0025-7l2.5/91 80.00 + .20
Peptic Ulcer Disease
Peptic U leer Pathophysiology
H.R. Mertz, MD,* andJ.H. Walsh, MDt
Recent advanccs have led to improved understanding of peptic ulcer pathophysiology. A basic paradigm for ulcer disease is the imbalance between the digestive activity of acid and pepsin and the protective mechanisms in place to resist mucosal digestion. Although many derangements in the normal physiology of the stomach and duodenum have been identified in ulcer patients, it remains to be determined which abnormalities are most important. The critical defect may vary between individuals, or multiple defects may contribute to the final common denominator of ulceration (Fig. 1). It is possible to divide peptic ulcers into three etiologic groups: those due to massive acid peptic hypersecretion in the Zollinger-Ellison syndrome; those due to nonsteroidal anti-inflammatory drugs (NSAIDs); and ulcers associated with Helicobacter pylori infection. H. pylori-related ulcers form the largest and least well understood subset of ulcer disease and will be emphasized in this article. Gastric and duodenal ulcers have overlapping epidemiologic and pathophysiologic features, but they have significant differences. Duodenal ulcer patients have a younger age of onset and on average have increased parietal cell mass and acid secretion. IO Gastric ulcer patients have normal or decreased acid secretion, which is often associated with decreased mucosal defense. However, some gastric ulcers are associated with duodenal ulcers and have the increased acid secretion typical of duodenal ulcer disease. These ulcers usually are found in the distal antrum or pyloric channel.
*Fellow,
Gastroenterology Division, Department of Medicine, University of California, Los Angeles, School of Medicine, and UCLA Medical Center. Los Angeles, California tChief. Gastroenterology Division, UCLA Medical Center; Director, Center for Ulcer Research and Education (CURE)/UCLA Digestive Disease Center; and Stram Professor of 'vledicine, University of California, Los Angeles, School of Medicine, Los Angeles, Califlmlia
Medical Clinics of North America-Vo!' 75, Ko. 4, July 1991
799
800 AGGRESSION Acid Pepsin NSAIDs H. pylori
II. H. DEFENSE Bicarbonate Blood flow Mucus Cell junctions Apical resistance
Y!ERTZ At\j)
J. H.
WALSH
REPAIR Restitution Mucoid cap Proliferation Growth factors
Figure I. Aggressive bctors that promote ulceration counterbalanced by defensive and rcparative processes.
ACID AND PEPTIC ACTIVITY Acid The increased acid secretion in duodenal ulcer, the model of gastrinoma, and the response of ulcers to H 2 -blockers underscore the importance of acid/peptic activity. Schwartz's dictum "no acid, no ulcer" is still felt to be true. H7 Normal control of acid secretion dcpends on endocrine (gastrin), neural (vagal cholinergic nerves), and paracrine (histamine) limbs. Ingestion of a meal causes increased acid and pepsin secretion due to an increase in gash-in release and vagally mediated cephalic stimulus to the parietal cell. After gastric and duodenal pH has been lowered, gastrin release is inhibited and acid secretion returns to baseline. I? Pepsinogen is secreted from the chief cell in response to gastrin and histamine. In the presence of acid, pepsinogen is cleaved to pepsin, which is active at pH less than 4. 83 It has been shown that acid is much more damaging to intestinal mucosa in the presence of pepsinogen. 9? In duodenal ulcer patients, a number of abnormalities in acid secretion have been found, although none are universal. Parietal cell mass is often increased 1..5 to 2 times. lO Basal, nocturnal, and maximal acid output are also elevated in subsets of patients. IS . .10 Infection with H. pylori, seen in more than 9.5% of duodenal ulcer patients, is associated with abnormalities in the acid regulatory process. Patients infected with H. pylori have elevated serum gastrin responses to a meal. In addition, ulcer patients positive for H. pylori have higher mealstimulated acid secretion than H. pylori-negative subjects.;;] H. pyloriinfected patients without ulcer are found to have elevated meal-stimulated gash-ins compared with H. pylori-negative controls, but acid secretion is equivalent. 