Gut 1996; 39: 348-52

PAPERS

Prostaglandin E2 and prostaglandin F2,biosynthesis in human gastric mucosa: effect ofchronic alcohol misuse

C Bode, G Maute, J C Bode

HohenheimUniversity, Institute140, Department ofPhysiology ofNutritionStuttgart, GermanyC Bode

Department ofMedicine,Robert-Bosch-Hospital, Stutgart,GermanyC MauteJ C BodeCorrespondence to:Professor J C Bode,Department ofMedicine,Robert-Bosch-Hospital,Auerbachstralle 1 10, D -

70376 Stuttgart, Germany.Accepted for publication4 April 1996

Dedicated to ProfessorWolfgang Gerok, DirectorEmeritus, Department ofMedicine, University ofFreiburg on the occasion ofhis 70th birthday.

AbstractBackground and Aims-The results ofexperimental studies support the hypoth-esis that decreased prostaglandin pro-duction might play a part in the gastricmucosal injury induced by alcohol. In thisstudy, it was investigated whether alcoholmisuse impairs the synthesis of prosta-glandin E2 (PGE2) and prostaglandin F2c(PGF2a) in gastric mucosa.Patients-Fifty six alcoholic patients and66 subjects without alcohol misuse wereincluded in the study.Methods-Mucosal biopsy specimenswere obtained from the antrum and bodyof the stomach. Maximal synthesis ratesof PGE2 and PGF2a were determined inthe microsomal fraction of the biopsyspecimens.Results-The rates of synthesis of bothprostaglandins in biopsy specimens fromthe antrum were not significantly differentfrom those obtained in the body. Synthesisof both prostaglandins was significantlyreduced in alcoholic patients whoabstained less than five days comparedwith the non-alcoholic group with normalmucosa (PGE2-40%, PGF2a-42% respect-ively). In non-alcoholic patients withsevere gastritis PGE2 synthesis wasincreased (+30%, p<005) and PGF2.synthesis was decreased (-42.5%, p<0025).In alcoholic patients with severe gastritisPGE2 synthesis was depressed by almost60% (p<0.001) compared with the non-alcoholic group with severe gastritis.Neither colonisation of Helicobacter pylorinor smoking had a significant influence onthe prostaglandin synthesis.Conclusions-Chronic alcohol misuse isassociated with significantly reduced ca-pacity for prostaglandin synthesis ingastric mucosa and this alcohol induceddecrease in prostaglandin synthesis ismodulated by the presence and degree ofgastritis.(Gut 1996; 39: 348-352)

Keywords: alcohol misuse, gastric mucosa, gastritis,Helicobacterpylori, prostaglandins E2 and F2,a, stomach.

Alcohol is the most widely used and misuseddrug, the acute and chronic ingestion of which

was shown to lead to distinct functional dis-turbances and mucosal injury in the stomachof both animals and humans.' 2 Ethanol atconcentrations of 5°/o10% and more, disruptsthe mucosal barrier' 3 and causes focal areas ofpronounced mucosal hyperaemia, oedema,epithelial necrosis, and mucosal haemor-rhage.' 4 5 The mechanism by which alcoholleads to gastric mucosal injury has not yet beenclarified.Endogenous prostaglandins, especially

PGE2 and PGI2, are assumed to be ofimportance in maintaning the normal functionand structure of the gastric mucosa.6 7 Exo-genous PGE2 and its derivatives have beenshown to protect the gastric mucosa againstvarious noxious agents.68 The results ofexperimental studies support the hypothesisthat decreased prostaglandin production mightplay a part in the mucosal injury induced byalcohol.9 10 It has recently been reported thatthe acute ingestion of alcohol, at a concen-tration comparable to that ofwine, significantlyreduces the PGE2 output in gastric juice inhealthy subjects."

This study was performed to clarify thequestion whether or not prostaglandin synthesisis impaired in gastric mucosa of patients withchronic alcohol misuse. Because gastritis mightinfluence prostaglandin synthesis, the synthesisof PGE2 and PGFW2, was studied in gastricbiopsy specimens of alcoholic patients and innon-alcoholic controls with normal gastricmucosa and mild or severe gastritis.Smoking has been shown to influence

prostaglandin metabolism in the mucosa of thestomach.'2 13 Because smoking is often asso-ciated with alcohol misuse, the effect ofsmoking on prostaglandin synthesis wasevaluated separately.

