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Background: Different cytokines, including epidermal growth factor (EGF) and interleukin 1 beta (IL 1 beta), participate in the pathogenesis of gastric mucosal damage and repair by means of different mechanisms that are either paracrine or autocrine in nature., Aims: To study whether EGF and IL 1 beta affect pepsinogen secretion in vitro., Methods: Dispersed human peptic cells were prepared from endoscopically obtained biopsy specimens after collagenase digestion, mechanical disruption, and density gradient centrifugation., Results: EGF dose dependently increased basal pepsinogen secretion and mitogenic concentrations (0.1 nM) of EGF induced submaximal stimulation. Similar effects were observed with transforming growth factor alpha. EGF effects on pepsinogen secretion were in addition to that induced by CCK-OP and db-cAMP stimulated pepsinogen secretion. EGF stimulated pepsinogen secretion was completely inhibited by a human immunospecific EGF receptor antibody and reduced by both genistein and tyrphostin-25, two different tyrosine kinase inhibitors. IL 1 beta does not affect basal, CCK-OP or acetylcholine stimulated pepsinogen secretion. However, IL 1 beta dose dependently inhibited db-cAMP and histamine stimulated pepsinogen secretion., Conclusions: These results show that both EGF and IL 1 beta modulate human pepsinogen secretion in vitro and suggest that the paracrine effects of these cytokines on pepsinogen secretion might be involved in some pathological conditions of damage and inflammation of the gastric mucosa.

Background: Gastrointestinal bleeding is related to non-steroidal anti-inflammatory drug (NSAID) use, especially aspirin, but only a small subset of users bleed., Aim: To look for risk factors or mechanisms whereby aspirin may promote gastrointestinal bleeding., Patients: Sixty one patients with previous aspirin related upper gastrointestinal bleeding and 61 matched controls., Methods: Patients and controls were given 375 mg of aspirin and sequential skin bleeding time and blood aspirin levels were measured. Additional studies included platelet lumiaggregation, von Willebrand factor, Factor VIII, and coagulation studies., Results: Baseline skin bleeding time was similar in bleeders and controls, but bleeders had a more prolonged skin bleeding time after aspirin use. Hyper-response was more frequent in bleeders (30% v 9.3%; p < 0.01) and was associated with more than one previous separate bleeding event and a lower packed cell volume during the preceding bleeding episode. No differences were found in other factors studied. Logistic regression analysis identified prolonged skin bleeding time after aspirin use as an independent factor contributing to aspirin related gastrointestinal bleeding (RR = 5.4; 95% CI: 1.8 to 17.1)., Conclusions: 30% of patients with a history of aspirin related gastrointestinal bleeding have an exaggerated prolongation of skin bleeding time in response to aspirin, which may be a risk factor for bleeding. This intrinsic defect or to subclinical von Willebrand disease or different aspirin metabolism.

The effects of aspirin and ibuprofen on pepsinogen secretion were studied in isolated human peptic cells prepared from endoscopically obtained biopsy specimens after collagenase digestion, mechanical disruption, and percoll gradient centrifugation. Pharmacological concentrations of aspirin and ibuprofen (10(-8)-10(-4) M), potentiated histamine (10(-6)-10(-4)M) and forskolin (10(-5)M) stimulated pepsinogen secretion without affecting basal secretion, acetylcholine (10(-6)M) stimulated pepsinogen secretion or cell vitality. Augmentation of secretagogue stimulated pepsinogen secretion was dependent on extracellular calcium because potentiation was abolished by calcium depletion of the medium. Cimetidine inhibited the potentiation effect on histamine but not on forskolin stimulated pepsinogen secretion, thus suggesting that this augmentation was independent of histamine H2 receptors. Of interest, potentiation was also independent of endogenous prostaglandin inhibition because exogenous addition of prostaglandin E2 and D2 increased both basal and acetylcholine stimulated pepsinogen secretion in a dose dependent way, but they did not modify histamine or histamine plus aspirin or ibuprofen stimulated pepsinogen secretion. In conclusion, aspirin and ibuprofen potentiate secretagogue stimulated pepsinogen secretion by dispersed human peptic cells and this might be an additional mechanism of non-steroidal anti-inflammatory drug (NSAID) induced gastric injury. This potentiation effect is regulated by calcium, independent of endogenous prostaglandin inhibition and seems to act on pepsinogen secretion at a post-receptor site.