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Peptic Ulcer Disease: Absence of Antibodies Stimulating the Histamine Sensitive Adenylate Cyclase of Gastric Mucosal Cells

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Peptic Ulcer Disease: Absence of Antibodies Stimulating the Histamine Sensitive Adenylate Cyclase of Gastric Mucosal Cells 620 Gut, 1991,32,620-623 Peptic ulcer disease: absence ofantibodies stimulating the histamine sensitive adenylate cyclase Gut: first published as 10.1136/gut.32.6.620 on 1 June 1991. Downloaded from of gastric mucosal cells P Burman, S Mardh, L Loof, J Naesdal, F A Karlsson Abstract pylori and duodenal ulcer as well as gastritis has The possible presence of parietal cell been proposed." This issue is under current stimulating antibodies was examined in sera debate and awaits confirmation. from 57 patients with relapsing ulcer disease. It has been suggested that some forms of The sera were obtained at the time of sympto- duodenal ulcer may be of immunological matic relapse and all patients had ulcers origin.'2 Dobi and Lenkey'3 reported in 1982 confirmed by endoscopy. A sensitive assay that immunoglobulins prepared from sera of based on adenosine 3':5' cyclic monophos- patients with relapsing ulcers increased gastric phate (cAMP) production in isolated porcine acid secretion when injected into rats. Recently gastric mucosal cells was used as a measure. deLazarri etal claimed the existence ofhistamine cAMP production increased up to four hours receptor stimulating antibodies in 13 of 30 of incubation and was histamine responsive; duodenal ulcer patients.'4 In this study we an approximately 20-fold increase was found established a sensitive assay for detection of with histamine 104 moml. Sera from both parietal cell stimulation to explore this patients and healthy control subjects showed possibility. some inhibitory effect on basal cAMP production compared with incubation in medium only, whereas immunoglobulin Methods preparations had a weaker non-specific effect. No stimulation was found when the patients' PREPARATION OF PORCINE GASTRIC MUCOSAL AND http://gut.bmj.com/ sera and immunoglobulins (up to a concen- PARIETAL CELLS tration of 6 mglml) were examined. These Gastric mucosal cell preparations containing 15- results suggest that gastric acid hypersecretion 25% (mean 18%) parietal cells were obtained in duodenal ulcer disease is not an effect of from the corpus mucosa of porcine stomachs histamine receptor stimulating antibodies. after treatment with pronase and collagenase. The datathus argue against a recent hypothesis that severe chronic ulcer disease in some on September 28, 2021 by guest. Protected copyright. patients has an autoimmune origin. STIMULATION OF ADENOSINE 3' :5' CYCLIC MONOPHOSPHATE (cAMP) PRODUCTION OF GASTRIC MUCOSAL CELLS Peptic ulcer is a multifactorial disease that is not Porcine corpus mucosal cells were incubated at yet fully understood. Gastric acid is considered +37°C in Eagle's medium with 20 mmol/l Hepes to be a major aggressive factor and gastric acid pH 7-4 and 0.5 mmol/l isobutylmethylxanthine hypersection has been shown in patients with in an atmosphere of 95% 02/5% C02. In pre- duodenal ulcer disease.' A large parietal cell liminary experiments, cAMP was detectable in mass,2 enhanced sensitivity to pentagastrin,' and media, but not in cell lysates, after 30 minutes of increased gastrin secretion after meals have been incubation inthe presenceofaphosphodiesterase reported in subgroups of patients.4 Besides the inhibitor (0 5 mmol/l isobutylmethylxanthine). Departments of Internal presence of gastric acid, an impairment of We and others'6 have obtained analogous results Medicine and Medical mucosal defense mechanisms may be ofrelevance with respect to cAMPin experiments stimulating and Physiological in the development of ulcers. In several studies, the adenylate cyclase of thyroid cells in culture. Chemistry, Uppsala University, Uppsala, smoking has been associated with an increased Initially, concentrations of mucosal cells up to Sweden risk of relapse and slower ulcer healing rates.56 lOx 106/ml were used. A more appropriate P Burman Smoking reduces pancreatic bicarbonate output7 concentration was later found to be about S Mardh L Loof and thereby causes a decrease in duodenal pH. 2x 106/ml, and this concentration was used in F A Karlsson Furthermore, studies on intestinal mucosal experiments with patient immunoglobulins. blood flow in dogs have shown a negative effect After incubations with sera (20% v/v) or Department of Medicine, Bispebjerg Hospital, of nicotine.8 Impaired bicarbonate secretion immunoglobulin preparations (2-4 mg/ml or 6-0 University of from the proximal duodenal mucosa at rest and mg/ml) from patients and healthy subjects the Copenhagen, Denmark in response to luminal acidification has been mixtures were spun at 8000 g for 60 seconds. J Naesdal observed in patients with a history of duodenal The cell pellets were discarded and the amount Correspondence to: Dr P Burman, Department of ulcer disease.9 Chemical compounds such as of cAMP in the supernatants was assayed with a Internal Medicine, University aspirin and non-steroidal anti-inflammatory radioimmunoassay kit (Rianen cyclic AMP '251, Hospital, S-751 85 Uppsala, Sweden drugs have been associated with a high incidence Dupont). Submaximal and maximal stimulation Accepted for publication of gastric ulcers as well as ulcer bleeding.'