Involvement of interleukin-4 in down-regulation of endothelin-1 during gastric ulcer healing: Effect of ebrotidine

B. L. Slomiany, J. Piotrowski, A. Slomiany

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Aims: Healing gastric mucosal injury implies an orderly involvement of the signaling molecules that exert their influence on the processes leading to the restoration of the mucosal integrity. In this study, we investigated the effect of antiulcer agent, ebrotidine, on the course of events during gastric ulcer healing by analyzing the expression of interleukin-4 (IL-4), endothelin-1 (ET-1), tumor necrosis factor-α (TNF-α), and the mucosal activity of caspase-3, and constitutive (cNOS) and inducible (NOS-2) nitric oxide synthase. Methods: Rats with experimentally induced chronic gastric ulcers were administered twice daily for 14 days with either ebrotidine at 100 mg/kg or vehicle, and at different stages of treatment their stomachs were used for macroscopic and biochemical assessments. Results: The ulcer onset was characterized by a massive epithelial apoptosis associated with a significant increase in caspase-3, NOS-2, TNF-α and ET-1, and a decline in the mucosal expression of cNOS and IL-4. The healing was reflected in a rapid recovery in IL-4, decrease in apoptosis, caspase-3, TNF-α, ET-1 and NOS-2, and a slow recovery in cNOS, and the process was accelerated in the ebrotidine-treated group. In the absence of ebrotidine the expression of IL-4 returned to the level of normal mucosa by the seventh day of healing, and that of ET-1 and TNF-α by the fourteenth day. An accelerated ulcer healing (7 days) with ebrotidine treatment was associated with IL-4 recovery by the fourth day, ET-1 by the seventh day, and TNF-α and cNOS by the 10th day. However, in both groups of animals the apoptotic DNA fragmentation rate, and the expression of caspase-3 and NOS-2 remained significantly elevated even after the ulcer healed. Conclusions: Our findings suggest that a drop in the mucosal expression of IL-4 at the ulcer onset causes dysregulation of ET-1 production; induction of TNF-α and triggers the apoptotic events that affect the efficiency of the repair process. Ebrotidine, by eliciting rapid recovery in IL-4, is capable of suppression the mucosal apoptotic events and accelerate the ulcer healing.

Original languageEnglish (US)
Pages (from-to)55-68
Number of pages14
Issue number1
StatePublished - 2000

All Science Journal Classification (ASJC) codes

  • Immunology
  • Pharmacology
  • Pharmacology (medical)


  • CNOS
  • Caspase-3
  • ET-1
  • Ebrotidine
  • Gastric ulcer healing
  • IL-4
  • NOS-2
  • TNF-α

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