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Gastric defense mechanisms
Gastric Defense Mechanisms LESLIE WISE, FRCS, St Louis, Missouri WALTER F BALLINGER, II, MD, St Louis, Missouri
Much of the surgical literature of gastroduodenal ulceration has been devoted to the aggressive mechanisms which stimulate acid and pepsin production, Relatively little has been written about the various defensive mechanisms. Just as increased stimulation for the production of acid and pepsin may cause peptic ulceration, an aberration in the various defense mechanisms may also be the cause of some cases of ulceration. These defensive mechanisms will be discussed under the following headings: (1) inhibition of gastric acid secretion; (2) gastric mucus; and (3) integrity of gastric epithelium. Inhibition
of Gastric Acid Secretion
One reason why we know less about the inhibitory mechanisms than the stimulatory mechanisms is that, although it is simple to devise experiments which test the effect of stimulation on the basal state, inhibition can often, only be studied as a decrease in an already existent response evoked by some form of stimulation, and it is clear that the effect may be influenced by the nature of the stimulus. In fact, the study of a potential inhibitory mechanism is incomplete until it has been tested against the widest possible range of stimuli. Furthermore, the intensity of the “background” stimulus is important; for example, Code and Watkinson [I] have shown that the weaker the histamine background stimulus, the more effectively duodenal acidification inhibits gastric secretion in Pavlov pouches. The mechanism of inhibition may be “direct” or “indirect;” for example, the inhibitory effects of adrenaline and noradrenaline [2] or pituitrin [3] on gastric secretion are at least partly due to their vasoconstrictor effects, thereby depriving the gastric glands of the blood supply required for their response to the stimulus. Another form of indirect inhibition is that of interference with the operation of a stimulus. For descriptive purposes there are three phases of gastric stimulation: cephalic, gastric, and intestinal. Physiologic inhibition can similarly be described in three phases. The cephalic phme of stimulation depends on excitation of the central vagal nuclei by sight, smell, taste, swallowing, and psychic factors. Unattractive presentation of a meal, bad taste, or emotional From the Department of Surgery, Washington University School of Medicine. St Louis, Missouri 63110. This work was supported in part by US Public Health Service Grant Number AM 12333.
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disturbances can depress the cephalic phase of stimulation. The inhibition of the gmtric phase has been studied by Woodward et al [4], who have shown that at a pH of 1.5 or less, previously adequate mechanical or chemical stimuli of the antrum evoked almost no acid response in Heidenhain pouches. It has also been shown that acidification abolishes the vagal release of gastrin [5]. Since after the ingestion of food the intact stomach of both human subjects and dogs normally reaches a pH of this range, this seems to be a homeostatic mechanism terminating gastrin release by the meal. The process by which acidification of the antrum prevents gastrin production or release is not known. An alternative explanation is that acid in the antrum releases an inhibitory hormone [6] which has been named “antral chalone.” The work of Harrison, Lakey, and Hyde [7] suggests the possibility that acidification of the antrum causes the release of an inhibitory hormone. They first transplanted the distal half of the antrum into the colon, which induced the release of gastrin, with an increase in the acid output from Heidenhain pouches. The acid output was further increased when the remaining proximal half of the antrum, which was exposed to the increased acid secretion, was excised, suggesting the removal of an inhibitory hormone. Jordan and Sand [8] gave further support for a hormonal inhibitory mechanism. They prepared dogs with a Heidenhain pouch and two antral pouches. One antral pouch was irrigated with alcohol, which stimulated acid secretion from the Heidenhain pouch. Simultaneous irrigation of the other antral pouch with acid caused inhibition after one to three hours, The reason for the long latent period is obscure. Longhi et al [9], however, in a similar experiment did not observe any inhibition. An important piece of evidence against an antral inhibitory hormone came from Gillespie and Grossman [Zo], who showed that acidification of the antral muscosa had no inhibitory effect on the response of fundic pouch to exogenous gastrin. Gastrone is the gastric secretion-inhibitory factor found in gastric juice, and was discovered in 1939 by Brunschwig et al [II]. When human gastric juice or its alcoholic precipitate was injected into dogs with Heidenhain pouches which were secreting acid in response to feeding, a depression of gastric acid secretion ensued. This was more marked after the injection of
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anacid gastric juice, and was still greater with the gastric juice of patients with pernicious anemia or gastric carcinoma. Gastrone has been partially purified by Fiasse, Code, and Glass [12]. It is present in greater quantities in the antrum than in the body, and in greater amount in innervated than in denervated pouches. However, its physiologic or pathologic significance is still not known and its possible relationship to antral chalone is also still undefined. A gastric secretory inhibitor has also been demonstrated in the saliva of humans and dogs. It was originally discovered by Code et al [13] and recently purified by Baume, Baxter, and Nicholls [14]. Rudick and co-workers [15] reported that thoracic duct lymph contained an inhibitory material to gastric secretion in rats. Again the relationship of this substance to gastrone is not known. A gastric inhibitory factor has also been found in extracts of urine from normal human subjects [Z6] and also from patients with peptic ulcer [17]. Evidence for a possible vagal afferent mechanism in the antral inhibition of gastric acid secretion was reported by Iggo [18] and Hat et al [29]. Iggo [Z8] demonstrated changes in the electrical activity of vagal afferents after the application of acid solutions to the gastric mucosa. The threshold of the acid receptors was pH 3 or lower. These mucosal receptors were not excited by moderate gastric distention, nor by hypertonic or hypotonic solutions. Hat et al [19] prepared dogs with Heidenhain pouches and they also denervated the body and fundus of the main stomachs, leaving the vagal fibers to the antrum intact. Chronic electrodes were placed on the antral nerves. Stimulation of these nerves significantly reduced the secretory response to feeding from the Heidenhain pouches. From this observation they suggested that gastrin release may be controlled by an inhibitory vagovagal reflex mechanism. The intestinal phase of gastric inhibition may be considered in two parts: duodenal and jejunal. 