Role of caspase-3 and nitric oxide synthase-2 in gastric mucosal injury induced by indomethacin: Effect of sucralfate

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

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34 Scopus citations


Background: Apoptosis is the process of programmed cell death characterized by a series of distinct biochemical and morphological changes which involve activation of caspase proteases cascade that remains under the regulatory control or nitric oxide. Here, we investigated the activity of a key apoptotic protease, caspase-3, and the expression of inducible nitric oxide synthase (NOS-2) and tumor necrosis factor-α (TNF-α) associated with gastric epithelial cells apoptosis during indomethacin-induced gastric mucosal injury, and evaluated the effect of antiulcer agent sucralfate on this process. Methods: The experiments were conducted with groups od rats pretreated intragastrically with 200 mg/kg sucralfate or the vehicle, followed 30 min later by an intragastric dose of indomethacin at 60 mg/kg. The animals were killed 2 h later and their gastric mucosal tissue used for macroscopic assessment, assays or epithelial cells apoptosis and TNF-α, and the measurements of caspase-3 and NOS-2 activities. Results: In the absence of sucralfate, indomethacin caused multiple hemorrhagic lesions occupying 29.3 mm2 of the corpus area, and accompanied by a 20-fold enhancement in gastric epithelial cells apoptosis and a 47% increase in mucosal expression of TNF-α, while NOS-2 showed an 11.9-fold induction and the activity of caspase-3 increased 3.9-fold. Pretreatment with sucralfate produced a 59.7% reduction in the extent of mucosal damage caused by indomethacin, a 41.2% decrease in the epithelial cells apoptosis and a 33.4% reduction in TNF-α, while the activity of caspase-3 decreased by 45% and that of NOS-2 showed a 44.7% decline. Conclusions: The results implicate caspase-3 in the process of indomethacin-induced gastric epithelial cells apoptosis, and point towards participation of NOS-2 in the amplification of the cell death signaling cascade. Our findings also show that sucralfate protection against gastric mucosal injury caused by indomethacin involves the suppression of NOS-2 and the apoptotic events propagated by caspase-3.

Original languageEnglish (US)
Pages (from-to)3-16
Number of pages14
JournalJournal of Physiology and Pharmacology
Issue number1
StatePublished - Mar 1999

All Science Journal Classification (ASJC) codes

  • Physiology
  • Pharmacology


  • Apoptosis
  • Caspase-3
  • Indomethacin
  • Mucosal injury
  • NOS-2
  • Sucralfate
  • TNF-α


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