Role of gastric mucosal energy metabolism in the etiology of stress ulceration

It is generally agreed that mucosal ischemia of the gastrointestinal tract is one of the major consequences of the low-flow state, be it due to blood loss, fluid loss, or sepsis. In the present paper, arguments are presented in favor of the hypothesis that stress-induced mucosal injury which tends to occur preferentially in the proximal stomach, duodenum, and terminal ileum results from a mucosal energy deficit severe enough to cause cell death.

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Résumé On admet en général que l'ischémie des muqueuses digestives est une des conséquences les plus importantes des états de bas débit circulatoire, qu'ils soient dus à des pertes de sang ou de liquide ou à des infections. Certains arguments, que nous présentons dans cet article, suggèrent que les lésions muqueuses de stress, qui se développent surtout dans le fundus gastrique, dans le duodénum et dans l'iléon terminal, résultent d'un déficit d'énergie au niveau de la muqueuse, responsable de la mort cellulaire.

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Supported in part by United States Public Health Service Grant No. GM-24514.     

Superficial mucosal ulceration and the pathogenesis of acute appendicitis

Review of the appendixes and clinical histories of patients with acute appendicitis has revealed that superficial mucosal ulcers can be demonstrated frequently, particularly early in the disease and often before dilatation of the organ is demonstrable. These data support the concept that the primary lesion in acute appendicitis is superficial mucosal ulceration and is not related to obstruction of the appendiceal lumen.     

Experimental study on the pathogenesis of acute ulceration in obstructive jaundice--with reference to gastric mucosal blood flow

We prepared obstructive jaundice models in rats in order to study the mechanism of acute ulceration in obstructive jaundice centering on impediments to gastric wall blood flow and changes in gastric mucosal NA and PGE2 when the rats were subjected to water immersion restraint stress. The results were: In the obstructive jaundice 2 weeks group, when subjected to water immersion restraint stress, gastric mucosal NA reached a dried up stage from the incipient stage, causing gastric mucosal impediments at the same time, showing a significant decrease of gastric mucosal PGE2. Intragastric pH was at a similar level of excessive acidity in all groups; gastric acid is believed to be a secondary factor promoting ulceration. Gastric mucosal PGE2 showed a significant decrease coinciding with the increase in ulceration index, being a possible factor of ulceration; it is also presumed to regulate gastric wall blood flow alternatively with gastric mucosal NA. Pre-treatment with PGE2 prior to loading stress resulted in a decrease in gastric wall blood flow being significantly controlled. The administration of PGE2 brought about an improvement in gastric wall blood flow and a consequent increase in gastric mucosal NA, being judged effective for acute ulceration in obstructive jaundice.     

Stress ulceration and the gastric mucosal barrier.

The role of the gastric mucosal barrier in the pathogenesis of post-traumatic stress ulcerations is far from clear. Clinical studies on critically ill patients have shown disrupted gastric mucosal barriers with hydrogen ion back diffusion, but no correlation has been made between these findings and gastric erosions. In addition, numerous assumptions concerning gastric secretions, pyloric loss and esophageal contributions to the assayed gastric juice have to be made in these patients. There is contradictory experimental evidence concerning the theory that gastric mucosal ischemia or hypotension disrupts the normal gastric mucosal barrier. In subhuman primate studies, there is no increased back diffusion acid during hypotension or during the reinfusion periods. Even though there may not be increased permeability to H+, the presence of acid is a requirement for the development of stress ulcerations. The role of agents such as bile salts and aspirin is clearer. If these agents are present, increased back diffusion of acid is likely, but its role in the pathophysiology of post-traumatic gastric erosion awaits further clarification.     

Effect of obstructive jaundice on acute gastric ulceration viewed from gastric mucosal energy metabolism in rats

The mechanism of acute gastric ulceration in rats with obstructive jaundice was investigated in terms of the changes in the gastric mucosal energy metabolism. Rats were divided into 4 groups as follows: control, vagotomized, jaundiced, and jaundiced and vagotomized group. The water immersion and restraint procedures were performed and the ulcer index was calculated. The change of energy metabolism in the gastric mucosa of corpus and antrum was clarified by measuring ATP and energy charge. The following results were obtained: Vagotomized group showed significant decreased ulcer index, however, the gastric mucosal energy metabolism were unchanged compared to the control group after stress. Jaundiced group showed significant higher ulcer index, and the early, significant depression of the gastric mucosal energy metabolism compared to the control group. Jaundiced and vagotomized group showed significant improvement of ulcer index and gastric mucosal energy metabolism compared to the jaundiced group. The gastric energy metabolism of the corpus revealed more prominent depression than that of the antrum in jaundiced group, and jaundiced and vagotomized group. These data suggested that the deterioration of the gastric mucosal energy metabolism after stress was enhanced under the condition of obstructive jaundice and these results were improved by vagotomy.     

The maintenance of gastric mucosal barrier during the early erosive gastritis component of stress ulceration.