1. Duodenal inhibitory mechanisms: That acid in the duodenum causes gastric inhibition is shown by various methods. If gastric acid is prevented from reaching the duodenal mucosa either by occluding the pylorus surgically [20] or by draining the gastric juice to the exterior by a gastric fistula [21], the gastric acid output of fundic pouches is increased. Conversely, acidification of the duodenum inhibits gastric secretion. Pincus et al [22] studied the effect of duodenal ‘acidification and observed a 50 per cent inhibition both with Pavlov and Heidenhain pouches at a duodenal pH of 2.5. When the pH fell to 2.0 or lower, inhibition was almost complete. The introduction into the duodenum of fat or its digestive products will also inhibit gastric secretion [23]. Since inhibition by fat could be demonstrated in transplanted gastric pouches, a hormonal mechanism has been postulated [24]. The fat, however, must be in an
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absorbable form; thus, procedures which interfere with fat absorption, especially exclusion of bile and pancreatic juice, result in a lesser degree of inhibition [25]. Sircus [26] has shown that instillation of hypertonic saline, glucose, fructose, polysaccharide complexes, and peptone into the duodenum can all inhibit gastric secretion. Recognizable inhibition was obtained when a level of 275 mOsm was reached, and inhibition was marked when it rose above 425 mOsm. A less marked but still recognizable inhibition was obtained on the instillation of hypotonic (below 50 mOsm) tap water. All this work is suggestive of a common osmoreceptor mechanism, sensitive to various solutes above a critical level of osmolarity. The fact that osmotic inhibition can be produced in denervated fundic pouches indicates the action of a hormonal inhibitory factor. Code and Watkinson [Z] reported that duodenal acidification caused gastric inhibition against secretion stimulated by meals, ethanol, and insulin hypoglycemia with Pavlov pouches only and not with Heidenhain pouches, suggesting the presence of a vagal reflex. Andersson [27,28], however, has found that duodenal acidification caused gastric inhibition against a test meal or gastrin in both Pavlov and Heidenhain pouch dogs. It seems likely that both neural and hormonal mechanisms may be involved in gastric inhibition after duodenal acidification. We have suggested that this inhibition is at least partly affected through a neural mechanism mediated by serotonin [29]. This neural mechanism may act via the vagi or via a local intramural duodenogastric reflex. The end-organ of the duodenogastric inhibitory reflex could be either the gastric parietal cells or the antral gastrin secretory cells. Secretin may also play a role. Acid in the duodenum is known to stimulate the release of secretin from the duodenal mucosa, and Greenlee et al [30] have shown that crude secretin extract inhibits the antral phase of gastric secretion. Removal of the pancreas does not abolish this inhibitory effect of secretin preparations [31]. However, gastric secretion stimulated by histamine or by insulin hypoglycemia is not inhibited by secretin [32]. It seems, therefore, that the inhibitory effect of secretin on gastric secretion is exerted on the production or release of gastrin. These findings were confirmed by Jordan and Peterson [33]. Further support for a hormonal inhibitory mechanism came from Johnstone and Duthie [34], who have demonstrated that blood transfused from a person with acidified duodenum to another person inhibited gastric secretion in the latter. Gregory [3.5] produced evidence to suggest that secretin itself was not responsible for the inhibitory effects observed by Greenlee and his co-workers. Several crude but potent secretin extracts made by different methods had little or no inhibitory action on the antral mechanism of gastric secretory stimulation. However,
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Wormsley and Grossman [36], using a secretin preparation which probably represents the pure hormone, observed considerable inhibition of gastrin-stimulated response in Heidenhain pouch dogs. These results give support to the work of Greenlee et al [30]. Enterogastrone, described by Kosaka and Lim [37], was thought to be another gastric inhibitory hormone released by the duodenum, but it has never been isolated and since the enterogastrone extracts contained secretin, Gregory [38] has recently questioned its existence. 2. Jejunal inhibitory mechanisms: The role of the jejunum in gastric inhibition is controversial. We have studied the effect of acidification of the small intestine on Heidenhain pouch secretion in dogs, with ThiryVella loops at different levels of the small intestine [39]. Using horsemeat, histamine, or gastrin as the background stimulus, we elicited inhibition of gastric secretion from the proximal third of the small intestine, while acidification of the middle third had no effect. Perfusion of the promixal third of the small bowel with 50 per cent dextrose also resulted in inhibition, but not as marked as with acidification. We have also shown that resection or exclusion of the proximal third of the small bowel causes a marked gastric hypersecretion [40]. Resection or exclusion of the middle or distal third of the small intestine did not cause consistent significant changes in gastric secretion. These experiments suggest that normally the proximal jejunum plays an inhibitory role in gastric secretion, and again we made the suggestion that lack of serotonin release may be partly responsible for this. It should be noted that a number of previous workers [41-43] could not demonstrate inhibition of gastric secretion after acidification of the jejunum. However, Konturek and Grossman [23] have shown that fat in the jejunum and ileum will cause acid inhibition of Heidenhain pouches stimulated by gastrin. Gastric Mucus
