transforming-growth-factor-alpha and Peptic-Ulcer

Recent studies indicate that eradication of Helicobacter pylori might prevent peptic ulcer formation in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs). On the other hand, gastric adaptation after repeated exposures to aspirin (ASA) is well documented but the influence of H. pylori on this process remains to be elucidated.. To compare gastric damage and adaptation following repeated exposures to ASA in a group of patients with H. pylori infection, before and after eradication of the bacterium, and in H. pylori-negative controls.. Eight healthy volunteers without H. pylori infection and eight patients with duodenal ulcer (DU) history and H. pylori infection before and after H. pylori eradication were given ASA 2 g/day for a period of 14 days. Mucosal damage was evaluated by endoscopy and histology of biopsy samples. Gastric microbleeding, DNA synthesis in the gastric mucosa and mucosal expression, as well as luminal content of transforming growth factor-alpha (TGFalpha) were determined on days 0, 3, 7 and 14 of the ASA course.. In all patients aspirin-induced gastric damage reached a maximum on day 3. In H. pylori-positive patients, this damage was maintained at a similar level up to day 14, whereas in H. pylori-negative controls and H. pylori-eradicated patients this damage significantly lessened on day 14 and was accompanied by elevated DNA synthesis as well as increased mucosal expression and luminal release of TGFalpha.

Topics: Adaptation, Physiological; Adult; Aspirin; Cell Division; DNA; Female; Gastric Mucosa; Gastroscopy; Growth Substances; Helicobacter Infections; Helicobacter pylori; Humans; Male; Peptic Ulcer; Peptic Ulcer Hemorrhage; Transforming Growth Factor alpha

TGF-alpha inhibits gastric acid secretion and may play an important role in epithelial repair. We quantitated regional levels of TGF-alpha in the human proximal gastrointestinal tract and determined whether they are affected by acid suppression or aspirin-induced injury. Ten healthy volunteers were studied. After baseline endoscopy with biopsy, five randomly received no treatment, aspirin, omeprazole, or cimetidine for one week. Endoscopy was repeated and prior unhealed biopsy sites quantitated. TGF-alpha levels were measured by RIA. Five additional subjects then completed an extended protocol of three weeks duration. All subjects were free of H. pylori infection. TGF-alpha levels in the antrum, 34.76 +/- 5.54 pg TGF-alpha/micrograms DNA were threefold higher than in the gastric body and duodenum (11.03 +/- 2.60 and 10.41 +/- 1.64 respectively, P < 0.01). The number of unhealed sites in the aspirin group was significantly greater than in the control or acid inhibition groups; however, TGF-alpha levels were not different from-the surrounding mucosa. TGF-alpha increased in the controls after biopsy; the increase was significant in the body at week 2 only. Aspirin significantly increased TGF-alpha levels in the gastric body and duodenum after one week. The rise in antral TGF-alpha appeared delayed and blunted by the aspirin treatment compared to control. There was no relationship between the number of visible biopsy sites, degree of aspirin-induced injury, and the TGF-alpha level. Acid suppression was associated with a significant increase in TGF-alpha in the gastric body and antrum at one week. Immunochemical staining did not demonstrate differences in proliferation in any treatment group compared to controls. TGF-alpha levels vary by location in the proximal gastrointestinal tract, with significantly greater levels in the antrum. After biopsy, TGF-alpha levels increase; short-term aspirin and acid inhibitors modulate this effect. Aspirin significantly impaired the healing of endoscopic biopsies in the antrum; however, this was not associated with changes in TGF-alpha levels. TGF-alpha levels did not change in response to acid secretory state. Further studies of mucosal levels of TGF-alpha in response to aspirin-induced injury in humans appear warranted.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Aspirin; Biopsy, Needle; Cimetidine; Duodenum; Gastric Acid; Gastric Mucosa; Humans; Intestinal Mucosa; Omeprazole; Peptic Ulcer; Pyloric Antrum; Radioimmunoassay; Transforming Growth Factor alpha

