Effect of local injection with basic fibroblast growth factor (BFGF) and neutralizing antibody to BFGF on gastric ulcer healing, gastric secretion, angiogenesis and gastric blood flow

Exogenous administration of bFGF was shown to accelerate tissue repair pred ominantly due to an increase in the formation of new microvessels (angiogen esis) suggesting that bFGF plays an important role in healing of gastric ul cer. This study was designed: 1) to examine the effect of local application of bFGF with or without neutralizing antibody (NA) to bFGF and 2) to deter mine the role of gastric secretion, gastric blood flow (GBF) at the ulcer m argin and angiogenesis during gastric ulcer healing with or without local a pplication of NA, bFGF or the combination of NA and bFGF. Chronic gastric u lcers were induced in Wistar rats by subserosal application of acetic acid (ulcer area 28 mm(2)) and gastric secretion during ulcer healing was assess ed using animals additionally equipped with chronic gastric fistulas. The b FGF without or with NA to bFGF (10 ng/100 mul), irrelevant antibodies (rabb it IgG; 10 mug/100 mul) or vehicle (saline) were locally injected into the subserosa immediately upon ulcer induction (day 0) and at day 2. Rats with acetic acid ulcers without subserosal injections served as controls. At day 11, all animals were anaesthetized and GBF was determined at the ulcer bas e, ulcer margin as well as in intact mucosa using the H-2-gas clearance tec hnique and the area of gastric ulcers was measured by planimetry. Gastric m ucosa with ulcer was excised and the percentage of area covered with blood vessels, the number of fibroblasts and the percentage of connective tissue at the ulcer edge was assessed by histology. The gastric ulcers were healed spontaneously in control vehicle-treated rats at day I I and this was acco mpanied by the significant increase in the GBF and number of microvessels i n the ulcer area. The gastric secretion was suppressed immediately after ul cer induction and increased significantly at day 2 and day 11 but failed to return to that recorded in intact animals. In contrast, local application of bFGF inhibited gastric acid and pepsin outputs at each study time interv als tested and this effect was reversed by addition of NA to bFGF. Locally applied bFGF accelerated significantly ulcer healing and this was accompani ed by the greater rise in the GBF of ulcer margin and more marked increase in number of microvessels as compared to those in vehicle-treated rats. Sub serosal application of NA to bFGF prolonged significantly the ulcer healing and this effect was accompanied by a significant fall in the GBF at the ul cer margin and a decrease in number of capillaries in ulcer bed without sig nificant alteration in gastric acid and pepsin outputs. The ulcer healing e ffect of bFGF and accompanying increase in the GBF at ulcer margin and in t he number of microvessels as well as inhibition of gastric acid secretion e voked by bFGF were significantly attenuated by the addition of NA to bFGF. The number of fibroblasts and the distribution of connective tissue did not differ between groups studied. We conclude that; 1) depletion of endogenou s bFGF at the ulcer area by specific NA to bFGF delays healing of gastric u lcers, reduces angiogenesis of ulcer bed and impairs the microcirculatory e ffect of this growth factor at the ulcer margin indicating that the availab ility of bFGF in the ulcer area plays a crucial role in the ulcer healing t hrough induction of angiogenesis; 2) this prominent antiulcer effect of loc ally applied bFGF depends, at least in part, upon the inhibition of acid se cretion by this peptide.