Digestive Diseases and Sciences, Vol. 33, No. 10 (October 1988), pp~ 1338-1443

LETTERS TO THE EDITOR

SULFItYDRYLS AND GASTRIC MUCOSA

PROTECTION

To The Editor: It has been reported (I) that ethanol-induced

gastric lesions is associated with a rapid decrease in nonprotein sulfhydryl (SH) gastric pool and that synthetic sulfhydryls antagonize the formation of ethanol-induced gastric ulcers.

Since endogenous SH appears to play a role in aluminum hydroxide and mild irritants' antagonism toward ethanol-induced gastric lesions (2), it appeared worthwhile to determine whether the antiulcerogenic properties of bombesin, cholecystokinin-8 (CCK-8), sodium benzoate, and sulfasalazine (3-5) could be ascribed to a similar mechanism. Male albino rats (Sprague-Dawley Nossan strain, 180-200 g) were used. After a 24-hr fast, the rats received a subcuta- neous SH-blocking dose ofN-ethylmale imide (NEM,

�9 10 mg/kg) or vehicle. Bombesin (0.2 mg/kg subcuta- neous), cholecystokinin-8 (CCK-8, 0.1 mg/kg subcu- taneous), sodium benzoate (200 mg/kg per os), or sulfasalazine (50 mg/kg intraperitoneal) were adminis- tered after 30 rain. Ethanol (96% w/v) was given orally 30 min after the administration of the antiulcer agents. The animals were killed 1 hr after ethanol, and their stomachs were examined for the presence of ulcers whose degree was scored according to an arbitrary scale from 0 to 4 in relation to size, by an observer unaware of the treatment. All substances were admin- istered in a volume of 5 ml/kg. Incidence and degree

of ulcers were analyzed by means of chi-square test and Smirnov test for nonparametric data, respec- tively.

As shown in Table 1 bombesin reduced both incidence and degree, while CCK-8, sodium benzo- ate, and sulfasalazine reduced only the degree of gastric lesions. Pretreatment with NEM, in a dose which by itself did not affect the ulcerogenic prop- erties of ethanol, reversed the protective effects of all compounds under study.

These findings indicate that the antiulcer proper- ties of these compounds, reported to be dependent on (3, 4) or independent (5) of endogenous prosta- glandins, is mediated, at least in part, through a common mechanism involving endogenous SH.

S T E F A N O E V A N G E L I S T A

A L B E R T O M E L I

Pharmacology Department A. Menarini Pharmaceuticals

via Sette Santi 3 50131 Florence, Italy

REFERENCES

1. Szabo S, Trier JS, Frankel PW: Sulfhydryls compounds m ay mediate gastric cytoprotect ion. Science 214:200-202, 1981

2. Szelenyi I, Brune K: Possible role of sulfhydryls in mucosa l protect ion induced by a luminum hydroxide. Dig Dis Sci 31:1207-1210, 1986

3. Evangel is ta S, Meli A: Influence o f ant ioxidants and radical scavengers on e thanol- induced gastric ulcers in the rat. Gen Pharmacol 16:285-286, 1985

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TABLE 1. EFFECT OF N-ETHYLMALEIMIDE (NEM) ON BOMBESIN, CCK-8, NA BENZOATE, AND SULFASALAZINE PROTECTION AGAINST ETHANOL-INDUCED GASTRIC LESIONS

Gastric ulcers

Dose (mg/kg) and Incidence Degree Treatment route N (%) (mean score)

Vehicle + vehicle 13 100 2.69 N E M + vehicle 10 SC + - 9 100 3.33 Vehicle + bombes in - + 0.2 SC 8 50a* 0.88b* N E M + bombes in 10 SC + 0.2 SC 8 87.5 2.25d Vehicle + CCK-8 - + 0.1 SC 5 100 1.00b N E M + CCK-8 10 SC + 0.1 SC 5 100 2.00c Vehicle + Na benzoate - + 200 PO 5 60 0.30b N E M + Na benzoate 10 SC + 200 PO 5 100 2.00d Vehicle + sulfasalazine - + 50 IP 5 100 2.10a N E M + sulfasalazine 10 SC + 50 IP 5 100 3.10c

*a = P. < 0.05 and b = P < 0.01 as compared to vehicle + vehicle group; c = P < 0.05 and d = P < 0.01 as compared to respect ive vehicle groups.