Acute exposure to Helicobacter pylori causes cell damage and impairs the processes of cell migration and proliferation in cultured gastric mucosal cells in vitro. EGF-related growth factors play a major role in protecting gastric mucosa against injury, and are involved in the process of gastric mucosal healing. We therefore studied the acute effect of H. pylori on expression of EGF-related growth factors and the proliferative response to these factors in gastric mucosal cells (MKN 28) derived from gastric adenocarcinoma. Exposure of MKN 28 cells to H. pylori suspensions or broth culture filtrates upregulated mRNA expression of amphiregulin (AR) and heparin-binding EGF-like growth factor (HB-EGF), but not TGFalpha. This effect was specifically related to H. pylori since it was not observed with E. coli, and was independent of VacA, CagA, PicA, PicB, or ammonia. Moreover, H. pylori broth culture filtrates stimulated extracellular release of AR and HB-EGF protein by MKN 28 cells. AR and HB-EGF dose-dependently and significantly stimulated proliferation of MKN 28 cells in the absence of H. pylori filtrate, but had no effect in the presence of H. pylori broth culture filtrates. Inhibition of AR- or HB-EGF- induced stimulation of cell growth was not mediated by downregulation of the EGF receptor since EGF receptor protein levels, EGF binding affinity, number of specific binding sites for EGF, or HB-EGF- or AR-dependent tyrosine phosphorylation of the EGF receptor were not significantly altered by incubation with H. pylori broth culture filtrates. Increased expression of AR and HB-EGF were mediated by an H. pylori factor > 12 kD in size, whereas antiproliferative effects were mediated by both VacA and a factor < 12 kD in size. We conclude that H. pylori increases mucosal generation of EGF-related peptides, but in this acute experimental model, this event is not able to counteract the inhibitory effect of H. pylori on cell growth. The inhibitory effect of H. pylori on the reparative events mediated by EGF-related growth factors might play a role in the pathogenesis of H. pylori-induced gastroduodenal injury.

Topics: Adenocarcinoma; Amphiregulin; Cell Division; Cell Line; EGF Family of Proteins; Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Gastritis; Glycoproteins; Growth Substances; Helicobacter Infections; Helicobacter pylori; Heparin; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Peptic Ulcer; Recombinant Proteins; RNA, Messenger; Stomach Neoplasms; Transforming Growth Factor alpha; Up-Regulation; Virulence

Prostaglandins (PGs), hepatocyte growth factor (HGF), and induction of cyclooxygenase (PG synthetase, COX) play important roles in the repair process of gastric mucosa. We hypothesized that nonsteroidal anti-inflammatory drugs (NSAIDs), including indomethacin (IND), retard the healing of ulcers by suppressing these factors. In this study, we investigated the effects of cytokines, growth factors, and IND on production of PG and HGF, and induction of COX using cultured human gastric fibroblasts. Exogenous PGs significantly increased HGF production in a dose-dependent manner. Among various potential stimulants tested, interleukin-1 beta (IL-1 beta) dramatically increased PGE2 production and significantly stimulated HGF production. IL-1 beta induced COX-2 but not COX-1 protein. IND significantly reduced both basal and IL-1 beta-induced PGE2 release and HGF production. These results suggest that the IL-1 beta-PG-HGF pathway plays a role in the repair process of gastric mucosa. Further, NSAIDs may delay the healing of gastric mucosal ulcer, in part through suppression of HGF expression via inhibition of endogenous PG production.

Topics: Alprostadil; Anti-Inflammatory Agents, Non-Steroidal; Cholera Toxin; Cyclic AMP; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Fibroblasts; Gastric Mucosa; Gene Expression Regulation, Enzymologic; Hepatocyte Growth Factor; Humans; Indomethacin; Interleukin-1; Isoenzymes; Membrane Proteins; Peptic Ulcer; Prostaglandin Antagonists; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Stomach Ulcer; Transforming Growth Factor alpha; Tumor Necrosis Factor-alpha

We investigated the role of gastric mucosal proliferation and mucosal transforming growth factor-alpha (TGF alpha) in the healing of peptic ulcers in human subjects. During endoscopic observation, mucosal biopsy specimens were taken from the ulcer margin for flow cytometric analysis of the mucosal cell cycle and ELISA for mucosal TGF alpha content. Immunohistochemistry confirmed that biopsy specimens contained proliferating gastric epithelial cells, TGF alpha, and the TGF alpha receptor. When the stage of ulcer healing was categorized according to Sakita and Miwa, mucosal cell proliferation was less at active stages and gradually increased during the healing process. The mucosal TGF alpha level at the ulcer margin was not detectable at the A1 stage but increased to within the normal range during ulcer healing. After re-establishment of the epithelial layer at the site of the ulcer, cell proliferation returned to normal and TGF alpha remained within the normal range. Immunohistochemistry showed coexistence of TGF alpha and its receptor within PCNA-positive proliferating cells. These results suggest that TGF alpha and its receptor play an important role in gastric epithelial cell replication. The increase in TGF alpha at the ulcer margin might indicate a role in stimulation of gastric cell replication during ulcer healing.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Biopsy; Cell Division; Enzyme-Linked Immunosorbent Assay; ErbB Receptors; Female; Gastric Mucosa; Gastroscopy; Humans; Male; Middle Aged; Peptic Ulcer; Proliferating Cell Nuclear Antigen; Transforming Growth Factor alpha