26 Meal-stimulated hypergastrinemia was abolished following successful eradication of H. pylori from six duodenal ulcer patients. There was no immediate effect on acid secretion. 29 Prolonged hypergastrinemia due to H. pylori infection could cause trophic eHects on the oxyntic mucosa and increases in parietal cell mass and gastric acid secretion. The mechanism by which H. pylori infection causes elevated mealstimulated gastrin is unclear. Ammonia produced by H. pylori urease may be involved. Lichtenherger has found in rats that gastrin response to meals depends on the amino acid content of the chow. Rats fed deamidated chow
PEPTIC L'LCER PXrIlOPIIYSIOLOC;Y
801
had a .50% reduction in gash'in response; addition of NH 4 CI to the chow returned gastrin response to normal." Sinee H. pylori lives in the nearly neutral mueus gel layer and hydrolyzes urea into ammonia and carbon dioxide, there may well be significant amounts of nonprotonated ammonia (NHJ) that ean diffuse through the antral mucosa and influence G cells. Local alkalinization of the mucus by H. pylori-produced NHJ is another possible mechanism for increased postprandial gastrin release. Preliminary data from our laboratory, with meals at pH 7, still show increased gastrin in the H. pylori patients, making local alkalinization less likely as a mechanism of postprandial hypergastrinemia. Pepsin Superficial gastritis is associated' with elevated pepsinogen 1 (PG 1), and PG 1 is a marker for peptic ulcer disease. 84 It has subsequently been discovered that superficial gastritis is most often caused by H. pylori. 77 Treatment of H. pylori in children results in a significant reduction in serum PG1levels. 65 \Vhether this reduction in PGI results in lower luminal pepsin activity is unknown. If so, this may be an explanation for the dramatic reduction in duodenal ulcer relapse rate when H. pylori is eradicated and also may be an important factor in H. pylori-related ulcer disease. Motility In some duodenal ulcer patients, rapid gastric emptying of liquids is seen; this may allow gastric acid to overwhelm duodenal acid neutralization capabilities. 57 The importance of this abnormality has yet to be determined.
MUCOSAL PROTECTION Protection of the gastrointestinal mucosa from the powerful digestive effects of acid and pepsin is a biologic imperative. It is no surprise that the protective mechanisms are somewhat redundant. The first line of the mucosal defensive network is the mucus layer, which coats gastric and duodenal mucosa. It is composed of glycoprotein, which forms a gel with water. This gel impedes diffusion of pepsin and creates an unstirred aqueous layer that helps maintain a pH gradient. Secretion of bicarbonate from gastric surface epithelial cells and duodenal mucosa is critical to maintaining a mucosal pH gradient. Pancreatic bicarbonate also is important in neutralizing the gastric acid load. 98 Through these mechanisms, gastric and duodenal mucosal pH is maintained- above 6, even when luminal pH is as low as 1. 5. 7.3 The epithelial cells resist acid and peptic destruction. The gastric epithelial cells are connected by tight junctions that help prevent acid penetration. The apical surface of the gastric mucosa is resistant enough to acid flux that monolayers in vitro can maintain a transmembrane electrical potential difference for 4 hours at pH 2.8.5 If a mucosal break does occur, epithelial cells move laterally along the basement membrane to fill the gap in a matter of hours.
802
H. R.
'vlEHTz AI\ J)