Gastric mucus may be defined as the sum of all the macromolecular components of gastric juice, excluding cellular debris. Anacid native mucus is a viscous fluid, with a progressive increase in viscosity on acidification, until a pH of about 5 is reached, at which stage it “breaks” with the formation of “visible mucus” and “soluble mucus.” Visible mucus is the glistening layer of viscous material, which lines the surface of the gastric mucosa and is clearly seen by gastroscopists and surgeons. Soluble mucus is dissolved in gastric juice and cannot be separated from it by simple filtration or centrifugation but only by precipitation with organic precipitants. It forms part of Hollander’s alkaline component [44]. There are a number of ways in which mucus can
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Defense
Mechanisms
exert a protective action on the gastric mucosa [45]: (1) Adhesiveness, which is the measure of the force with which it remains attached to the surface epithelium of the stomach. (2) Cohesiveness, which is the measure of the force with which its molecules remain attached to each other. As a result of adhesiveness and cohesiveness, visible mucus forms a layer which covers the gastric mucosa and is seen clearly on tissue sections. Such a layer protects the underlying cells from chemical irritants. (3) Adsorption, which measures the capacity by which other substances become attached to the surface mucus layer. The adsorptive power of gastric mucus is thought to be responsible for its specific impermeability to pepsin and this is thought to be of physiologic importance [46]. Other toxic substances may also be adsorbed onto gastric mucus. (4) Buffering power. Using Heidenhain pouches in antrectomized dogs, Hollander [45] found native mucus to have a pH of 7.4 I+ 0.2. He also measured its buffering power [47] by titration with O.lN HCI to pH 7.0 and pH 3.5. The average values were about 10 mEq/L and 40 mEq/L, respectively. This acid-neutralizing power is ascribed in part to protein material and in part to bicarbonate and phosphate. Gastric mucus itself, of course, is also liable to acidpepsin degradation. It is not a chemically homogeneous substance and the detailed molecular structure of its components have not been worked out as yet. Essentially it is thought to consist of a protein core, with carbohydrate prosthetic groups branching out of it in such a way as to sterically hinder the action of proteolytic enzymes on the susceptible peptide bonds of the protein core [48]. Therefore, an increased number of carbohydrate prosthetic groups in dissolved gastric mucus may hinder the action of gastric pepsin. Studies from Menguy’s laboratory [49] have shown that cortisone and aspirin (both ulcerogenic agents) cause a fall in the carbohydrate to protein ratio of mucus from antral pouches in dogs. Conversely, using a total innervated gastric pouch, we demonstrated that increasing the gastric acidity with histamine [50], histalog [5Z], or gastrin pentapeptide [52] has caused an increase in the carbohydrate to protein ratio of gastric mucus. In addition, the increased gastric acidity was associated with an increase in total mucus output and a significant increase in the nondigestible component of the acid mucopolysaccharide moiety of mucus. All these are thought to help in counteracting acid-pepsin activity. In normal human subjects, however, histalog stimulation causes a fall in the carbohydrate to protein ratio [53]. The significance of this is not known at present. Integrity
of the Gastric
Epithelium
The layer of mucous epithelium is the last line of the
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gastric defense mechanisms. Application of topical irritants to canine gastric mucosa causes an increase in mucus secretion. After the mucus-secreting power of gastric mucosa has been exhausted, the injured mucosal cells are shed, followed by rapid epithelial repair. Recent studies [M] have shown that the surface plasma membrane of epithelial cells is coated by a filamentous material, which chemically is probably an acid mucopolysaccharide. This may possibly have a protective capacity. Hollander [45] has shown that after denudation of the mucosa, regeneration can take place within thirty-six hours. Teir has shown in both animal and human experiments that the average life span for gastric surface epithelial and mucous neck cells was two days [55]. There is no demonstrable physiologic renewal of the chief and parietal cells [56]. Acute stress causes a definite decrease in the mitotic count of the rat glandular stomach [57]. This suggests that the general healing tendency of the stomach is lowered during stress, which may lead to the formation of, erosions. In a study performed outside the actual disease process in human stomachs removed for peptic ulcer, a significant increase in mitotic count was observed in patients with gastric ulcer, but not in patients with duodenal ulcer, which suggests that in gastric ulcer the life span of the gastric cell population as a whole had become shorter [58]. Summary
Peptic ulceration is probably the result of an imbalance between the aggressive acid-pepsin and the defensive mucus-mucosal barrier factors. In persons without ulcer disease these two factors are in dynamic equilibrium. A breakdown in any of the gastric defense mechanisms discussed may result in peptic ulceration. References 1. Code CF, Watkinson
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7.
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G: Importance of vagal innervation in the regulatory effect of the acid in the duodenum on gastric secretion of acid. J Physiol 130: 233, 1955. Forrest ADM, Code CF: The inhibiting effect of epinephrine and norepinephrine on secretion induced by histamine in separated pouches of dogs. J Pharmacol Exp Ther 110: 447, 1954. Cutting WC, Doggs EC, Noble RL, Williams PC: Pituitary control of alimentary blood flow and secretion. The effect of posterior pituitary extract on the alimentary secretions of intact animals. Proc Roy Sot B 123: 27, 1937. Woodward ER, Robertson C, Fried W, Schapiro H: Further studies on the isolated gastric antrum. Gastroenterology 32: 868, 1957. Pe Thein M, Schofield 6: Release of gastrin from the pyloric antrum following vagal stimulation by sham feeding in dogs. J Physiol 148: 291, 1959. Thompson JC, Lerner HJ: Effect of the antral inhibitory hormone on phases of gastric secretion. Surg Forum 12: 268, 1961. Harrison RC, Lakey WH, Hyde HA: The production of an