The spectrum of gastric stress ulceration includes early erosive gastritis, which develops within 48 hours of injury, as well as a late ulcerative component. Previous clinical studies with young healthy volunteers as controls have implicated increased back diffusion of hydrogen ions in the pathogenesis of stress ulceration. The present study compares the gastric mucosal integrity of injured patients to an age-matched control population of patients who had undergone elective intra-abdominal operations. These control patients suffered operative injury similar to that of the injured patients and yet, unlike injured patients, they did not develop clinically overt stress ulceration. The patients were studied during the first 2 days following injury and/or operation. No differences were found in the gastric mucosal permeability to hydrogen ions, as measured by back diffusion of hydrogen ions (H+BD) and by absorption of lithium (delta(Li/PSP), between the injured patients and their age-matched controls, despite the subsequent development of clinically overt stress ulceration in 25% of the injured patients. Likewise, there were no differences between the traumatized patients who developed stress ulceration and either their age-matched controls or the remainder of the traumatized patients. These date suggest that increased back diffusion of hydrogen ions cannot be implicated in the erosive gastritis which is the early component of stress ulceration.     

Focal gastric mucosal blood flow in aspirin-induced ulceration.

Focal gastric mucosal blood flow was studied during aspirin injury by hydrogen gas clearance in a chambered segment model of canine gastric corpus. Measurements were made simultaneously every 15 minutes at ulcerated and nonulcerated areas 1.5 hours before, during (20 mM of aspirin in 150 mM of HCl for 1 hour), and 2 hours after exposure of the mucosa to topical aspirin. There was a highly significant decrease (p less than 0.001) in flow at the ulcerated areas 30 minutes after exposure to aspirin, coinciding with the appearance of focal mucosal pallor followed by subsequent hemorrhagic foci and ulceration. This was not followed by recovery to basal flow values. Blood flow to the non-ulcerated areas was significantly but less severely reduced than in the ulcerated areas (p less than 0.05) 90 minutes after exposure to aspirin. This was followed by recovery to basal levels. It is proposed that aspirin induces reduction of focal mucosal blood flow of varying degrees and that mucosal areas with flow reduced to below a "critical value" develop gross damage.     

Assessment of gastric mucosal ulceration by computerized image processing

The absence of a rapid, objective, and reproducible method for assessing mucosal ulceration has long been a frustration to research in the field of gastric physiology. This study compared assessment of mucosal injury by computerized image processing with values obtained by the shed microsphere technique. An ex vivo gastric chamber model based on miniature swine was used. Five chambers were subjected to hemorrhagic shock and acid-bile solution and five chambers were maintained in normotension and exposed to normal saline (controls). After 3 hr, mucosal injury was assessed by both techniques. The chambers exposed to shock and acid-bile all developed visible ulceration ranging from 1.8 to 99.7 cm2 by computerized image processing. These values correlated well with the results obtained by the shed microsphere technique (23 to 419 mg, r = 0.99, P less than .05). No ulceration developed in the control chambers. Implementation of computerized image processing as well as its limitations is discussed.     

The role of gastric mucosal blood flow and H+ back-diffusion in the pathogenesis of acute gastric erosions.

To evaluate the relationship between ischemia and disruption of the gastric permeability barrier in the pathogenesis of acute gastric erosions, we studied the effect of (1) hemorrhagic shock, (2) topical application of p-chloromercuribenzene sulfonate (PCMBS), and (3) shock plus PCMBS on total and mucosal blood flow, H⁺ back-diffusion, and mucosal injury in 14 dogs. The fractional distribution of blood flow through the layers of gastric tissue remained unchanged during control, shock, and reinfusion periods. Exposure of the mucosa to PCMBS resulted in a significant increase in H⁺ back-diffusion, which was accompanied by a rise in mucosal blood flow. Hemorrhagic shock alone caused a marked mucosal ischemia without disruption of the permeability barrier. The severest mucosal injury occurs only under experimental conditions where ischemia and increased H⁺ back-diffusion are induced simultaneously. These results suggest that: (1) A cause-effect relationship does not exist between ischemia and barrier disruption in the pathogenesis of acute ulcerations. (2) Mucosal blood flow may play an important role in the disposal of H⁺ permeating the mucosa. (3) The ratio of mucosal blood flow to back-diffusion of H⁺ may determine the degree of mucosal injury.     

Focal gastric mucosal blood flow at the site of aspirin-induced ulceration

Focal gastric mucosal blood flow as measured by the hydrogen gas clearance method was compared with total gastric blood flow as determined by venous outflow in an isolated segment of canine stomach before, during, and after exposure to aspirin. Despite an increase in total gastric blood flow from 10.8 +/- 1.6 ml/min per chamber to 17.4 +/- 1.9 ml/min per chamber and mucosal blood flow at nonulcerated sites from 29.5 +/- 4.3 ml/min per 100 g to 83 +/- 14.4 ml/min per 100 g, mucosal blood flow at the site of aspirin-induced ulceration was significantly reduced from 29.5 +/- 4.3 ml/min per 100 g to 12.5 +/- 2.5 ml/min per 100 g. After the removal of aspirin, mucosal blood flow returned to control levels. Such a redistribution of mucosal blood flow in response to aspirin is consistent with the localized nature of acute aspirin-induced injury. The findings also explain the inability of previous methods measuring blood flow of the entire stomach to demonstrate mucosal ischemia during such injury.     

