Role of tumor necrosis factor alpha release and leukocyte margination in indomethacin-induced gastric injury in rats

Gastroenterology. 1995 Feb;108(2):393-401. doi: 10.1016/0016-5085(95)90065-9.


Background/aims: Several studies have shown that polymorphonuclear neutrophil leukocyte (PMN) margination is an early and critical event in the pathogenesis of gastric mucosal injury caused by nonsteroidal anti-inflammatory drugs. Tumor necrosis factor (TNF) alpha is a proinflammatory cytokine that causes PMN margination by up-regulating expression of adhesion molecules on both PMN and endothelial cells. This study investigated whether substances that modulate TNF synthesis and release influence PMN margination and indomethacin-induced gastric damage.

Methods: Rats were treated with several doses of indomethacin alone or in association with substances known to increase (interleukin 2 and lipopolysaccharide) or inhibit (pentoxifylline, dexamethasone, granulocyte colony-stimulating factor [G-CSF]) TNF synthesis and release.

Results: Indomethacin administration caused dose-dependent damage and increased PMN margination and plasma TNF concentrations. Pretreatment with interleukin 2 and lipopolysaccharide significantly increased TNF release, PMN margination, and gastric mucosal damage, but administration of dexamethasone, pentoxifylline, and G-CSF provided almost total protection. The administration of G-CSF alone caused a significant increase in gastric PMN margination but protected against the indomethacin-induced gastropathy.

Conclusions: Agents that regulate TNF synthesis and release influence gastric susceptibility to indomethacin by modulating PMN margination. G-CSF increased PMN infiltration but protected against the mucosal injury, suggesting that PMN margination alone is not sufficient to induce mucosal damage.

MeSH terms

  • Animals
  • Dexamethasone / pharmacology*
  • Gastric Acid / metabolism
  • Gastric Mucosa / drug effects
  • Gastric Mucosa / metabolism*
  • Granulocyte Colony-Stimulating Factor / pharmacology*
  • Indomethacin
  • Interleukin-2 / pharmacology*
  • Lipopolysaccharides / pharmacology*
  • Lymphocyte Activation*
  • Male
  • Neutrophils
  • Pentoxifylline / pharmacology*
  • Pepsin A / drug effects
  • Pepsin A / metabolism
  • Peroxidase / drug effects
  • Peroxidase / metabolism
  • Rats
  • Rats, Wistar
  • Tumor Necrosis Factor-alpha / drug effects
  • Tumor Necrosis Factor-alpha / metabolism*


  • Interleukin-2
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Granulocyte Colony-Stimulating Factor
  • Dexamethasone
  • Peroxidase
  • Pepsin A
  • Pentoxifylline
  • Indomethacin