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. 2001 Jun;48(6):774–781. doi: 10.1136/gut.48.6.774

Acid regulates inflammatory response in a rat model of induction of gastric ulcer recurrence by interleukin 1β

T Watanabe 1, K Higuchi 1, K Tominaga 1, Y Fujiwara 1, T Arakawa 1
PMCID: PMC1728306  PMID: 11358894

Abstract

BACKGROUND—In a previous study we showed that interleukin 1β (IL-1β) caused recurrence of gastric ulcers in rats, and that adhesion molecules (intercellular adhesion molecule 1 and leucocytic β2 integrins) play a role in this recurrence. Although gastric acid plays an important role in many types of gastric injuries, including peptic ulcer recurrence, the mechanism(s) remains unclear.
AIMS—To examine the involvement of gastric acid in induction of ulcer recurrence by IL-1β, and to investigate the role of gastric acid in inflammatory responses during ulcer recurrence.
METHODS—Rats with healed ulcers were used. Rats were given 1 µg/kg IL-1β intraperitoneally. Another group of rats was given 20 mg/kg omeprazole for three days to inhibit acid secretion, and received IL-1β 20 hours after the first administration of omeprazole. They were then given 0.15 N HCl or vehicle at 0, 12, 24, and 36 hours after IL-1β treatment. Some rats were given acid alone at the same time points. Expression of adhesion molecules was examined immunohistochemically and concentrations of IL-1β and tumour necrosis factor α (TNF-α) were measured by ELISA in scar tissue 24 hours after IL-1β treatment.
RESULTS—IL-1β increased expression of adhesion molecules and concentrations of IL-1β and TNF-α in scar tissue by 24 hours after IL-1β treatment, and nine of 11 healed ulcers had recurred by 48 hours. Omeprazole inhibited the effects of IL-1β. HCl acid abolished the inhibitory effects of omeprazole. Acid alone affected neither expression of adhesion molecules nor cytokine concentrations, and did not cause recurrence.
CONCLUSIONS—Gastric acid is required for recurrence of gastric ulcers caused by IL-1β, and gastric acid stimulates the inflammatory process in scarred mucosa during ulcer recurrence.


Keywords: ulcer recurrence; gastric acid; inflammatory cytokines; adhesion molecules; inflammation

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Figure 1  .

Figure 1  

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Expression of intercellular adhesion molecule 1 (ICAM-1) in scarred mucosa 24 hours after injection of interleukin 1β (IL-1β). A marked increase in expression of ICAM-1 was observed by 24 hours in rats given IL-1β (A) while there was no increase in expression of ICAM-1 in rats administered omeprazole together with IL-1β (B). Original magnification ×40.

Figure 2  .

Figure 2  

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Comparison of numbers of infiltrating leucocytes positive for lymphocyte function associated antigen 1 (LFA-1) or Mac-1 in scarred mucosa. The numbers of LFA-1 or Mac-1 positive cells infiltrating scarred mucosa were counted, and the mean numbers of such cells were compared with those in control animals (not given IL-1β). Results are mean (SEM), n=6. OPZ, omeprazole; IL-1β, interleukin 1β; ICAM-1, intercellular adhesion molecule 1. *p<0.05, **p<0.01 compared with control animals.

Figure 3  .

Figure 3  

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Comparison of numbers of infiltrating leucocytes positive for lymphocyte function associated antigen 1 (LFA-1) or Mac-1 in normal mucosa. The numbers of LFA-1 or Mac-1 positive cells infiltrating the normal mucosa were counted, and the mean numbers of such cells were compared with those in control animals (not given IL-1β). Results are mean (SEM), n=6. OPZ, omeprazole; IL-1β, interleukin 1β; ICAM-1, intercellular adhesion molecule 1. 

Figure 4  .

Figure 4  

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Comparison of numbers of lymphocyte function associated antigen 1 (LFA-1) and Mac-1 positive leucocytes in superficial and deep portions of scarred mucosa at 24 hours. LFA-1 and Mac-1 positive cells were counted separately in the deep and superficial portions of scarred mucosa, and the mean numbers of cells were compared with those in control animals (not given IL-1β). Results are mean (SEM), n=6. OPZ, omeprazole; IL-1β, interleukin 1β; ICAM-1, intercellular adhesion molecule 1. **p<0.01 compared with control animals.

Figure 5  .

Figure 5  

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Interleukin 1β (IL-1β) and tumour necrosis factor α (TNF-α) concentrations in scar tissue at 24 hours. Concentrations of IL-1β (A) and TNF-α (B) in scar tissue were assayed 24 hours after IL-1β treatment. Results are mean (SEM), n=6. OPZ, omeprazole. *p<0.05, **p<0.01 compared with control animals (not given IL-1β).

Figure 6  .

Figure 6  

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Cellular infiltration and immunohistochemical staining for interleukin 1β (IL-1β) and tumour necrosis factor α (TNF-α) in superficial mucosa at 24 hours after IL-1β treatment. (A) IL-1β induced infiltration by leucocytes, including neutrophils, in the superficial portion of scarred mucosa. (B) Monocytes/macrophages were abundant in this region. IL-1β (C) and TNF-α (D) were detected mainly in inflammatory cells in the superficial mucosa. The numbers of cells stained for IL-1β (E) and TNF-α (F) were small in rats given the antibody against intercellular adhesion molecule 1. Original magnification ×200 (A-D) and ×50 (E, F).

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