Influence of cold on stress ulceration and on gastric mucosal blood flow and energy metabolism.

"Ice-cold" gastric lavage is an important part of the treatment of bleeding from stress ulceration. The purpose of this study was to find out if cooling modifies ischemic injury of the gastric mucosa. Four series of experiments were performed in rabbits. In the first, we studied the influence of cooling on the rate of breakdown of gastric mucosal high energy phosphates during complete, ex vivo ischemia achieved by rapid excision of the stomach. We then studied the influence of cold versus warm gastric lavage on the severity of gastric mucosal injury and on the rate of breakdown of gastric mucosal adenosine phosphates during hemorrhagic shock. In a fourth series of experiments, we examined the influence of cold versus warm gastric lavage on gastric mucosal blood flow measured by injection of radioactive microspheres. Although the rate of breakdown of mucosal high energy phosphates was less rapid during a short period of complete, ex vivo ischemia when the stomach was cooled, this rate was more rapid during hemorrhagic shock under in vivo conditions when the stomach was lavaged with cold solution. The latter also increased the severity of shock-induced gastric mucosal injury. Cold gastric lavage reduced gastric mucosal blood flow before, during and after hemorrhagic shock.     

Gastric mucosal energy metabolism and "stress ulceration"

Acute gastric erosions following hemorrhagic shock (stress ulceration) have been attributed to gastric hyperacidity, altered gastric secretion of mucus and an abnormal permeability of the gastric mucosa to H(+). This report aims at presenting evidence supporting an alternate hypothesis: the event linking shock-induced gastric mucosal ischemia to mucosal necrosis is a deficit in gastric mucosal energy metabolism. Our experimental procedure consisted of harvesting the stomachs of rats and rabbits by "stop-freeze" (liquid N(2)) at different intervals after the induction of hemorrhagic shock. Levels of adenosine-phosphates and of glycolytic intermediates in gastric mucosa were measured. We studied the changes in the levels of these substrates produced by shock as well as by factors capable, when combined with shock, of rendering the gastric mucosa more vulnerable to stress ulceration. The influence of shock and of these modifying factors were evaluated by comparison with data from appropriately designed control experiments. In parallel experiments we examined the frequency of stress ulceration (gross and microscopic) under these same standard conditions. There have emerged from these studies a number of observations all based upon data with the highest statistical significance. The data are consonant with the hypothesis stated above: an energy deficit severe enough to cause cellular necrosis is the event linking shock-induced gastric mucosal ischemia and stress ulceration.     

Profile of gastric stress ulceration following acute cervical cord injury: an animal model

A reproducible model of acute gastric stress ulceration has been described in the tetraplegic rat. The characteristics of the development of acute gastric ulceration and the concentrations of plasma gastrin have been examined. There was a significant increase in gastric stress ulceration within 4 h of producing the tetraplegia. The ulceration was confined to the glandular portion of the stomach and occurred equally on crests and rugal troughs. Plasma gastrin concentrations were not changed by spinal cord section. This characterized model can serve as a basis for further investigation of the aetiology and prophylaxis of acute gastric ulceration in quadriplegia.     

Effect of gastric cold irrigation on stress ulceration

Gastric cold irrigation is widely used in the treatment of gastric bleeding. The purpose of this study was that of studying the effect of cooling on gastric mucosal lesions induced by hemorrhagic shock. The gastric transmucosal potential difference (GTPD) and the severity of ulceration were assessed in rats subjected to continuous gastric irrigation with 0.1 N HCl at a temperature of 37 or 5 degrees C. The effect of gastric cooling was evaluated in basal conditions and in rats subjected to hemorrhagic shock. Although gastric cooling has been able to cause ulcers in basal conditions, it showed a protective effect during hemorrhagic shock, reducing the degree of ulceration and improving the GTPD recovery. It is likely that the decrease in cellular metabolic requirements induced by cooling plays an important role in mucosal protection during hemorrhagic shock.     

Relationship between gastric mucosal pH and site of peptic ulceration.

Measurements of mucosal pH of resected stomachs were carried out in gastric and duodenal ulcer patients. Low mucosal pH along the lesser curvature and relatively higher gastric pepsin levels were found. It is suggested that this lower pH affects gastric ulcer occurrence in the limited "lesser curvature area" where 63 per cent of the ulcers were situated. It is also suggested that increased pepsin activity present in gastric ulcer patients may be another factor affecting gastric ulcer formation by virtue of pepsins activated at higher pH. In duodenal ulcer patients, these factors are "overshadowed" by high acid-pepsin secretory activity of gastric juice.