Methods

PATIENTSOne hundred and twenty two patients in whoman upper gastrointestinal diagnostic endoscopywas performed were included in the study. Inall cases, the examination was carried out toinvestigate upper abdominal complaints, suchas bloating, or pain, or heartburn. Fifty sixwere alcohol misusers and had been con-suming an average daily amount of alcohol in

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excess of 60 g for more than two years. In 46of these patients the period of abstinencebefore the endoscopy was less than one week.On histological examination 17 had normalgastric mucosa, 19 had mild gastritis, and 10had severe gastritis in accordance with theclassification proposed by Wyatt and Dixon.'4In these patients the gastroscopy was per-formed within five days after the last alcoholintake. In addition, another group of 10 alco-holic patients who had been abstinent for atleast 12 days before endoscopy were studied(six patients with normal mucosa and fourpatients with mild gastritis on histology). Sixtysix patients with no history of alcohol misuse(mean alcohol consumption <20 g/day) servedas controls (non-alcoholic group). Eleven ofthese had a normal gastric mucosa, 38 hadmild gastritis, and 17 had severe gastritis onhistology. Criteria for exclusion from the studywere: use of non-steroidal anti-inflammatorydrugs, glucocorticoids, antacids or carbo-anhydrase blockers within the last two weeks.Patients with cirrhosis or gastric or duodenalulcer were also excluded from the study.Table I summarises the data on the distributionof age, sex, smoking, and the presence ofHelicobacter pylori.The study was approved by the ethics

committee of the Robert-Bosch-Hospital, andall the patients gave their informed consent.

BIOPSY SPECIMENSThe endoscopy was performed by twoexperienced gastroenterologists who togetherdecided where in the stomach the biopsyspecimens should be obtained from. Inaddition to tissue from the antrum, corpus, andfundus taken for routine histology and a rapidurease test, three specimens were obtainedfrom the antrum 3-4 cm from the pyloric ring(mean (SD)) fresh weight 14.6 (6.3) mg formeasurement of prostaglandin formation. Tobe able to compare prostaglandin synthesis indifferent parts of the stomach, additionalbiopsy specimens were taken from the upperpart of the body of the stomach in 10 non-alcoholic patients (seven with normal gastricmucosa, three with mild gastritis).

STUDY DESIGN

Specimens for histology were fixed in formalinbuffered saline and embedded in paraffin wax,

TABLE I Patient characteristics andH pylon colonisationofalcohol misusers and controls without alcohol misuse

Non- Alcohol misusersalcoholic Duration ofabstinencegroup <5 days >12 days

Patients (n) 66 46 10Male:female 36:30 20:16 8:2Meanage(y) 55(15)* 52(13)* 48(6)*Smokers (%) 18-2 50 70Hpylori colonisation (%) 56 52-2 40Histology: normal mucosa (n)* 11 (4) 17 (4) 6 (2)Mild gastritis (n)* 38 (18) 19 (13) 4 (2)Severe gastnitis (n)* 17 (15) 10 (7)

*Number of patients Hpytori positive are given in parentheses.

and 5 mm sections were prepared for lightmicroscopy in the standard manner. Sectionswere stained for H pylori with haematoxylinand eosin or cresyl violet.'5 In addition, Hpyloricolonisation was determined by a gel basedrapid urease test (CLO-test, ASTRA Chemi-cals GmbH, Wedel). A positive result wasindicated by a colour change at four hours.

Biopsy specimens taken for measurement ofprostaglandin synthesis were immediatelytransferred to an ice cold 1P15% solution ofKCI. Microsomes were prepared within 90minutes, and than suspended in 200 ml Krebs-Ringer-HEPES buffer, pH 7-4 (100 mM NaCl,4.78 mM KC1, 1P15 mM K2HPO4, 8.8 mMHEPES).`0 Incubation, prostaglandin extrac-tion and estimation of PGE2 and PGFW2 wereperformed as described earlier.'0 Briefly, toachieve optimal synthesis of prostaglandins,glutathione (5 mM), haemin (1 mM), MgSO4(3 mM) and CaCl2 (5 mM) were added to theincubation medium.

