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. 1999 Oct;45(4):523–528. doi: 10.1136/gut.45.4.523

Indomethacin induced gastropathy in CD18, intercellular adhesion molecule 1, or P-selectin deficient mice

Z Morise 1, D Granger 1, J Fuseler 1, D Anderson 1, M Grisham 1
PMCID: PMC1727689  PMID: 10486359

Abstract

BACKGROUND—Neutrophil-endothelial cell interactions are thought to play a critical role in the pathophysiology of non-steroidal anti-inflammatory drug (NSAID) induced gastropathy.
AIMS—To optimise a mouse model of NSAID induced gastropathy and to evaluate the importance of adhesion molecules using adhesion molecule deficient mice.
METHODS—Gastropathy was induced in C57BL/6 mice or their adhesion molecule deficient counterparts via oral administration of indomethacin (20 mg/kg). Lesion scores, mucosal permeability, and histopathology were used to assess gastric mucosal injury.
RESULTS—Intragastric administration of indomethacin induced linear haemorrhagic mucosal lesions, primarily in the corpus of the stomach that were first observed at six hours. These lesions continued to develop over the next six hours with maximal lesion scores and mucosal permeabilities at 12 hours. When indomethacin was administered to mice deficient in CD18, intercellular adhesion molecule 1 (ICAM-1), or P-selectin, there were significant decreases in lesion scores compared with their C57BL/6 controls. In addition, mucosal permeabilities were found to be significantly lower in CD18 or ICAM-1 deficient mice observed at 12 hours.
CONCLUSION—Certain leucocyte and endothelial cell adhesion molecules are important determinants for full expression of indomethacin induced gastropathy. It is proposed that this modification of the mouse model may be useful for the investigation of other pathophysiological mechanisms of NSAID induced gastropathy.


Keywords: indomethacin; gastropathy; cyclooxygenase; intercellular adhesion molecule; VCAM; vascular cell adhesion molecule; P-selectin

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Figure 1  .

Figure 1  

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Histopathology of C57BL/6 mouse gastric mucosa resulting from indomethacin treatment. (A) Normal (untreated) mucosa. Typical distribution of apical located surface and mucous neck cells and more basal located chief and parietal cells. (B) Indomethacin treated mucosa of the wild type C57BL/6 mouse. Typical lesion showing erosion of the mucosa with predominant loss of the surface and mucous neck cells and loss of the integrity of the apical region of the glands. (C) Indomethacin treated mucosa of the CD18 deficient C57BL/6 mouse. Typical mucosa showing substantial protection to indomethacin treatment. The apical region of the glands appears disorganised, but does not exhibit erosion. (D) Indomethacin treated mucosa of the P-selectin deficient C57BL/6 mouse. Typical mucosa showing moderate protection to indomethacin treatment. The apical region of the glands appears disorganised with some general loss of surface mucous and mucous neck cells. Distinct regions of erosive lesion are not apparent. (E) Indomethacin treated mucosa of the ICAM-1 deficient C57BL/6 mouse. The absence of ICAM-1 expression had little protective effect. Typical lesions are found showing substantial erosion of the mucosa with loss of the integrity of the glands and loss of cells. However, ICAM-1 deficiency seemed to reduce the number of lesions.

Figure 2  .

Figure 2  

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Time course of gastric mucosal lesion score (A) and mucosal permeability (B) following oral administration of indomethacin (20 mg/kg) to healthy wild type (C57BL/6) mice. *p<0.05 versus 0 hour.

Figure 3  .

Figure 3  

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Gastric mucosal lesions (A) and mucosal permeability (B) induced by varying doses of indomethacin to healthy wild type mice. *p<0.05 versus control.

Figure 4  .

Figure 4  

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Gastric mucosal lesion score (A) and mucosal permeability (B) in wild type (C57BL/6), ICAM-1, CD18, and P-selectin deficient mice 12 hours following oral administration of indomethacin (20 mg/kg). *p<0.05 and **p<0.01 versus C57BL/6 mice.

Selected References

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