J. H.
WALSII
This process, restitution, rcquircs an intact basement membrane and a mucoid cap compriscd of extruded proteinaceous debris and bicarbonate. In animal models, maintenance of mucosal hlood flow during experimental injury is important in prevention of sevcrc mucosal damagc, -Iq and some have postulated that loss of blood flow is the difh,rence betwccn a mucosal break that hecomes a chronic ulcer and one that is rapidly repaired by restitution. Cl.5 Growth factors may play a role in healing and restitution, particularly epidermal growth factor (EGF) and transforming growth factor alpha (TGFa). These peptides share substantial homology and interact with the same receptor. mR='JA for TGFa and its receptor has been found in human gastric mucosa, particularly in the parietal cell fraction, I indicating gastric secretion and site of action of this f~lctor. EGF has heen found to stimulate gastrointcstinal mucosal DNA synthesis and ornithine decarboxylase activity in rats and mice, respcctively.I). Hi This activity may translate into improved mucosal protection or restitution. In rats, EGF has bcen found to prcvent stress-induced gastric ulcers.42 \Vhen chronic duodenal ulcers are induced by cysteamine in rats, oral urogastrone (identical to EGF) has been shown to induce healing to the same extent as cimetidine. \Vhen urogastrone and cimctidine are administered concomitantly, there is an additive benefit for healing. Sincc oral urogastrone had no effect on acid secretion in this study, it appcars the additional benefit provided by urogastrone is due to improved mucosal dcfense. 66 Abnormal Mucus Alterations in the mucus layer that protects gastric and duodenal mucosa have been found in hoth duodenal ulccr and gastric ulcer patients. Ulcer patients have an increased proportion of low molecular weight dextrans, which are associated with weaker mucus. 102 The physical propertics of gastric mucus differ between ulcer patients and controls. Hydrophohicity of gastric mucus has becn assesscd by goniometry (which determines the contact angle between mucus and a drop of water) in duodcnal and gastric ulcer patients and dyspeptic controls. There is a significant reduction in hydrophobicity in both groups of ulcer patients. Prescnce of H. pylori gastritis is associated with a significant decrease in hydrophobicity in the controls, to the same level as the ulcer patients. 93 This suggests H. pylori as the mediator of the abnormal mucus. H. pylori extracts, thought to contain an endopeptidase, have heen shown to digest gastric mucus S9 and result in decreased viscosity and increased acid permeability. S6 Trcatment of H. pylori with antibiotics, but not placebo, results in regencration of mucus, as assessed microscopically. 61 Although microscopic asscssments arc crude, these data suggcst that H. pylori causcs or cxacerbates mucus depletion. Impairment in prostaglandin production may be important in mucus depletion. Prostaglandins are endogenous mediators of mucus production 4, and may be suppressed in aspirin-induced mucus disruption. The importance of mucus disruption in thc pathogenesis of pcptic ulcer remains to be determined.
PEPTIC CLCER P~"TIIOPIIYSI()L()CY
80:3
Bicarbonate Abnormalities in the secretion of bicarbonate from the gastroduodenal mucosa have been implicated in duodenal ulcer disease. Buffering of the acid load fi~om the stomach is clearly vital to protection of the duodenum. Approximately half of the gastric acid that enters the duodenum is neutralized by bicarbonate secreted by the duodenal mucosa. The remainder is neutralized by pancreatieobiliary secretions. 22 \Vhile only about one-third of duodenal ulcer patients have abnormalities in acid secretion, most have diminished basal and peak duodenal bulb bicarbonate secretion.']3 The mechanism for decreased sccretion is unknown. Prostaglandins of the E class (PGEs) are known agonists and NSAIDs are known inhibitors of duodenal bicarbonate secretion. This is consistent with the known protective effects of prostaglandins and deleterious effects of NSAIDs on the gastrointestinal tract. Duodenal ulcer patients stimulated with luminal acid showcd a significantly lower 1 hour duodenal bicarbonate secretion despitc a 1 hour PGE 2 output nearly three times higher than in the controls. 7;] This may represent a compensatory increase in PGE 2 in response to diminished bicarbonate output. The abnormalities in bicarbonate secretion are parallelcd by loss of mucosal acid buffering capacity in duodenal ulcer patients. Mieroelectrode studics in duodenal ulcer paticnts demonstrate a greater than lO-fold increase in juxtamucosal acid concentration compared with controls when luminal pH is less than 3. 