After preincubation at 37°C for threeminutes, the reaction was started by the addi-tion of 50 ml arachidonic acid (100 mg/ml) andstopped after 0 (blank value), 2.5, or fiveminutes by adding 50 ml acetylsalicylic acid(10 mM) and immediately heating in a boilingwater bath for five minutes. The assay ofprostaglandin synthesis was linear between 0and five minutes. All tests were done in dupli-cate. The PGE2 and PGF2a contents of thesamples were determined by radioimmunoassayas described recently." The recovery rate ofPGE2 was 85%/95% and that of PGF2a was95%/--100%; the intra-assay variations were3.5% and 5.4% respectively." The DNA con-tent of samples of the homogenates was deter-mined by the method of Fiszer-Szafarz et al.'6Determination ofDNA was chosen as the refer-ence variable so as to avoid such confoundingfactors as variations in the amounts of mucusand fluid adhering to the biopsy specimens.

STATISTICS

Group results are expressed as means (SEM).For between group comparisons the unpairedt test or its non-parametric analogue, theWilcoxon two sample test, were used.

Results

PROSTAGLANDIN SYNTHESIS

Antrum versus bodyComparison of the rates of prostaglandin syn-thesis between biopsy specimens from theantrum and those from the corpus in 10patients disclosed no significant differences:PGE2 97 (14) v 101 (17) and PGF2a 42.1 (16)v 39 (14) pg/mg DNAXmin respectively.

Non-alcoholic patients with and without gastritisIn patients with mild gastritis the PGE2 syn-thesis did not differ significantly from that innon-alcoholic group with normal gastricmucosa (92 (13) and 105-5 (17) pg/mg

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50 r

T T40 1-

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iL L

Alcohol No Alcoholl alcohol

E

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Normal Mild Severegastritis gastritis

Figure 1: Influence ofchronic alcohol misuse (alcohol) ongastric mucosal PGE2 synthesis in patients with normalmucosa (normal), mild gastritis, and severe gastritis.Values are means (SEM). No alcohol=patients notmisusing alcohol.

DNAXmin respectively), whereas in non-

alcoholic group with severe gastritis, PGE2synthesis was greatly increased (137 (24),pg/mg DNAXmin, p<005; Fig 1). Synthe-sis of PGF2a, in non-alcoholic patients withmild gastritis was decreased by 23% com-

pared with non-alcoholic patients with normalmucosa (33 (4.0) and 43.5 (6.5) pg/mgDNAXmin respectively, p<005). The reduc-tion of PGF2n synthesis was more pro-nounced in non-alcoholic patients with severe

gastritis (25 (5) pg/mg DNAXmin, p<0O025;Fig 2).

Alcoholic patients with and without gastritisThe synthesis of PGE2 was clearly reduced(-40%) in the alcoholic patients with normalmucosa who continued to drink within five daysof their endoscopy compared with the non-

alcoholic group with normal mucosa (Fig 1,

p<0O05). In alcoholic patients with mild gas-tritis, PGE2 synthesis was not significantlydecreased compared with the correspondingnon-alcoholic group (Fig 1, p>0 05). How-ever, in alcoholic patients with severe gas-

tritis, PGE2 synthesis was depressed byalmost 60% (49 (22) pg/mg DNAXmin) com-

pared with the non-alcoholic patients withsevere gastritis (137 (24) pg/mg DNAXmin;p<oool).

In the subgroups with normal mucosa, syn-thesis of PGF2I was significantly reduced inthe alcoholic patients who continued to drinkto within five days of their endoscopycompared with the non-alcoholic patients(Fig 2, p<0 025). Although PGF2. synthesiswas not influenced by the degree of mucosalinflammation in the alcoholic patients (Fig 2),in the group of alcoholic patients with mildgastritis PGF2a synthesis was still significantlylower than in the corresponding control group(p<0O025).

T30 H

I20 H

10 H

TL

No Alcohol No Alcohol No Alcoholaicohol alcohol alcohol

Normal Mild Severegastritis gastritis

Figure 2: Influence ofchronic alcohol misuse (alcohol) ongastric mocosal PGF2 synthesis in patients with normalmucosa (normal), mild gastritis, and severe gastritis.Values are means (SEM). No alcohol=patients notmisusing alcohol.

Effect of alcohol abstinenceIn the group of alcoholic patients who abstainedfrom alcohol for more than 12 days, PGE2synthesis exhibited almost normal values (93.5(27) pg/mg DNAXmin) whereas PGF2,, syn-thesis was still diminished (28.5 (19; p<005).

