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Effect of Hydrochloric Acid and Prostaglandins on Pepsinogen Synthesis and Secretion in Canine Gastric Chief Cell Monolayer Cultures

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Effect of Hydrochloric Acid and Prostaglandins on Pepsinogen Synthesis and Secretion in Canine Gastric Chief Cell Monolayer Cultures Gut: first published as 10.1136/gut.30.6.774 on 1 June 1989. Downloaded from Gut, 1989, 30, 774-781 Effect of hydrochloric acid and prostaglandins on pepsinogen synthesis and secretion in canine gastric chief cell monolayer cultures J DEFIZE AND RICHARD H HUNT From the Intestinal Disease Research Unit, McMaster University, Hamilton, Ontario, Canada SUMMARY The actions ofhydrochloric acid, natural PGEI, PGE2 and a synthetic commercial PGE1 preparation, Enisoprost (Searle) on pepsinogen synthesis and secretion were studied in canine chief cell monolayer cultures. Hydrochloric acid, applied directly to the apical surface of chief cells using culture plate inserts (Millipore) had no effect on secretion, nor did it affect the action of any secretagogue in the basolateral medium. All prostaglandins tested showed significant stimulation of pepsinogen secretion. Basal secretion of pepsinogen after 90 min was 9.4 (1.3)% to total initial monolayer content. At 10`6 M, PGE1 stimulated secretion was 2641 (3.8)%; PGE2 27.9 (4)% and Enisoprost 28.8 (4.2)% of initial pepsinogen content. Stimulations by all tested prostaglandins were additive with carbachol (10-4 M) and CCK (10-9 M), but not with VIP (10-6 M), dbcAMP (10-3M) or forskolin (10` M) responses. All three prostaglandins stimulated pepsinogen synthesis as measured by 14C labelled amino acid incorporation into pepsinogen. Time course experiments were similar to those for forskolin and showed shorter time delays between stimulus and increased synthesis rate than carbachol but longer than dbcAMP. Stimulated pepsinogen secretion was inhibited by high in the medium. The inhibition abolished simultaneous pepsin concentrations (>800 Fg/ml) http://gut.bmj.com/ carbachol induced stimulation of synthesis but prostaglandin or forskolin stimulation only after two hours. Combined with the shorter response time, as compared with carbachol, these data support our previous findings that potent stimulators of cAMP production can stimulate pepsinogen synthesis directly by stimulation of mRNA synthesis, independently from an increased secretion. The additivity of effects with carbachol or CCK and similarity with forskolin stimulated synthesis supports the suggestion that the actions of prostaglandins are mediated by cAMP. on September 27, 2021 by guest. Protected copyright. We have previously studied modulation of cAMP cell content, are capable of a more direct pepsinogen synthesis as a response to increased stimulation of pepsinogen synthesis by activation of secretion in monolayer cultures of canine chief DNA transcription or cAMP dependent protein cells.' Our results showed that pepsinogen synthesis kinase, resulting in increased mRNA production. can be stimulated by an increased secretion but that Agents using cellular calcium as mediator seem to synthesis response is faster when secretion is stimulate synthesis indirectly through a feed back stimulated by potent stimulators of cAMP synthesis, mechanism triggered by an increased secretion. such as forskolin, than by secretagogues that Because this increase in cAMP is concomitant with act presumably through cellular calcium.' It was an increased secretion, however, it is difficult to hypothesized that these agents, through raising differentiate between the two processes. In this study we have therefore investigated the Address for correspondence: Dr J Defize, Intestinal Disease Research Unit, MeMaster University, HSc, Room 3N5, 12(X) Main Street West, Hamilton, possibility of uncoupling secretion and synthesis by Ontario L8N 3Z5, Canada. establishing a selective feed back inhibition on secre- Accepted for publication 8 November 1988. tion by high concentrations of pepsin in the culture 774 Gut: first published as 10.1136/gut.30.6.774 on 1 June 1989. Downloaded from Prostaglandins in chiefcell monolayers 775 medium. We have further investigated the effects of Methods hydrochloric acid and prostaglandins on pepsinogen synthesis and secretion. These studies necessitate ANIMALS separation of basolateral and luminal solutions of the Canine gastric chief cells were isolated as described chief cell cultures, and this was achieved by culture of earlier with minor modifications.3 14 Dogs were killed cells on culture plate inserts (Millipore). This under anaesthesia using sodium pentothal (100 mg/ enabled the assessment of the effect of acid and kg). Gastric glands were first isolated by a modifica- pepsin on the apical membranes of the chief cell tion of the technique by Berglindh et al."'6 Gastric directly. mucosa from the fundic part of the stomach was The so called cytoprotective