2 Few physiologic abnormalities in peptic ulcer disease are as prevalent as the impairment in duodenal bicarbonate secretion. Studies in humans show not only decrcased secretion of bicarbonate but concomitant impairment of the duodenal mucosal pH gradient. This evidence supports a major role for disordered bicarbonate secretion in duodenal ulcer (Fig. 2). Blood Flow Blood flow is clearly essential to the maintenance of gastroduodenal integrity, as it is in any tissue. Whether reductions of mucosal blood flow are clinically important in ulcer disease is difficult to say. There is abundant animal data showing that reduction in blood flow to the gastroduodenal mucosa results in acute lesion formation. In rats, the stomach is more resistant to ischemia than the duodenum. Gastric lesions are not seen until flow is reduced below a threshold of 40% of baseline. Conversely, duodenal lesion formation is related in a linear manner to reduction in flow without a threshold level. 3l Other animal data show vascular stasis in capillary beds and dccreased blood flow in response to topical 100% ethanol. Hemorrhagic mucosal lesions subsequently dcvelop. Pretreatment with dimethyl PGE 2 or sodium thiosulfate prevents the vascular changcs and lesion formation without consistently increasing baseline blood How. 71 Others have also shown dimethyl PG E2 to reduce lesion f
Peptic Ulcer Disease
Peptic U leer Pathophysiology
H.R. Mertz, MD,* andJ.H. Walsh, MDt
Recent advanccs have led to improved understanding of peptic ulcer pathophysiology. A basic paradigm for ulcer disease is the imbalance between the digestive activity of acid and pepsin and the protective mechanisms in place to resist mucosal digestion. Although many derangements in the normal physiology of the stomach and duodenum have been identified in ulcer patients, it remains to be determined which abnormalities are most important. The critical defect may vary between individuals, or multiple defects may contribute to the final common denominator of ulceration (Fig. 1). It is possible to divide peptic ulcers into three etiologic groups: those due to massive acid peptic hypersecretion in the Zollinger-Ellison syndrome; those due to nonsteroidal anti-inflammatory drugs (NSAIDs); and ulcers associated with Helicobacter pylori infection. H. pylori-related ulcers form the largest and least well understood subset of ulcer disease and will be emphasized in this article. Gastric and duodenal ulcers have overlapping epidemiologic and pathophysiologic features, but they have significant differences. Duodenal ulcer patients have a younger age of onset and on average have increased parietal cell mass and acid secretion. IO Gastric ulcer patients have normal or decreased acid secretion, which is often associated with decreased mucosal defense. However, some gastric ulcers are associated with duodenal ulcers and have the increased acid secretion typical of duodenal ulcer disease. These ulcers usually are found in the distal antrum or pyloric channel.
*Fellow,
Gastroenterology Division, Department of Medicine, University of California, Los Angeles, School of Medicine, and UCLA Medical Center. Los Angeles, California tChief. Gastroenterology Division, UCLA Medical Center; Director, Center for Ulcer Research and Education (CURE)/UCLA Digestive Disease Center; and Stram Professor of 'vledicine, University of California, Los Angeles, School of Medicine, Los Angeles, Califlmlia
Medical Clinics of North America-Vo!' 75, Ko. 4, July 1991
799
800 AGGRESSION Acid Pepsin NSAIDs H. pylori
II. H. DEFENSE Bicarbonate Blood flow Mucus Cell junctions Apical resistance
Y!ERTZ At\j)
J. H.
WALSH
REPAIR Restitution Mucoid cap Proliferation Growth factors
Figure I. Aggressive bctors that promote ulceration counterbalanced by defensive and rcparative processes.
ACID AND PEPTIC ACTIVITY Acid The increased acid secretion in duodenal ulcer, the model of gastrinoma, and the response of ulcers to H 2 -blockers underscore the importance of acid/peptic activity. Schwartz's dictum "no acid, no ulcer" is still felt to be true. H7 Normal control of acid secretion dcpends on endocrine (gastrin), neural (vagal cholinergic nerves), and paracrine (histamine) limbs. Ingestion of a meal causes increased acid and pepsin secretion due to an increase in gash-in release and vagally mediated cephalic stimulus to the parietal cell. After gastric and duodenal pH has been lowered, gastrin release is inhibited and acid secretion returns to baseline. I? Pepsinogen is secreted from the chief cell in response to gastrin and histamine. In the presence of acid, pepsinogen is cleaved to pepsin, which is active at pH less than 4. 83 It has been shown that acid is much more damaging to intestinal mucosa in the presence of pepsinogen. 9? In duodenal ulcer patients, a number of abnormalities in acid secretion have been found, although none are universal. Parietal cell mass is often increased 1..5 to 2 times. lO Basal, nocturnal, and maximal acid output are also elevated in subsets of patients. IS . .10 Infection with H. pylori, seen in more than 9.5% of duodenal ulcer patients, is associated with abnormalities in the acid regulatory process. Patients infected with H. pylori have elevated serum gastrin responses to a meal. In addition, ulcer patients positive for H. pylori have higher mealstimulated acid secretion than H. pylori-negative subjects.;;] H. pyloriinfected patients without ulcer are found to have elevated meal-stimulated gash-ins compared with H. pylori-negative controls, but acid secretion is equivalent. 