Effect ofH pylori colonisationA comparison of the non-alcoholic groupnegative for H pylori with those colonised withthe organism disclosed that the rates of syn-thesis of PGE2 and PGF2U were not different(Table II). In the H pylon positive group ofalcoholic patients PGE2 synthesis was slightlyreduced compared with the H pylori negativegroup (p>0 05), whereas PGF2c. values did notdiffer (Table II). Colonisation ofH pylon hadno significant influence on the prostaglandinsynthesis in either subgroup of patients withnormal mucosa or mild gastritis (data notshown).

Effects ofsmokingThe mean values of PGE2 synthesis wereslightly lower in smokers, both in the non-alcoholic group and the group of alcoholicpatients, but the differences were not significant(p>0.05; Table III). An investigation of the

TABLE II Effect ofH pylori colonisation on prostaglandinsynthesis in antral mucosa

H pylori n PGE2 PGF2aNon-alcoholic group Negative 29 98-4 (14-4) 39.7 (8.3)

Positive 37 103-7(18-1) 31-6(65)Alcohol misusers Negative 22 71-8 (21) 24-2 (7.4)

Positive 24 55-6 (24) 22-4 (5.3)

Values for PGE2 and PGF2. are pg/,ug DNAXmin (mean(SEM)).

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TABLE iII Effect ofsmoking on prostaglandin synthesis inantral mucosa

Patients Smoking n PGE2 PGF2.Non-alcoholic patients no 54 108-1 (21)* 33-2 (7.2)

yes 12 95-2 (19-2) 29-1 (6.7)Alcoholic patients no 23 67-6 (22-3) 22-6 (5-9)

yes 23 59-6 (24) 24-3 (7-1)

Values for PGE2 and PGF2. are pg prostaglandin/,ugDNAXmin (mean (SEM)).

influence of smoking on PGE2 synthesis in thesubgroups with and without gastritis also failedto disclose any significant differences. Thisapplied in particular to the subgroups withsevere gastritis (Fig 1), although the number ofcases were few (smokers in the non-alcoholicgroup three of 17, in the alcoholic patients fourof 10). The synthesis of PGF2o, was notinfluenced by smoking (Table III).

DiscussionFor the purpose of studying factors that mightaffect prostaglandin metabolism in the humanstomach, different approaches have been used.Determination of prostaglandin content inmucosal biopsy specimens,6 and the measure-ment of the production of prostaglandins fromendogenous or exogenous prostaglandin pre-cursors (in particular arachidonic acid) in muco-sal biopsy specimens'7 18 have both been applied.Each of these methods has its own particularproblems with respect to the interpretation ofthe data obtained. A major disadvantage ofusingwhole mucosal biopsy specimens or homo-genates of mucosal biopsy specimens is thepronounced influence of sample removal andhomogenisation on the results.6 7 The measure-

ment of prostaglandin formation from the endo-genous substrate or from added exogenousarachidonic acid in mucosal biopsy specimens isadditionally influenced by the conditions ofincubation and the concentration of the sub-strate.'7-'9 Also, gastric mucosa has a high cata-bolic capacity for prostaglandins,17 20 makinginterpretation of the results obtained in wholetissue difficult. To overcome these problems,prostaglandin synthesis was assessed in themicrosomal fraction, in which the enzymes ofprostaglandin formation are localised, but whereprostaglandin degradation does not occur.2'

In earlier investigations into the effect ofalcohol on prostaglandin production in gastricmucosa, the main line of approach has been tostudy the action of acute alcohol admin-istration. 6-8 22 Depending on the concentrationof the alcohol administered, results havediffered. Numerous studies have reported aninhibition of prostaglandin production ingastric mucosa of laboratory animals after theacute administration of concentrated alcohol(50/%-100%) as used to produce mucosalnecrosis in the stomach.68 22 On the otherhand, experiments on rats to investigate theeffect ofthe moderate concentrations of alcoholcommonly found in alcoholic beveragesshowed an increase in PGF1 formation23 and inPGE2 and PGF2,-like material24 has beenreported. In humans, acute ingestion of 12.5%

alcohol reduced the output of prostaglandin E2in gastric juice, whereas the output of PGF2Iand 6-keto PGF2, remained unchanged."The effect of chronic administration of

moderate concentrations of alcohol has, todate, been investigated only in animals.Feeding rats a liquid diet containing ethanolfor one to three months reduced the capacityof gastric mucosa to synthesise PGE2 by40%-/o60%. The findings of this study - namelythat chronic alcohol misuse was associatedwith reduced mucosal acitivity in terms ofPGE2 and PGF2a synthesis - accords with theresults obtained in these animal experiments.The relevance of alcohol misuse as a cause

