Activation of genes for superoxide dismutase, interleukin-1 beta, tumor necrosis factor-alpha, and intercellular adhesion molecule-1 during healing of ischemia-reperfusion-induced gastric injury

Pc. Konturek et al., Activation of genes for superoxide dismutase, interleukin-1 beta, tumor necrosis factor-alpha, and intercellular adhesion molecule-1 during healing of ischemia-reperfusion-induced gastric injury, SC J GASTR, 35(5), 2000, pp. 452-463
Citations number
Categorie Soggetti
Gastroenerology and Hepatology","da verificare
Journal title
ISSN journal
0036-5521 → ACNP
Year of publication
452 - 463
SICI code
Background: Ischemia followed by reperfusion (I/R) induces gastric lesions, probably due to excessive formation of free radicals, but the role of the scavenger of these radicals, proinflammatory cytokines such as interleukin- 1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), in the heal ing of these lesions has not been extensively studied. It is also unknown w hether expression of intercellular adhesion molecule-1 (ICAM-1), which medi ates neutrophil-induced injury and neutrophil infiltration, is involved in the recovery from I/R lesions. Methods: I/R lesions were induced in Wistar rats by applying a small clamp to the celiac artery for 30 min (ischemia ph ase), followed by the removal of the clamp for 60 min (reperfusion phase). The influence of I/R on gastric secretion was also tested in mts equipped w ith a gastric fistula (GF) without or with the exposure to a standard perio d of VR. Two series of rats (A and B) were used to determine the effects of exogenous and endogenous superoxide dismutase SOD (series A) and allopurin ol, a xanthine oxidase inhibitor (series B), on the mucosal recovery from t he gastric lesions induced by I/R. The animals were killed immediately afte r the exposure to I/R (0 h) and at 3 h, 24 h, or 3, 5, or 10 days after thi s I/R, the area of gastric lesions being measured by planimetry, and the ga stric blood flow (GBF) determined by the H-2 gas clearance method. Blood wa s withdrawn for measurement of plasma IL-1 beta and TNF-alpha levels with e nzyme-linked immunosorbent assay, and plasma gastrin with radioimmunoassay. Biopsy samples of oxyntic mucosa were taken for the assessment of SOD, IL- 1 beta, TNF-alpha, and ICAM-1 mRNAs by reverse-transcription polymerase cha in reaction and Southern blot. Results: Exposure to I/R resulted in acute g astric erosions, with the maximal increase of the area of these lesions obs erved 3 h after the end of VR. This effect was accompanied by a decrease in the GBF, a significant increase in blood free radicals and plasma gastrin increments, and almost complete suppression of gastric secretion. Starting 24 h after I/R, the gastric superficial lesions progressed into deeper ulce rs that healed progressively within 10 days, and this was accompanied by gr adual restoration of the gastric secretion and the GBF. Treatment with SOD and allopurinol accelerated significantly the healing of VR erosions, and t his effect was accompanied by a significant increase in the GBF and the att enuation of blood free radicals. At 0, 3, and 12 h after YR a significant d ecrease in SOD mRNA was observed, whereas expression of TNF-alpha, IL-1 bet a, and ICAM-1 showed a progressive increase starting immediately after YR, reaching a maximum on day 3. The plasma level of TNF-alpha and IL-1 beta st arted to increase on day 3 and peaked on day 5 after I/R, being still signi ficantly higher at day 10 than that measured in the vehicle-treated control gastric mucosa. On day 10 the gastric ulcers were almost completely healed , and a decrease in the expression for TNF-alpha, IL-1 beta, and ICAM-1 mRN A and an increase in the expression of SOD mRNA were observed. Conclusions: 1) exposure to VR produces gastric lesions mediated by the exc essive formation of free radicals, resulting in suppression of both gastric microcirculation and secretory activity of the stomach; 2) SOD and allopur inol accelerate the healing of I/R lesions, probably due to suppression of oxygen free radicals and improvement of gastric microcirculation; and 3) th e upregulation of SOD mRNA, with subsequent increase in the SOD production and local release of IL-1 beta and TNF-alpha may activate ICAM-1 expression and neutrophil infiltration, which appear to play an important role in the progression of I/R-induced acute gastric erosions into chronic ulcers.