26 Meal-stimulated hypergastrinemia was abolished following successful eradication of H. pylori from six duodenal ulcer patients. There was no immediate effect on acid secretion. 29 Prolonged hypergastrinemia due to H. pylori infection could cause trophic eHects on the oxyntic mucosa and increases in parietal cell mass and gastric acid secretion. The mechanism by which H. pylori infection causes elevated mealstimulated gastrin is unclear. Ammonia produced by H. pylori urease may be involved. Lichtenherger has found in rats that gastrin response to meals depends on the amino acid content of the chow. Rats fed deamidated chow
PEPTIC L'LCER PXrIlOPIIYSIOLOC;Y
801
had a .50% reduction in gash'in response; addition of NH 4 CI to the chow returned gastrin response to normal." Sinee H. pylori lives in the nearly neutral mueus gel layer and hydrolyzes urea into ammonia and carbon dioxide, there may well be significant amounts of nonprotonated ammonia (NHJ) that ean diffuse through the antral mucosa and influence G cells. Local alkalinization of the mucus by H. pylori-produced NHJ is another possible mechanism for increased postprandial gastrin release. Preliminary data from our laboratory, with meals at pH 7, still show increased gastrin in the H. pylori patients, making local alkalinization less likely as a mechanism of postprandial hypergastrinemia. Pepsin Superficial gastritis is associated' with elevated pepsinogen 1 (PG 1), and PG 1 is a marker for peptic ulcer disease. 84 It has subsequently been discovered that superficial gastritis is most often caused by H. pylori. 77 Treatment of H. pylori in children results in a significant reduction in serum PG1levels. 65 \Vhether this reduction in PGI results in lower luminal pepsin activity is unknown. If so, this may be an explanation for the dramatic reduction in duodenal ulcer relapse rate when H. pylori is eradicated and also may be an important factor in H. pylori-related ulcer disease. Motility In some duodenal ulcer patients, rapid gastric emptying of liquids is seen; this may allow gastric acid to overwhelm duodenal acid neutralization capabilities. 57 The importance of this abnormality has yet to be determined.
MUCOSAL PROTECTION Protection of the gastrointestinal mucosa from the powerful digestive effects of acid and pepsin is a biologic imperative. It is no surprise that the protective mechanisms are somewhat redundant. The first line of the mucosal defensive network is the mucus layer, which coats gastric and duodenal mucosa. It is composed of glycoprotein, which forms a gel with water. This gel impedes diffusion of pepsin and creates an unstirred aqueous layer that helps maintain a pH gradient. Secretion of bicarbonate from gastric surface epithelial cells and duodenal mucosa is critical to maintaining a mucosal pH gradient. Pancreatic bicarbonate also is important in neutralizing the gastric acid load. 98 Through these mechanisms, gastric and duodenal mucosal pH is maintained- above 6, even when luminal pH is as low as 1. 5. 7.3 The epithelial cells resist acid and peptic destruction. The gastric epithelial cells are connected by tight junctions that help prevent acid penetration. The apical surface of the gastric mucosa is resistant enough to acid flux that monolayers in vitro can maintain a transmembrane electrical potential difference for 4 hours at pH 2.8.5 If a mucosal break does occur, epithelial cells move laterally along the basement membrane to fill the gap in a matter of hours.
802
H. R.
'vlEHTz AI\ J)
J. H.
WALSII
This process, restitution, rcquircs an intact basement membrane and a mucoid cap compriscd of extruded proteinaceous debris and bicarbonate. In animal models, maintenance of mucosal hlood flow during experimental injury is important in prevention of sevcrc mucosal damagc, -Iq and some have postulated that loss of blood flow is the difh,rence betwccn a mucosal break that hecomes a chronic ulcer and one that is rapidly repaired by restitution. Cl.5 Growth factors may play a role in healing and restitution, particularly epidermal growth factor (EGF) and transforming growth factor alpha (TGFa). These peptides share substantial homology and interact with the same receptor. mR='JA for TGFa and its receptor has been found in human gastric mucosa, particularly in the parietal cell fraction, I indicating gastric secretion and site of action of this f~lctor. EGF has heen found to stimulate gastrointcstinal mucosal DNA synthesis and ornithine decarboxylase activity in rats and mice, respcctively.I). Hi This activity may translate into improved mucosal protection or restitution. In rats, EGF has bcen found to prcvent stress-induced gastric ulcers.42 \Vhen chronic duodenal ulcers are induced by cysteamine in rats, oral urogastrone (identical to EGF) has been shown to induce healing to the same extent as cimetidine. \Vhen urogastrone and cimctidine are administered concomitantly, there is an additive benefit for healing. Sincc oral urogastrone had no effect on acid secretion in this study, it appcars the additional benefit provided by urogastrone is due to improved mucosal dcfense. 