Expression of Epidermal Growth Factor and Transforming Growth Factor Alpha during Ulcer Healing: Time Sequence Study

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Abstract
Background: Growth factors such as epidermal growth factor (EGF) and transforming growth factor alpha (TGFα) have been shown to share common receptor (EGFR) and to accelerate ulcer healing due to stimulation of cell proliferation, but the time sequence of expression of EGF and TGFα during ulcer healing has not been investigated. In this study the rate of cell proliferation and the gastric secretion and gene expression of mRNA for EGF and TGFα were determined during ulcer healing. Methods: Gastric ulcers were induced in 150 Wistar rats by serosal application of 100% acetic acid (ulcer area, 14 mm). Some of these animals were also equipped with a gastric fistula for the assessment of gastric secretion during ulcer healing. The animals were killed 0, 2, 4, 6, or 8 days after ulcer induction, and the ulcer area was determined. The mucosal sections with gastric ulcer were immunostained for proliferating cell nuclear antigen (PCNA) and for immunoexpression of EGF, TGFα, and EGFR. The expression of mRNA EGF and mRNA TGFα was also determined in the ulcer margin by reverse transcriptase (RT) polymerase chain reaction (PCR) using specific primers. Results: Two, 4, 6, and 8 days after ulcer induction the gastric ulcer area was gradually reduced from the initial size (day 0) by 47%, 70%. 80%, and 87%. respectively, and this was accompanied by an increase in PCNA with its maximum on day 4. The gastric acid and pepsin secretion was significantly reduced by 75% and 79%, respectively, on day 2 after ulcer induction but then the secretion tended to return to normal value by day 8. The expression of EGF, TGFα, and EGFR was negligible on day 0 but increased significantly during the healing, reaching maximum on day 4. Expression of EGF mRNA was detected on days 2, 4, and 6, and that of TGFα mRNA on days 2, 4. 6. and 8 after ulcer induction, with the most intense signals for both transcripts observed on day 2. Conclusions: 1) The enhancement in cell proliferation during ulcer healing may be mediated by increased release of EGF and TGFα; 2) the expression of EGF and TGFα mRNA precedes the overexpression of these growth factors at the ulcer margin during ulcer healing; and 3) the overexpression of growth factors coincides with the inhibition of gastric secretion and increased blood flow at the ulcer margin, indicating that these factors affect gastric secretion and blood flow in the course of ulcer healing.