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acid inhibitor by the gastric antrum. Ann Surg 144: 441, 1956. Jordan DH, Sand BF: A study of the gastric antrum as an inhibitor of gastric juice production. Surgery 42: 40, 1957. Longhi EH, Greenlee HB, Bravo JL, Guerrero JD, Drag stedt LR: Question of an inhibitory hormone from the gastric antrum. Amer J Physiol 191: 64, 1957. Gillespie IE, Grossman Ml: Effect of acid in pyloric pouch on response of fundic pouch to injected gastrin. Amer J Physiol 203: 557, 1962. Brunschwig A, Prohaska J van, Clarke TH, Kandel E: A secretory depressant in gastric juice of patients with pernicious anemia. J Clin Invest 18: 415, 1939. Fiasse R, Code CF, Glass GBJ: Fractionation and partial purification of gastrone. Gastroenterology 54: 1018, 1968. Code CF, Ratke HV, Livermore GR Jr, Lundberg W: Occurrence of gastric secretory inhibitor activity in fresh gastric and salivary mucin. Fed Proc 8: 26, 1949. Baume PE, Baxter CH, Nicholls A: Concentration and partial characterization of human salivary gastrone. Amer J Dig Dis 12: 965, 1967. Rudick J, Gajewski AK, Pitts CL, Semb LS, Fletcher TL, Harkins HN, Nyhus LM: Inhibition of gastric secretion by fractionated lymph. Elaboration of gastronelike substance during digestive phases in dogs. Amer Surg 32: 513, 1966. Gray JS, Wieczorowski E, Wells JA, Harris SC: The prep aration and properties of urogastrone. Endocrinology 30: 129, 1942. Gray JS, Culmer CV, Wells JA, Wieczorowski E: Factors influencing the excretion of urogastrone. Amer J Physiol 134: 623, 1941. lggo A: Gastric mucosal chemoreceptors with vagal afferent fibers in the cat. Quart J Exp Physiol 42: 398, 1957. Hat W, Welsch KH, Klempa J, Schutzler W: Die Vagalantrale Hemmung des Gastrinmechanismus. Z Gastroent 6: 257, 1968. Andersson S: Gastric secretory inhibition arising from duodenal mechanisms. The Physiology of Gastric Secretion (Semb LS, Myren J ed). Oslo, 1968, Universitetsforlaget. Cooke AR: Observations on the effect of diversion of acid from the duodenum in response to gastrin and histamine. Gastroenterology 55: 268, 1968. Pincus IJ, Friedman MHF, Thomas JE, Rehfuss ME: A quantitative study of the inhibitory effect of acid in the intestine on gastric secretion. Amer J Dig Dis
11: 205, 1944. 23. Konturek S, Grossman
Ml: Effect of perfusion of intestinal loops with acid, fat or dextrose on gastric secretion. Gastroenterology 49: 481, 1965. 24. Kosaka T, Lim RKS: Demonstration of humoral agent in fat inhibition of gastric secretion. Proc Sot Exp Biol Med 27: 890, 1930. 25. Menguy R: Studies on the role of pancreatic and biliary secretions in the mechanism of gastric inhibition by fat. Surgery 48: 195, 1960. 26. Sircus W: Studies on the mechanisms in the duodenum inhibiting gastric secretion. Quart J Exp Physiol 43: 114, 1958. 27. Andersson S: Inhibitory effects of hydrochloric acid in antrum and duodenum on gastric se:retory responses to test meal in Pavlov and Heidenhain pouch dogs. Acta Physiol Stand 49: 231, 1960. 28. Andersson S: Inhibitory effects’ of hydrochloric acid in duodenum on gastrin-stimulated gastric secretion in Heidenhain pouch dogs. Acta Physiol Stand 50: 105, 1960. 29. Wise L, Burkholder J, Zagaloff A, Schuck M, Ballinger
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WF II: Studies on the role of serotonin in the inhibition of gastric acid secretion by the duodenum. Ann Surg 168: 824, 1968. Greenlee HB, Longli EH, Guerrero JD, Nelson TS, ElBedri AL, Dragstedt LR: Inhibitory effect of pancreatic secretion on gastric secretion. Amer J Physiol 190: 396,1957. Kennedy JA, Hallenbeck GA: The pancreas and gastric secretion: failure of pancreatectomy to prevent inhibition of gastric secretion by secretin. Gut 4: 58, 1963. Dragstedt LR: Duodenal inhibition of gastric secretion. Amer J Surg 117: 841, 1969. Jordan PH Jr, Peterson ND: Effects of secretin upon gastric secretion. Ann Surg 156: 914, 1962. Johnstone D, Duthie HL: Inhibition of histaminestimulated gastric secretion by acid in the duodenum in man. Gut 7: 58, 1966. Gregory RA: Secretory mechanisms of the gastro-intes tinal tract, p 131. London, Edward Arnold, 1962. Wormsley KG, Grossman Ml: Inhibition of gastric acid secretion by secretin and by endogenous acid in the duodenum. Gastroenterology 47: 72, 1964. Kosaka T, Lim RKS: Demonstration of humoral agent in fat inhibition of gastric secretion. Proc Sot Exp Biol Med 27: 890, 1930. Gregory RA: Enterogastrone-A reappraisal of the problem. Gastric Secretion: Mechanisms and Control. (Schnitka TK, Gilbert JAL, Harrison RC, ed). New York, The Pergamon Press, 1967. Schuck M, Santillana M, Wise L, Ballinger WF II: Studies on the inhibition of gastric secretion by the small intestine. Surg Gynec Obstet 127: 1295, 1968. Santillana M, Wise L, Schuck M, Ballinger WF II: Changes in gastric acid secretion following resection or exclusion of different segments of the small intestine. Surgery 65: 777, 1969. Ivy AC, Mcllvain GB: The excitation of gastric secretion by application of substances to the duodenal and jejunal mucosa. Amer J Physiol 67: 124, 1923. Sircus W: The intestinal phase of gastric secretion. Quart J Exp Physio138: 1, 1953. Konturek S, Grossman Ml: Localization of the mechanism for inhibition of gastric secretion by acid in intestine. Gastroenterology 49: 74, 1965. Hollander F: Factors which reduce gastric acidity: a survey of the problem. Amer J Dig Dis 5: 364, 1938.
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48.
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Hollander F: The two-component mucous barrier. Arch Int Med 93: 107, 1954. Komarov SA: The inactivation of pepsin and its relation to peptic ulcer. Rev Gastroenterol 9: 165, 1942. Hollander F: The buffer power of native gastric mucus. Abstracts of Communications: XIX International Physiological Congress, Montreal, p 476, 1953. Gottschalk A: Sialic acids: their molecular structure and biological function in mucoproteins. Bull Sot Chim Biol42: 1387, 1960. Menguy R: Regulation of gastric mucus secretion. Gastric Secretion: Mechanism and Control. (Schnitka TK, Gilbert JAL, Harrison RD, ed). New York, The Pergamon Press, 1967. Wise L, Ballinger WF II: The effect of change in the hydrogen ion content of gastric juice on gastric mucus secretion. Surnerv. 66: 723. 1969. Wise L, Ballinger WF II: The’effect of histalog on canine gastric acid, mucus and pepsin secretion. Ann Surg
171: 229, 1970. 52. Wise L, Ballinger WF II: Effect of gastrin
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54.