of gastric mucosal injury including haemorr-hagic erosive gastritis in humans has becomeapparent from several endoscopy studies.' 25However, the pathomechanism of alcohol-induced mucosal damage has not been clarified.Suspected factors are disturbances in thepermeability of the mucosa21 26 and in the micro-circulation.' 25 27 Moreover, inhibition of protec-tive mechanisms of the gastric mucosa - forexample, the breakdown of the mucosal 'bicar-bonate barrier'25 28 - brought about by the acuteaction of alcohol, might contribute to mucosaldamage. The reduction in the ability to syn-thesise PGE2 and PGF2a shown in this studymight have an influence on several of the factorsconsidered to be of relevance for the patho-genesis of the alcohol induced mucosal injury inthe stomach. PGE2 stimulates gastric mucosalblood flow29 and bicarbonate output,30 as well asthe production of mucus.3' Also PGE2 inhibitsthe release of inflammatory mediators fromintestinal mucosal mast cells such as plateletactivating factor and tumour necrosis factor at.32Moreover, a trophic effect of PGE2 on mucosalepithelium has also been reported.33

In the control group PGE2 synthesisremained unchanged in patients with mildgastritis, where there was a significant increasein the patients with severe gastritis. On theother hand, gastritis was associated with adecrease in the ability to synthesise PGF2a.Other studies on the effect of mucosal inflam-mation on the prostaglandin synthesis haveproduced varying results. When the activity ofprostaglandin synthesis was measured afterincubation of homogenates of gastric biopsyspecimens with 14C-labelled arachidonic acid,no significant differences were seen in the sumof cyclooxygenase products (prostaglandinsA2+B2, D2, E2 and F2) in the mucosa ofpatients with erosive or non-erosive type Bgastritis and controls with normal mucosa.34Similarly, no difference was found for thecombined PGE2 and PGF2a content of biopsyspecimens from the antrum in patients withand without mucosal inflammation.'2Smoking has been shown to influence

prostaglandin metabolism in the mucosa of thestomach. 12-3'5 Active smoking reduces PGE2concentration in gastric juice,33 and decreasesmucosal 6-keto-PGF, synthesis.35 In anotherstudy significant decreases in mucosal prostag-landin content were found in biopsy specimensfrom the body and antrum of patients who hadsmoked within the two days immediately

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352 Bode, Maute, Bode

preceding endoscopy.`2 Because in the presentstudy the percentage of smokers was higheramong alcoholic patients, smoking mightcontribute to the lower rate of PGE2production in these patients. However, activesmoking did not significantly influence theresults in terms of prostaglandin synthesis inthe group of alcoholic patients.The presence of H pylori in the biopsy

specimens had no influence on prostaglandinsynthesis. This accords with the results of otherstudies on prostaglandin synthesis in homo-genates of antrum specimens of patients withand without H pylon.34 36 Moreover, thepresence of H pylon did not influence thecontent of PGE2 in the antrum and body ofthe stomach.`2 Reduced PGE2 synthesis in themucosa of the antrum and corpus in H pylonpositive patients reported by others37 might beexplained by the type of measurement used,and also by the fact that values were expressedin terms ofwet weight.

In patients with alcoholic cirrhosis andportal hypertension the PGE2 content in biopsyspecimens from the gastric antral mucosa wasshown to be significantly lower than in controlswithout liver disease.38 39 In these studies thepatients abstained from alcohol for more thantwo weeks38 or eight days39 respectively. Inaddition, PGE2 content in cirrhotic patientswithout portal hypertension were not signifi-cantly different from the controls without liverdisease.38 Therefore, it was concluded that thedecrease in PGE2 tissue concentrations isrelated to the presence of portal hyper-tension.39 In this study alcoholic patients withcirrhosis were excluded to avoid a potentialoverlap of the effect of portal hypertension withthe effect of chronic alcohol misuse.

In conclusion, chronic alcohol misusereduces the rate of synthesis of PGE2 andPGF2. in the gastric mucosa in humans. Thedecreased capacity for prostaglandin pro-duction might be a factor in the increasedvulnerability of mucosa in alcoholic patients.The reasons for the reduced capacity forprostaglandin synthesis in gastric mucosa inalcoholic patients remain to be clarified.This study was supported by the Robert-Bosch-Stiftung (grantF2). We thank Dr P Fritz and Dr V Voudouri for performingand evaluating the histological studies.

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