
cytokines may contribute to increase in expression of adhesion molecules, leading
to neutrophil inŽ ltration.

3. RECURRENCE OF GASTRIC ULCER

3.1. Spontaneous recurrence of acetic acid-induced gastric ulcer
Treatment of rat stomach with acetic acid causes chronic gastric ulcers that resemble
human peptic ulcers both macroscopically and histologically (Takagi et al., 1969).
A striking feature of these experimental ulcers is that some recur spontaneously
after healing (Uchida et al., 1990). Therefore, this animal model of gastric ulcer
is useful for investigating both the process of ulcer healing (Tominaga et al., 1997;
Watanabe et al., 1995, 2002) and the pathogenesis of recurrence of peptic ulcers in
humans (Uchida et al., 1990).
 Ulcer recurrence and in ammation 295

Administration of indomethacin during the early stage of healing of acetic

acid-induced gastric ulcers increases the rate of future ulcer recurrence in rats
(Arakawa et al., 1996). Interestingly, numerous neutrophils were inŽ ltrating
scarred mucosa even after cessation of administration of this drug. Ornoprostil,
a synthetic prostaglandin (PG) E1 , together with indomethacin reduced the number
of neutrophils to control level in scarred mucosa and resulted in the lower rate of
ulcer recurrence. Furthermore, rebamipide, a PG-inducing gastroprotective drug,
reduces the recurrence of acetic acid-induced gastric ulcer when given together with
cimetidine (Arakawa et al., 1995). Since cimetidine is known to reduce PG content
in gastric mucosa (Arakawa et al., 1988), these Ž ndings indicate that PG deŽ ciency
during the early stage of ulcer healing causes persistent inŽ ltration of neutrophils
in scarred mucosa, resulting in future ulcer recurrence. However, it is unclear why
deŽ ciency of PG affects neutrophil inŽ ltration even after ulcers have healed, and
after cessation of administration of drugs such as indomethacin.

3.2. Induction of gastric ulcer recurrence by IL-1¯

Acetic acid-induced gastric ulcers spontaneously recur. We performed endoscopy
for sequential observation of ulcers in individual animals, and found that only about
30% of healed acetic acid-induced ulcers had recurred and ulcer recurrence occurs
at random (Arakawa et al., 1996). An animal model of ulcer recurrence is thus
needed to investigate mechanisms of recurrence in detail.
Since H. pylori and NSAIDs, which are major causes of peptic ulcer recurrence,
increase expression of in ammatory cytokines, as described above, we examined
whether IL-1¯ can enhance in ammation in scarred mucosa and cause recurrence
of acetic acid-induced gastric ulcer.
Rats found to have healed ulcers on endoscopy received an intraperitoneal in-
jection of IL-1¯ (0.01 to 1 ¹g / kg). IL-1¯ increased the numbers of neutrophils and
macrophages inŽ ltrating the scarred mucosa within 12 h, and at 24 h after treatment
with IL-1¯ the surface of the epithelium was disrupted and had been inŽ ltrated by
neutrophils. At 48 h, seven of the eight healed ulcers in rats treated with 1 ¹g / kg
IL-1¯ and one of the seven healed ulcers in rats treated with 0.1 ¹g /kg IL-1¯ had
recurred in the scarred mucosa. IL-1¯ at a dose of 0.01 ¹g / kg induced no ulcer
recurrence (Watanabe et al., 1997). Thus, approximately 90% of healed ulcers
recurred within 48 h after the injection of 1 ¹g /kg IL-1¯ and ulcers recurred at sites
of scarred mucosa. This animal model of ulcer recurrence is useful for investigation
of mechanisms of recurrence.

3.3. Mechanisms of IL-1¯-induced ulcer recurrence

Neutrophils play key roles in the development of injury and in ammation in a
variety of tissues, including gastric mucosa. In our model of gastric ulcer recurrence
by IL-1¯, neutrophils accumulated in scarred mucosa, especially where the surface
epithelium was disrupted. Neutrophils were also numerous in both the margins and
296 T. Watanabe et al.