55. 56. 57.
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pentapeptide on canine gastric mucus, pepsin and acid secretion. Current Topics in Surgical Res,earch, vol 2. (Zuidema GD and Skinner DB, ed). New York, Academic Press, 1970. Wise L, Ballinger WF II: Human gastric mucus: quantitative and qualitative studies. Surg forum, 20: 332, 1969. Ito S: The fine structure of the gastric mucosa. Gastric Secretion: Mechanism and Control. (Schnitka TK, Gilbert JAL, Harrison RE, ed). New York, The Pergamon Press, 1967. Lipkin M: Cell replications in the gastrointestinal tract in man. Gastroenterology 48: 616, 1965. Leblond CP, Walker BE: Renewal of cell populations. Physiol Rev 36: 355, 1956. Rasanen T: Fluctuations in the mitotic frequency of the glandular stomach and intestine of rat under the influence of ACTH, glucocorticoids, stress and heparin. Acta Physiol Stand 58: 201, 1963. Teir H, Rasanen T: A study of mitotic rate in renewal zones of non-diseased portions of gastric mucosa in cases of peptic ulcer and gastric cancer, with observations on differentiation and so-called “intestinalization” of gastric mucosa. J Nat Cancer lnst 27: 949, 1961.
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Much of the surgical literature of gastroduodenal ulceration has been devoted to the aggressive mechanisms which stimulate acid and pepsin production, Relatively little has been written about the various defensive mechanisms. Just as increased stimulation for the production of acid and pepsin may cause peptic ulceration, an aberration in the various defense mechanisms may also be the cause of some cases of ulceration. These defensive mechanisms will be discussed under the following headings: (1) inhibition of gastric acid secretion; (2) gastric mucus; and (3) integrity of gastric epithelium. Inhibition
of Gastric Acid Secretion
One reason why we know less about the inhibitory mechanisms than the stimulatory mechanisms is that, although it is simple to devise experiments which test the effect of stimulation on the basal state, inhibition can often, only be studied as a decrease in an already existent response evoked by some form of stimulation, and it is clear that the effect may be influenced by the nature of the stimulus. In fact, the study of a potential inhibitory mechanism is incomplete until it has been tested against the widest possible range of stimuli. Furthermore, the intensity of the “background” stimulus is important; for example, Code and Watkinson [I] have shown that the weaker the histamine background stimulus, the more effectively duodenal acidification inhibits gastric secretion in Pavlov pouches. The mechanism of inhibition may be “direct” or “indirect;” for example, the inhibitory effects of adrenaline and noradrenaline [2] or pituitrin [3] on gastric secretion are at least partly due to their vasoconstrictor effects, thereby depriving the gastric glands of the blood supply required for their response to the stimulus. Another form of indirect inhibition is that of interference with the operation of a stimulus. For descriptive purposes there are three phases of gastric stimulation: cephalic, gastric, and intestinal. Physiologic inhibition can similarly be described in three phases. The cephalic phme of stimulation depends on excitation of the central vagal nuclei by sight, smell, taste, swallowing, and psychic factors. Unattractive presentation of a meal, bad taste, or emotional From the Department of Surgery, Washington University School of Medicine. St Louis, Missouri 63110. This work was supported in part by US Public Health Service Grant Number AM 12333.
Vol.
119, May 1970
disturbances can depress the cephalic phase of stimulation. The inhibition of the gmtric phase has been studied by Woodward et al [4], who have shown that at a pH of 1.5 or less, previously adequate mechanical or chemical stimuli of the antrum evoked almost no acid response in Heidenhain pouches. It has also been shown that acidification abolishes the vagal release of gastrin [5]. Since after the ingestion of food the intact stomach of both human subjects and dogs normally reaches a pH of this range, this seems to be a homeostatic mechanism terminating gastrin release by the meal. The process by which acidification of the antrum prevents gastrin production or release is not known. An alternative explanation is that acid in the antrum releases an inhibitory hormone [6] which has been named “antral chalone.” The work of Harrison, Lakey, and Hyde [7] suggests the possibility that acidification of the antrum causes the release of an inhibitory hormone. They first transplanted the distal half of the antrum into the colon, which induced the release of gastrin, with an increase in the acid output from Heidenhain pouches. The acid output was further increased when the remaining proximal half of the antrum, which was exposed to the increased acid secretion, was excised, suggesting the removal of an inhibitory hormone. Jordan and Sand [8] gave further support for a hormonal inhibitory mechanism. They prepared dogs with a Heidenhain pouch and two antral pouches. One antral pouch was irrigated with alcohol, which stimulated acid secretion from the Heidenhain pouch. Simultaneous irrigation of the other antral pouch with acid caused inhibition after one to three hours, The reason for the long latent period is obscure. Longhi et al [9], however, in a similar experiment did not observe any inhibition. An important piece of evidence against an antral inhibitory hormone came from Gillespie and Grossman [Zo], who showed that acidification of the antral muscosa had no inhibitory effect on the response of fundic pouch to exogenous gastrin. Gastrone is the gastric secretion-inhibitory factor found in gastric juice, and was discovered in 1939 by Brunschwig et al [II]. When human gastric juice or its alcoholic precipitate was injected into dogs with Heidenhain pouches which were secreting acid in response to feeding, a depression of gastric acid secretion ensued. This was more marked after the injection of