Digestive Diseases and Sciences, Vol. 33, No. 10 (October 1988)

0163-2116/88/1000-1338506.00/0 �9 1988 Plenum Publishing Corporation

LETTERS TO THE EDITOR

4. Evangelista S, Maggi CA, Meli A: Influence of peripherally administered peptides on ethanol-induced gastric ulcers in the rat. Gen Pharmacol 18:647--649, 1987

5. Berry CN, Lloyd KG: Effects of sulfasalazine and PHCL 28A on gastric ulcer formation and prostaglandin metabolism in the rat. Br J Pharmacol 90:54P, 1987

CYTOPROTECTION--ONCE MORE

To The Editor: In a recent correspondence, Dr. J. C. Meeroff

(from the United States) (1) and Dr. J. L. Wallace (from the United Kingdom) (2) discussed the suit- ability, or rather the lack of suitability, of the expression cytoprotection. The discussion seems strangely scholastic. Instead of investigating and clearly defining a powerful biologic phenomenon, some gastroenterologists seem to disregard the con- cept for terminological reasons and to ignore its impact in gastrointestinal pathophysiology.

Drs. A. Robert and E. Jacobsen were the first to use the term cytoprotection for the protective effect of E2 prostaglandins in the gastric mucosa (3). In this study Robert et al had to introduce new dam- aging agents in order to safely separate the effect from the already described protective action of acid-reducing drugs. As pointed out by Robert, damaging agents such as absolute ethanol or hyper- tonic hydrochloric acid were indeed drastic. Nev- ertheless, he was able to demonstrate that prosta- glandins, particularly of the E series and when given orally, protected the gastric mucosa against such damage. It was later found that prostaglandins share this ability with other agents, such as sulfhy- dryl compounds (4), carbenoxolone (5), and sucralf- ate (6), some of which may act by increasing local prostaglandin concentrations.

It is easy to say in retrospect that the concept should have been better protected and to regret that cytoprotection was not properly demonstrated in an acid-insensitive lesion model in man. It is entirely correct that the concept was eventually redefined and misused, particularly by pharmaceutical com- panies. It is also correct that prostaglandins and other compounds did not protect every single gas- tric cell against the damaging action of absolute ethanol (7). It is more difficult to understand how this failure allowed gastric cytoprotection to be ridiculed. It seems so reasonable to attribute the failure to protect all surface cells to the potency of

the damaging agent rather than to absence of a biologic action, the more so when it became appar- ent that prostaglandins protected against damage to other parts of the gastrointestinal tract (8), other organs (9), and in vitro (10).

When cellular immunology was young, it was rec- ognized that certain cells had cytotoxic properties, i.e., could cause lysis of target cells. Cytotoxicity and its prevention by other cells, cellular components, or pharmaceutical agents was not very well defined when introduced but was readily accepted as a useful tool for a closer understanding of biology. As a consequence, the concept of cytotoxicity had an enormous impact for the rapid development of clinical immunology, particularly tumor immunology and autoimmune disease. Against this perspective, gastro- enterologists may seem shortsighted.

Why not use an important observation and disci- pline ourselves to investigate what cytoprotection is about, instead of discussing who is and who is not using the proper term at the proper occasion?

CATJA JOHANSSON, MD Division of Gastroenterology

Department of Medicine CARLOS RUBIO, MD

Department of Pathology Karolinska Hospital

S-104 O1 Stockholm, Sweden

REFERENCES

1. Meeroff JC: Mechanism of cytoprotection. Dig Dis Sci 30:697--698, 1985

2. Wallace JL: "Cytoprotection"---define it or dispose of it. Dig Dis Sci 31:667-668, 1986

3. Robert A, Nezamis JE, Lancaster C, Hanchar AJ: Cytopro- tection by prostaglandins in rat. Gastroenterology 77:433- 443, 1979

4. Szabo S, Trier JS, Frankel PW: Sulfhydryl compounds may mediate gastric cytoprotection. Science 214:200-202, 1981

5. Derelanko M J, Long JF: Carbenoxolone sodium protects rat gastric mucosa against ethanol-induced necrosis. Proc Exp Biol and Med 166:394-397, 1981

6. Hollander D, Tarnawski A, Gergely H, Zipser RD" Sucralf- ate protection of the gastric mucosa against ethanol induced injury: A prostaglandin mediated process? Scand J Gastro- enterol 19:97-102, 1984

7. Lacy ER, Ito S: Microscopic analysis of ethanol damage to rat gastric mucosa after treatment with a prostaglandin. Gastroenterology 83:619--625, 1982

8. Lancaster C, Robert A: Intestinal lesions produced by prednisolone; prevention by 16,16-dimethyl prostaglandin E2. Am J Physiol 235:E703-E708, 1978

9. Kelley VE, Winkelstein A: Effect of prostaglandin El treat- ment on murine acute immune complex glomerulonephritis. Clin Immunol 16:326--323, 1980

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