property of prosta- digested by collagenase (Sigma type IA) and incu- glandins, produced by the gastric mucosa,' seems to bated in oxygenated incubation solution at 37°C for be partly caused by an inhibition of basal and 45 minutes. Free glands were collected by centrifuga- stimulated acid secretion. This inhibition has been tion at 50 g and further digested (15 min) into free observed in a number of in vivo78 and in vitro studies.9 cells by pronase (1 mg/ml) in calcium free medium to The prostaglandins seem to block the stimulatory which was added 2 mM EDTA. Parietal and chief action of histamine of cAMP synthesis, thereby cells were separated on Percoll gradient centrifuga- removing the major pathway for the excitation of tion.3 14'1' The top of the gradient, containing parietal parietal cells by histamine or other secretagogues cells was discarded, the pellet at the bottom, contain- such as gastrin.' The reduced acid secretion could ing the chief cells was taken out by syringe, washed supposedly influence pepsinogen secretion. In con- with Dulbeco's medium (3x), and finally resuspen- trast," prostaglandins have been found to stimulate ded in Dulbeco's medium, supplemented with 10% cAMP synthesis in a non-parietal cell population of fetal calf serum. Cells were cultured at 37°C and 5% the gastric mucosa. C02/95% 02-3 Cells (0.5 ml, containing approxi- In vivo studies concerning the effects of prosta- mately 106 cells) were cultured in 24 well plates glandins on pepsin secretion have reported a (Nunc) on Millipore HA culture plate inserts decrease in gastric secretion volume, usually with (Millicell HA; 12 mm). Monolayers were formed constant remaining pepsin concentration," 12 indicat- after approximately 48 hours. Peptic cells were ing a reduction in total pepsin output. Recently, identified by immunohistological staining, using anti- however, an in vitro study, using isolated gastric human pepsinogen antibodies.8 Viabilty of cells was http://gut.bmj.com/ glands from guinea pig stomach reported an increase tested by trypan blue exclusion. of pepsinogen secretion by prostaglandins.'3 More- over, this study indicated that the actions of the DE NOVO SYNTHESIS OF PEPSINOGEN prostaglandins were mediated by cAMP, as the Pepsinogen synthesis and secretion of this newly authors found potentiation of actions only between synthesised pepsinogen was studied by culturing prostaglandin and those secretagogues whose actions chief cell monolayers in 14C labelled amino acid are believed to be mediated by changes in cellular supplemented medium.3 16 Reagents were added to on September 27, 2021 by guest. Protected copyright. calcium. the serosal medium in the well and cells were cultured The results from our study indicate that prosta- for additional time intervals to a maximum of four glandin induced changes in acid output are not hours. At different time intervals, 100 [tl aliquots responsible for changes in pepsin output. were taken by pipette from the luminal medium in the inserts of duplicate wells to determine secreted labelled pepsinogen. The insert was taken out of the Apical medium medium, cells were detached from the insert mem- brane by trypsinisation for three minutes at 37°C (trypsin/EDTA no 670-5040, Gibco) and lysed by sonification in 0-5 ml 0-1 M phosphate buffer, pH 8. Pepsinogen was purified from cell lysates or medium by polyacrylamide gel electrophoresis (PAGE) of cell lysates and medium (50 Ill aliquots). Gels Basolateral medium were stained for proteolytic activity to identify the + / secretagogues pepsinogen bands in the gel or developed for fluoro- Fig. 1 Schematic representation ofthe Millicell culture graphic detection of 14C labelled proteins.3 1619 insert technique. The chiefcell monolayer isformed on the Quantitative determination of labelled pepsinogen insert membrane and separates apical and basolateral in cells and medium was done as previously des- solutions. Secretagogues are added to the basolateral cribed.3 "'1 4C incorporation specifically in pepsinogen medium. was determined by cutting the pepsinogen pattern Gut: first published as 10.1136/gut.30.6.774 on 1 June 1989. Downloaded from 776 Defize and Hunt for an additional 30-90 minutes. The insert medium was then assayed for peptic activity, using the human haemoglobin digestion method.2' Crystalline porcine pepsinogen (Sigma) was used as standard. Appropri- ate blanks were used in all assays. Stored pepsinogen secretion was expressed as percentage of initial pepsinogen content of the monolayer or as percent- m age of basal secretion. As for total protein content, 0 initial total pepsinogen content was determined in ° 20- four untreated monolayers from each cell prepara- 0- tion. 0 Carbachol, dbcAMP, TPA, forskolin, VIP, c CCK-8, PGEI, and PGE2 were obtained from cm SIGMA (St Louis, USA). Enisoprost was a gift from a)W Searle. c_ 10- C)d STATISTICAL ANALYSIS 0 1 Statistical significance of differences
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