` More with histamine (10-6 and 10 4M) were determined 20 August 1990 recently a causal relation between Helicobacter in each separate run. The interassay coefficient Peptic ulcerdisease: absence ofantibodies stimulating the histamine sensitive adenylate cyclase ofgastric mucosalcells 621 PATIENTS 100- Fifty seven patients (31 men and 26 women) aged A 20-78 years (mean 54 years) were included in the All but four had a of Gut: first published as 10.1136/gut.32.6.620 on 1 June 1991. Downloaded from o / * ~~~~~~Fetalcc alfserum study. patients history mean _t / 0 Mediurnalf serum relapsing ulcer disease for one to 30 years, A Fetal caalf serum, histamine 10-4mol/l 10.8 years. Two patients had earlier been treated o /A Mediu n, histamine 10-4mo1/l for Graves' disease, another two were having thyroxine substitution treatment because of E autoimmune thyroiditis, two had non-insulin dependent diabetes mellitus, two had hyper- tension, and two patients suffered from claudi- o catio intermittens. Thirty five of the patients were smokers, the majority of whom smoked 1 4 5 20 > 10 cigarettes per day. The patients were Time (hours) referred from general practitioners, ward units, Figure 1: Time dependent adenosijine 3':5' cyclic and outpatient clinics for endoscopy because of monophosphate(cAMP)productiu on in porcinegastric mucosal cells. Cells, S.8X 10/ml (20% parrietal cells) were incubated symptomatic ulcer relapse. Forty eight were at 370 in Eagle's medium containing05 mmol/l found to have duodenal ulcers while nine had isobutylmethylxanthine with 20% fetal calfsemum. prepyloric ulcerations. Treatment was begun Maximal cAMP production was eetstimated in the presence of with either H2 receptor antagonists, omeprazole, 10-4 moll histamine. Reactions were stopped by centrifugation, see methods sectioni. The results are expressed or rioprostil. With regard to the outcome of the as the mean ofduplicate incubations. ulcer medication, the patients could be separated into two groups. In 25 patients, including the four with a first attack ofulcer disease, the ulcers of variation, derived from,six duplicates of basal healed in less than two months on daily doses of ml either g cimetidine, 600 pg rioprostil, or 40 cAMP production with 1016 parietal cells per mg omeprazole.0-8 In the remaining 32 patients was 18%. there was a poor response to treatment. None of the ulcers healed after eight weeks on ranitidine IMMUNOGLOBULIN PREPARiATIONS 300 mg daily or cimetidine 0.8-1 g daily. In this Immunoglobulins were pirecipitated from sera group blood samples were taken within two with 1.6 mol/l ammoniuim sulphate, dialysed months ofan endoscopy showing an active ulcer. In the first group, in whom ulcers responded to against Eagle's medium plH 7.4 and studied at a http://gut.bmj.com/ serum were obtained at the concentration of 2.4 mgV/ml. In subsequent treatment, samples experiments with higher concentrations of time of the first endoscopy. Control sera were immunoglobulins, the precipitates were more drawn from 24 healthy blood donors (14 men, 10 extensively dialysed agailibtn L dg1C Z Atmli-.M women; 22 to 65 years of age, mean 41 years). with 20 mmol/l Hepes pEI 7.4 and 0.5 mmol/l isobutylmethylxanthine in order to min imse thle non-specific inhibition of parietal1 cAMP Results on September 28, 2021 by guest. Protected copyright. In the initial we searched for formation. Final protein concentratioins ranged experiments .8 mg/mle conditions that would optimise the assay. cAMP between 14X6 and 25.5 mg/L ml, mean 19 detection in the media increased as a function of the as assessed by the BioRad dye protein incubation time and reached a plateau at about kit. four hours (Fig 1). The cAMP production was stimulated by histamine. The response was nega- tively correlated to the cell concentration during the incubations, possibly by favouring anaerobic conditions or changes in pH. Thus, with -;; 250 Histamine 10-4m( histamine 10 mmol/l and 2 or lOx 106 cells/ml, -i 20 or sevenfold increases in cAMP were found, was a m respectively. The observation confirmed in 0 second set of experiments with various concen- trations ofcells (Fig 2). In further experiments, a E 150 four hour incubation period and cell concen- trations at about 2 x 106/ml were used routinely. U _~~~~ aa The effect ofhistamine was dose dependent (Fig ,o,0 0 3). The stimulatory effect of histamine was 05 reproducible and was confirmed with each cell 50 preparation. In six consecutive experiments the response to histamine 10`6mol/1 was 1-6-2*8-fold O (2-29 (0.21) mean (SEM)), while stimulation 0 2 6 8 10|0 121'2 with histamine 10` mol/l gave a 10 to 25-fold Gastric mucosal cells (106/ml) (18-5 (2.16)) increase, and 10-3 mol/l in two Figure 2: Effect ofcell concentration on adenosine 3':5' cyclic experiments gave >25-fold stimulation.
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