(A)

(B)
Figure 1. An ulcer that had recurred 48 h after treatment with 1 ¹g/ kg IL-1¯. Ulcer recurrence had
occurred 48 h after treatment with 1 ¹g/ kg IL-1¯ (A). There are numerous neutrophils in both ulcer
margins and ulcer beds (B).

the bed of recurrent ulcers (Fig. 1). We hypothesized that neutrophils are responsible
for the induction of ulcer recurrence by IL-1¯. Antibody to neutrophils completely
prevented ulcer recurrence (Watanabe et al., 1997), suggesting that this model of
ulcer recurrence is neutrophil-dependent.
As described above, adhesion molecules play important roles in neutrophil-
mediated tissue injuries including gastric mucosal injury. Our immunohistochemi-
cal study showed that IL-1¯ markedly increased the expression of ICAM-1 on en-
 Ulcer recurrence and in ammation 297

(A)

(B)

(C)
Figure 2. Expression of adhesion molecules in scarred mucosa 24 h after treatment with 1 ¹g/ kg
IL-1¯. IL-1¯ induced overexpression of ICAM-1 (A), LFA-1 (B) and Mac-1 (C) in scarred mucosa.
298 T. Watanabe et al.

dothelial cells and the number of leukocytes expressing LFA-1 and Mac-1 in scarred
mucosa (Fig. 2), but did not affect the expression of these adhesion molecules in nor-
mal mucosa. Furthermore, monoclonal antibodies to ICAM-1, LFA-1 and Mac-1 in-
hibited both ulcer recurrence and neutrophil inŽ ltration induced by IL-1¯ (Watan-
abe et al., 1997). These results suggest that in our model, neutrophil inŽ ltration
into scarred mucosa is mediated via mechanisms involving ICAM-1/LFA-1 and
ICAM-1/Mac-1 pathways.
It is of interest that IL-1¯ causes ulcer recurrence in scarred mucosa, but does
not affect the expression of adhesion molecules and does not injure normal mucosa.
Direct effects of IL-1¯ alone do not explain such phenomena. Macrophages, which
can produce various cytokines and chemical mediators, regulate in ammatory
responses in a variety of tissues. Macrophages were abundant in scarred mucosa
of rats without IL-1¯ treatment, and IL-1¯ further increased the number of
macrophages in scarred mucosa, but did not do so in normal mucosa (Watanabe
et al., 1997). These Ž ndings may explain why IL-1¯ causes mucosal in ammation
and injury only in scarred mucosa. We found that IL-1¯ increased the expression of
transforming growth factor-¯1 and monocyte chemoattractant protein-1 in scarred
mucosa (Tominaga et al., 1998). Since these cytokines can promote migration of
macrophages, they may play crucial roles in macrophage inŽ ltration in response to
IL-1¯ stimulation. For whatever reason, the sensitivity of scarred mucosa to IL-1¯
is high.

3.4. Roles of gastric acid in ulcer recurrence

Maintenance treatment with histamine-H 2 -receptor antagonists or proton pump
inhibitors reduced the rate of peptic ulcer recurrence in humans (Gudmand-Høyer
et al., 1978; Lauritsen et al., 1991). Since these drugs alone cannot eradicate
H. pylori, these clinical Ž ndings indicate that gastric acid plays crucial roles in
peptic ulcer recurrence. Using a rat model of ulcer recurrence, we investigated
the mechanism by which gastric acid induces ulcer recurrence.
We found that sufŽ cient inhibition of gastric acid by omeprazole completely in-
hibited the ulcer recurrence induced by IL-1¯ and inhibited in ammatory responses
including the expression of adhesion molecules (ICAM-1, LFA-1 and Mac-1) and
in ammatory cytokines (IL-1¯ and TNF-®) (Watanabe et al., 2001). Since these
inhibitory effects of omeprazole were abolished by exogenous acid, these results
suggest that gastric acid may regulate in ammatory responses during ulcer recur-
rence.

4. CONCLUSIONS

Ulcerogenic factors such as H. pylori, NSAIDs, and stress can increase the expres-
sion of in ammatory cytokines. Since the sensitivity of scarred mucosa to in am-
 Ulcer recurrence and in ammation 299

Figure 3. Working hypothesis for ulcer recurrence.

matory cytokines such as IL-1¯ is high, these factors may cause overexpression of
cytokines in scarred mucosa in the presence of gastric acid. This overexpression of
cytokines may lead to substantial neutrophil inŽ ltration, resulting in recurrence of
peptic ulcer (Fig. 3).

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