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anacid gastric juice, and was still greater with the gastric juice of patients with pernicious anemia or gastric carcinoma. Gastrone has been partially purified by Fiasse, Code, and Glass [12]. It is present in greater quantities in the antrum than in the body, and in greater amount in innervated than in denervated pouches. However, its physiologic or pathologic significance is still not known and its possible relationship to antral chalone is also still undefined. A gastric secretory inhibitor has also been demonstrated in the saliva of humans and dogs. It was originally discovered by Code et al [13] and recently purified by Baume, Baxter, and Nicholls [14]. Rudick and co-workers [15] reported that thoracic duct lymph contained an inhibitory material to gastric secretion in rats. Again the relationship of this substance to gastrone is not known. A gastric inhibitory factor has also been found in extracts of urine from normal human subjects [Z6] and also from patients with peptic ulcer [17]. Evidence for a possible vagal afferent mechanism in the antral inhibition of gastric acid secretion was reported by Iggo [18] and Hat et al [29]. Iggo [Z8] demonstrated changes in the electrical activity of vagal afferents after the application of acid solutions to the gastric mucosa. The threshold of the acid receptors was pH 3 or lower. These mucosal receptors were not excited by moderate gastric distention, nor by hypertonic or hypotonic solutions. Hat et al [19] prepared dogs with Heidenhain pouches and they also denervated the body and fundus of the main stomachs, leaving the vagal fibers to the antrum intact. Chronic electrodes were placed on the antral nerves. Stimulation of these nerves significantly reduced the secretory response to feeding from the Heidenhain pouches. From this observation they suggested that gastrin release may be controlled by an inhibitory vagovagal reflex mechanism. The intestinal phase of gastric inhibition may be considered in two parts: duodenal and jejunal. 1. Duodenal inhibitory mechanisms: That acid in the duodenum causes gastric inhibition is shown by various methods. If gastric acid is prevented from reaching the duodenal mucosa either by occluding the pylorus surgically [20] or by draining the gastric juice to the exterior by a gastric fistula [21], the gastric acid output of fundic pouches is increased. Conversely, acidification of the duodenum inhibits gastric secretion. Pincus et al [22] studied the effect of duodenal ‘acidification and observed a 50 per cent inhibition both with Pavlov and Heidenhain pouches at a duodenal pH of 2.5. When the pH fell to 2.0 or lower, inhibition was almost complete. The introduction into the duodenum of fat or its digestive products will also inhibit gastric secretion [23]. Since inhibition by fat could be demonstrated in transplanted gastric pouches, a hormonal mechanism has been postulated [24]. The fat, however, must be in an
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absorbable form; thus, procedures which interfere with fat absorption, especially exclusion of bile and pancreatic juice, result in a lesser degree of inhibition [25]. Sircus [26] has shown that instillation of hypertonic saline, glucose, fructose, polysaccharide complexes, and peptone into the duodenum can all inhibit gastric secretion. Recognizable inhibition was obtained when a level of 275 mOsm was reached, and inhibition was marked when it rose above 425 mOsm. A less marked but still recognizable inhibition was obtained on the instillation of hypotonic (below 50 mOsm) tap water. All this work is suggestive of a common osmoreceptor mechanism, sensitive to various solutes above a critical level of osmolarity. The fact that osmotic inhibition can be produced in denervated fundic pouches indicates the action of a hormonal inhibitory factor. Code and Watkinson [Z] reported that duodenal acidification caused gastric inhibition against secretion stimulated by meals, ethanol, and insulin hypoglycemia with Pavlov pouches only and not with Heidenhain pouches, suggesting the presence of a vagal reflex. Andersson [27,28], however, has found that duodenal acidification caused gastric inhibition against a test meal or gastrin in both Pavlov and Heidenhain pouch dogs. It seems likely that both neural and hormonal mechanisms may be involved in gastric inhibition after duodenal acidification. We have suggested that this inhibition is at least partly affected through a neural mechanism mediated by serotonin [29]. This neural mechanism may act via the vagi or via a local intramural duodenogastric reflex. The end-organ of the duodenogastric inhibitory reflex could be either the gastric parietal cells or the antral gastrin secretory cells. Secretin may also play a role. Acid in the duodenum is known to stimulate the release of secretin from the duodenal mucosa, and Greenlee et al [30] have shown that crude secretin extract inhibits the antral phase of gastric secretion. Removal of the pancreas does not abolish this inhibitory effect of secretin preparations [31]. However, gastric secretion stimulated by histamine or by insulin hypoglycemia is not inhibited by secretin [32]. It seems, therefore, that the inhibitory effect of secretin on gastric secretion is exerted on the production or release of gastrin. These findings were confirmed by Jordan and Peterson [33]. Further support for a hormonal inhibitory mechanism came from Johnstone and Duthie [34], who have demonstrated that blood transfused from a person with acidified duodenum to another person inhibited gastric secretion in the latter. Gregory [3.5] produced evidence to suggest that secretin itself was not responsible for the inhibitory effects observed by Greenlee and his co-workers. Several crude but potent secretin extracts made by different methods had little or no inhibitory action on the antral mechanism of gastric secretory stimulation. However,
The
American
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Gastric