66 Abnormal Mucus Alterations in the mucus layer that protects gastric and duodenal mucosa have been found in hoth duodenal ulccr and gastric ulcer patients. Ulcer patients have an increased proportion of low molecular weight dextrans, which are associated with weaker mucus. 102 The physical propertics of gastric mucus differ between ulcer patients and controls. Hydrophohicity of gastric mucus has becn assesscd by goniometry (which determines the contact angle between mucus and a drop of water) in duodcnal and gastric ulcer patients and dyspeptic controls. There is a significant reduction in hydrophobicity in both groups of ulcer patients. Prescnce of H. pylori gastritis is associated with a significant decrease in hydrophobicity in the controls, to the same level as the ulcer patients. 93 This suggests H. pylori as the mediator of the abnormal mucus. H. pylori extracts, thought to contain an endopeptidase, have heen shown to digest gastric mucus S9 and result in decreased viscosity and increased acid permeability. S6 Trcatment of H. pylori with antibiotics, but not placebo, results in regencration of mucus, as assessed microscopically. 61 Although microscopic asscssments arc crude, these data suggcst that H. pylori causcs or cxacerbates mucus depletion. Impairment in prostaglandin production may be important in mucus depletion. Prostaglandins are endogenous mediators of mucus production 4, and may be suppressed in aspirin-induced mucus disruption. The importance of mucus disruption in thc pathogenesis of pcptic ulcer remains to be determined.
PEPTIC CLCER P~"TIIOPIIYSI()L()CY
80:3
Bicarbonate Abnormalities in the secretion of bicarbonate from the gastroduodenal mucosa have been implicated in duodenal ulcer disease. Buffering of the acid load fi~om the stomach is clearly vital to protection of the duodenum. Approximately half of the gastric acid that enters the duodenum is neutralized by bicarbonate secreted by the duodenal mucosa. The remainder is neutralized by pancreatieobiliary secretions. 22 \Vhile only about one-third of duodenal ulcer patients have abnormalities in acid secretion, most have diminished basal and peak duodenal bulb bicarbonate secretion.']3 The mechanism for decreased sccretion is unknown. Prostaglandins of the E class (PGEs) are known agonists and NSAIDs are known inhibitors of duodenal bicarbonate secretion. This is consistent with the known protective effects of prostaglandins and deleterious effects of NSAIDs on the gastrointestinal tract. Duodenal ulcer patients stimulated with luminal acid showcd a significantly lower 1 hour duodenal bicarbonate secretion despitc a 1 hour PGE 2 output nearly three times higher than in the controls. 7;] This may represent a compensatory increase in PGE 2 in response to diminished bicarbonate output. The abnormalities in bicarbonate secretion are parallelcd by loss of mucosal acid buffering capacity in duodenal ulcer patients. Mieroelectrode studics in duodenal ulcer paticnts demonstrate a greater than lO-fold increase in juxtamucosal acid concentration compared with controls when luminal pH is less than 3. 2 Few physiologic abnormalities in peptic ulcer disease are as prevalent as the impairment in duodenal bicarbonate secretion. Studies in humans show not only decrcased secretion of bicarbonate but concomitant impairment of the duodenal mucosal pH gradient. This evidence supports a major role for disordered bicarbonate secretion in duodenal ulcer (Fig. 2). Blood Flow Blood flow is clearly essential to the maintenance of gastroduodenal integrity, as it is in any tissue. Whether reductions of mucosal blood flow are clinically important in ulcer disease is difficult to say. There is abundant animal data showing that reduction in blood flow to the gastroduodenal mucosa results in acute lesion formation. In rats, the stomach is more resistant to ischemia than the duodenum. Gastric lesions are not seen until flow is reduced below a threshold of 40% of baseline. Conversely, duodenal lesion formation is related in a linear manner to reduction in flow without a threshold level. 3l Other animal data show vascular stasis in capillary beds and dccreased blood flow in response to topical 100% ethanol. Hemorrhagic mucosal lesions subsequently dcvelop. Pretreatment with dimethyl PGE 2 or sodium thiosulfate prevents the vascular changcs and lesion formation without consistently increasing baseline blood How. 71 Others have also shown dimethyl PG E2 to reduce lesion f
