Reduction of EGF is associated with the delay of gastric ulcer healing by cigarette smoke in rats

Abstract

Epidemiological studies have shown that cigarette smoking is associated with peptic ulceration and also delays ulcer healing in man. This could be due to the disturbance of physiological feedback mechanisms in response to ulcer formation, especially those of growth factors in the body. Aim: To investigate whether reduction of epidermal growth factor (EGF) is responsible for the ulcerogenic mechanism by which cigarette smoking delays ulcer healing. Methods: Male Sprague-Dawley rats (180-200 g) were induced with kissing ulcers in the stomachs by applying 60% acetic acid to the luminal surfaces. Twenty-four hours after ulcer induction, rats were exposed to different concentrations of cigarette smoke (0, 2 or 4%) for l-hr period given once daily for 3 or 6 days. During these periods, ulcer sizes, gastric blood flow, mucosal and serum EGF levels were assessed. In addition, angiogenesis in the granulation tissue at the ulcer base and epithelial cell proliferation at the ulcer margin were also determined by immunohistochemical methods for yon WiUebrand Factor expression and 5-bromo-2'-deoxyuridine (BrdU) incorporation, respectively, in the formalin fixedand paraffin-embedded sections. Results: Cigarette smoke exposure delayed ulcer healing which was accompanied by a reduction of gastric blood flow and a decrease in both angiogenesis in granulation tissue at the ulcer base and epithelial cell proliferation at the ulcer margin. Further study showed that a marked upregulation of EGF was observed 1 day after ulcer induction in serum and 4 days after ulcer induction in the gastric mucosa. However, cigarette smoke exposure significantly depressed these beneficial responses 4 days after ulcer induction. Intravenous administration of EGF (10 or 20 tag/kg) before each cigarette smoke exposure completely reversed the delaying effect of cigarette smoke exposure on ulcer healing and also attenuated the adverse actions on gastric blood flow, angiogenesis and epithelial cell proliferation by cigarette smoke exposure. Conclusion: Reduction of EGF level is one of the mechanisms involved in the delay of ulcer healing induced by cigarette smoking. This study was supported in part by a grant from the Hong Kong Research Grant Council.