Wormsley and Grossman [36], using a secretin preparation which probably represents the pure hormone, observed considerable inhibition of gastrin-stimulated response in Heidenhain pouch dogs. These results give support to the work of Greenlee et al [30]. Enterogastrone, described by Kosaka and Lim [37], was thought to be another gastric inhibitory hormone released by the duodenum, but it has never been isolated and since the enterogastrone extracts contained secretin, Gregory [38] has recently questioned its existence. 2. Jejunal inhibitory mechanisms: The role of the jejunum in gastric inhibition is controversial. We have studied the effect of acidification of the small intestine on Heidenhain pouch secretion in dogs, with ThiryVella loops at different levels of the small intestine [39]. Using horsemeat, histamine, or gastrin as the background stimulus, we elicited inhibition of gastric secretion from the proximal third of the small intestine, while acidification of the middle third had no effect. Perfusion of the promixal third of the small bowel with 50 per cent dextrose also resulted in inhibition, but not as marked as with acidification. We have also shown that resection or exclusion of the proximal third of the small bowel causes a marked gastric hypersecretion [40]. Resection or exclusion of the middle or distal third of the small intestine did not cause consistent significant changes in gastric secretion. These experiments suggest that normally the proximal jejunum plays an inhibitory role in gastric secretion, and again we made the suggestion that lack of serotonin release may be partly responsible for this. It should be noted that a number of previous workers [41-43] could not demonstrate inhibition of gastric secretion after acidification of the jejunum. However, Konturek and Grossman [23] have shown that fat in the jejunum and ileum will cause acid inhibition of Heidenhain pouches stimulated by gastrin. Gastric Mucus
Gastric mucus may be defined as the sum of all the macromolecular components of gastric juice, excluding cellular debris. Anacid native mucus is a viscous fluid, with a progressive increase in viscosity on acidification, until a pH of about 5 is reached, at which stage it “breaks” with the formation of “visible mucus” and “soluble mucus.” Visible mucus is the glistening layer of viscous material, which lines the surface of the gastric mucosa and is clearly seen by gastroscopists and surgeons. Soluble mucus is dissolved in gastric juice and cannot be separated from it by simple filtration or centrifugation but only by precipitation with organic precipitants. It forms part of Hollander’s alkaline component [44]. There are a number of ways in which mucus can
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exert a protective action on the gastric mucosa [45]: (1) Adhesiveness, which is the measure of the force with which it remains attached to the surface epithelium of the stomach. (2) Cohesiveness, which is the measure of the force with which its molecules remain attached to each other. As a result of adhesiveness and cohesiveness, visible mucus forms a layer which covers the gastric mucosa and is seen clearly on tissue sections. Such a layer protects the underlying cells from chemical irritants. (3) Adsorption, which measures the capacity by which other substances become attached to the surface mucus layer. The adsorptive power of gastric mucus is thought to be responsible for its specific impermeability to pepsin and this is thought to be of physiologic importance [46]. Other toxic substances may also be adsorbed onto gastric mucus. (4) Buffering power. Using Heidenhain pouches in antrectomized dogs, Hollander [45] found native mucus to have a pH of 7.4 I+ 0.2. He also measured its buffering power [47] by titration with O.lN HCI to pH 7.0 and pH 3.5. The average values were about 10 mEq/L and 40 mEq/L, respectively. This acid-neutralizing power is ascribed in part to protein material and in part to bicarbonate and phosphate. Gastric mucus itself, of course, is also liable to acidpepsin degradation. It is not a chemically homogeneous substance and the detailed molecular structure of its components have not been worked out as yet. Essentially it is thought to consist of a protein core, with carbohydrate prosthetic groups branching out of it in such a way as to sterically hinder the action of proteolytic enzymes on the susceptible peptide bonds of the protein core [48]. Therefore, an increased number of carbohydrate prosthetic groups in dissolved gastric mucus may hinder the action of gastric pepsin. Studies from Menguy’s laboratory [49] have shown that cortisone and aspirin (both ulcerogenic agents) cause a fall in the carbohydrate to protein ratio of mucus from antral pouches in dogs. Conversely, using a total innervated gastric pouch, we demonstrated that increasing the gastric acidity with histamine [50], histalog [5Z], or gastrin pentapeptide [52] has caused an increase in the carbohydrate to protein ratio of gastric mucus. In addition, the increased gastric acidity was associated with an increase in total mucus output and a significant increase in the nondigestible component of the acid mucopolysaccharide moiety of mucus. All these are thought to help in counteracting acid-pepsin activity. In normal human subjects, however, histalog stimulation causes a fall in the carbohydrate to protein ratio [53]. The significance of this is not known at present. Integrity
of the Gastric
Epithelium
The layer of mucous epithelium is the last line of the
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Wise and Ballinger
gastric defense mechanisms. Application of topical irritants to canine gastric mucosa causes an increase in mucus secretion. After the mucus-secreting power of gastric mucosa has been exhausted, the injured mucosal cells are shed, followed by rapid epithelial repair. Recent studies [M] have shown that the surface plasma membrane of epithelial cells is coated by a filamentous material, which chemically is probably an acid mucopolysaccharide. This may possibly have a protective capacity. Hollander [45] has shown that after denudation of the mucosa, regeneration can take place within thirty-six hours. Teir has shown in both animal and human experiments that the average life span for gastric surface epithelial and mucous neck cells was two days [55]. There is no demonstrable physiologic renewal of the chief and parietal cells [56]. Acute stress causes a definite decrease in the mitotic count of the rat glandular stomach [57]. This suggests that the general healing tendency of the stomach is lowered during stress, which may lead to the formation of, erosions. In a study performed outside the actual disease process in human stomachs removed for peptic ulcer, a significant increase in mitotic count was observed in patients with gastric ulcer, but not in patients with duodenal ulcer, which suggests that in gastric ulcer the life span of the gastric cell population as a whole had become shorter [58]. Summary
Peptic ulceration is probably the result of an imbalance between the aggressive acid-pepsin and the defensive mucus-mucosal barrier factors. In persons without ulcer disease these two factors are in dynamic equilibrium. A breakdown in any of the gastric defense mechanisms discussed may result in peptic ulceration. References 1. Code CF, Watkinson
2.
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7.
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G: Importance of vagal innervation in the regulatory effect of the acid in the duodenum on gastric secretion of acid. J Physiol 130: 233, 1955. Forrest ADM, Code CF: The inhibiting effect of epinephrine and norepinephrine on secretion induced by histamine in separated pouches of dogs. J Pharmacol Exp Ther 110: 447, 1954. Cutting WC, Doggs EC, Noble RL, Williams PC: Pituitary control of alimentary blood flow and secretion. The effect of posterior pituitary extract on the alimentary secretions of intact animals. Proc Roy Sot B 123: 27, 1937. Woodward ER, Robertson C, Fried W, Schapiro H: Further studies on the isolated gastric antrum. Gastroenterology 32: 868, 1957. Pe Thein M, Schofield 6: Release of gastrin from the pyloric antrum following vagal stimulation by sham feeding in dogs. J Physiol 148: 291, 1959. Thompson JC, Lerner HJ: Effect of the antral inhibitory hormone on phases of gastric secretion. Surg Forum 12: 268, 1961. Harrison RC, Lakey WH, Hyde HA: The production of an
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11: 205, 1944. 23. Konturek S, Grossman
Ml: Effect of perfusion of intestinal loops with acid, fat or dextrose on gastric secretion. Gastroenterology 49: 481, 1965. 24. Kosaka T, Lim RKS: Demonstration of humoral agent in fat inhibition of gastric secretion. Proc Sot Exp Biol Med 27: 890, 1930. 25. Menguy R: Studies on the role of pancreatic and biliary secretions in the mechanism of gastric inhibition by fat. Surgery 48: 195, 1960. 26. Sircus W: Studies on the mechanisms in the duodenum inhibiting gastric secretion. Quart J Exp Physiol 43: 114, 1958. 27. Andersson S: Inhibitory effects of hydrochloric acid in antrum and duodenum on gastric se:retory responses to test meal in Pavlov and Heidenhain pouch dogs. Acta Physiol Stand 49: 231, 1960. 28. Andersson S: Inhibitory effects’ of hydrochloric acid in duodenum on gastrin-stimulated gastric secretion in Heidenhain pouch dogs. Acta Physiol Stand 50: 105, 1960. 29. Wise L, Burkholder J, Zagaloff A, Schuck M, Ballinger
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WF II: Studies on the role of serotonin in the inhibition of gastric acid secretion by the duodenum. Ann Surg 168: 824, 1968. Greenlee HB, Longli EH, Guerrero JD, Nelson TS, ElBedri AL, Dragstedt LR: Inhibitory effect of pancreatic secretion on gastric secretion. Amer J Physiol 190: 396,1957. Kennedy JA, Hallenbeck GA: The pancreas and gastric secretion: failure of pancreatectomy to prevent inhibition of gastric secretion by secretin. Gut 4: 58, 1963. Dragstedt LR: Duodenal inhibition of gastric secretion. Amer J Surg 117: 841, 1969. Jordan PH Jr, Peterson ND: Effects of secretin upon gastric secretion. Ann Surg 156: 914, 1962. Johnstone D, Duthie HL: Inhibition of histaminestimulated gastric secretion by acid in the duodenum in man. Gut 7: 58, 1966. Gregory RA: Secretory mechanisms of the gastro-intes tinal tract, p 131. London, Edward Arnold, 1962. Wormsley KG, Grossman Ml: Inhibition of gastric acid secretion by secretin and by endogenous acid in the duodenum. Gastroenterology 47: 72, 1964. Kosaka T, Lim RKS: Demonstration of humoral agent in fat inhibition of gastric secretion. Proc Sot Exp Biol Med 27: 890, 1930. Gregory RA: Enterogastrone-A reappraisal of the problem. Gastric Secretion: Mechanisms and Control. (Schnitka TK, Gilbert JAL, Harrison RC, ed). New York, The Pergamon Press, 1967. Schuck M, Santillana M, Wise L, Ballinger WF II: Studies on the inhibition of gastric secretion by the small intestine. Surg Gynec Obstet 127: 1295, 1968. Santillana M, Wise L, Schuck M, Ballinger WF II: Changes in gastric acid secretion following resection or exclusion of different segments of the small intestine. Surgery 65: 777, 1969. Ivy AC, Mcllvain GB: The excitation of gastric secretion by application of substances to the duodenal and jejunal mucosa. Amer J Physiol 67: 124, 1923. Sircus W: The intestinal phase of gastric secretion. Quart J Exp Physio138: 1, 1953. Konturek S, Grossman Ml: Localization of the mechanism for inhibition of gastric secretion by acid in intestine. Gastroenterology 49: 74, 1965. Hollander F: Factors which reduce gastric acidity: a survey of the problem. Amer J Dig Dis 5: 364, 1938.
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Hollander F: The two-component mucous barrier. Arch Int Med 93: 107, 1954. Komarov SA: The inactivation of pepsin and its relation to peptic ulcer. Rev Gastroenterol 9: 165, 1942. Hollander F: The buffer power of native gastric mucus. Abstracts of Communications: XIX International Physiological Congress, Montreal, p 476, 1953. Gottschalk A: Sialic acids: their molecular structure and biological function in mucoproteins. Bull Sot Chim Biol42: 1387, 1960. Menguy R: Regulation of gastric mucus secretion. Gastric Secretion: Mechanism and Control. (Schnitka TK, Gilbert JAL, Harrison RD, ed). New York, The Pergamon Press, 1967. Wise L, Ballinger WF II: The effect of change in the hydrogen ion content of gastric juice on gastric mucus secretion. Surnerv. 66: 723. 1969. Wise L, Ballinger WF II: The’effect of histalog on canine gastric acid, mucus and pepsin secretion. Ann Surg
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pentapeptide on canine gastric mucus, pepsin and acid secretion. Current Topics in Surgical Res,earch, vol 2. (Zuidema GD and Skinner DB, ed). New York, Academic Press, 1970. Wise L, Ballinger WF II: Human gastric mucus: quantitative and qualitative studies. Surg forum, 20: 332, 1969. Ito S: The fine structure of the gastric mucosa. Gastric Secretion: Mechanism and Control. (Schnitka TK, Gilbert JAL, Harrison RE, ed). New York, The Pergamon Press, 1967. Lipkin M: Cell replications in the gastrointestinal tract in man. Gastroenterology 48: 616, 1965. Leblond CP, Walker BE: Renewal of cell populations. Physiol Rev 36: 355, 1956. Rasanen T: Fluctuations in the mitotic frequency of the glandular stomach and intestine of rat under the influence of ACTH, glucocorticoids, stress and heparin. Acta Physiol Stand 58: 201, 1963. Teir H, Rasanen T: A study of mitotic rate in renewal zones of non-diseased portions of gastric mucosa in cases of peptic ulcer and gastric cancer, with observations on differentiation and so-called “intestinalization” of gastric mucosa. J Nat Cancer lnst 27: 949, 1961.
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