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The pathogenesis of peptic ulcer disease is multifactorial, including the effects of Helicobacter pylori, gastric acid, pepsin, gastroduodenal motility, smoking and nicotine, and the complex interaction of an array of other so-called aggressive and protective factors. Since the discovery and acceptance of H. pylori as a major etiologic agent in peptic ulcer disease, the role of smoking has received less attention. Smokers are more likely to develop ulcers, ulcers in smokers are more difficult to heal, and ulcer relapse is more likely in smokers. These clinical observations may be explained by the adverse effects that smoking has on mucosal aggressive and protective factors. Of the aggressive factors, smoking appears to have no consistent effect on acid secretion. However, smoking impairs the therapeutic effects of histamine-2 antagonists, may stimulate pepsin secretion, promotes reflux of duodenal contents into the stomach, increases the risk for and harmful effects of H. pylori, and increases production of free radicals, vasopressin, secretion by the pituitary, secretion of endothelin by the gastric mucosa, and production of platelet activating factor. Smoking also affects the mucosal protective mechanisms. It decreases gastric mucosal blood flow and inhibits gastric mucous secretion, gastric prostaglandin generation, salivary epidermal growth factor secretion, duodenal mucosal bicarbonate secretion, and pancreatic bicarbonate secretion. These adverse effects of smoking on aggressive and protective factors quality it as an important contributor to the pathogenesis of peptic ulcer disease and indicate that smoking plays a significant facilitative role in the development and maintenance of peptic ulcer disease.

Renewal of the gastrointestinal (GI) epithelium fulfills the normal functions of maintaining the integrity of the mucosa, repairing mucosal injury, and replenishing the specialized cells of the epithelium. Alterations in epithelial renewal also are intimately involved in transformation of the epithelium to benign and malignant neoplasms. Certain abnormalities in epithelial proliferation, including an increase in the rate of proliferation and expansion of proliferating cells beyond the normal zone of proliferation, are closely linked to the predisposition for and frank development of GI cancer. These abnormalities are common to all human premalignant conditions studied, including Barrett's epithelium, chronic gastritis, inflammatory bowel disease, and colon polyps; they also occur in experimental carcinogenesis. The same proliferative abnormalities have also been observed in some relatives of patients with colon neoplasms who themselves do not have any colon polyps or cancer. Several agents, including calcium, vitamins A, C, and E, and omega-3 fatty acids, have been shown to reverse the abnormal proliferation under some laboratory and clinical conditions. Moreover, some nonsteroidal anti-inflammatory drugs appear to decrease the size of colon polyps in familial polyposis and to reduce the risk for colon cancer in the general population. We await further clinical trials that will indicate whether such ordinary supplements as calcium, vitamins, fish oil, or aspirin have a role in the treatment of patients with premalignant conditions of the gastrointestinal tract.

The constant rapid renewal of the epithelium of the gastrointestinal (GI) tract is important in the development of neoplasms that are derived from the epithelium as well as in maintaining the functional integrity of the mucosa. An abnormality of epithelial proliferation, characterized by an increase in numbers of proliferating cells and expansion of the proliferative zone, is common to all human premalignant conditions of the GI tract that have been studied, including Barrett's epithelium, chronic gastritis, ulcerative colitis, and colonic polyps, and is a consistent observation after the use of experimental carcinogens, such as N-methyl-N-amylnitrosamine and N-methyl-N'-nitro-N-nitrosoguanidine. These abnormalities also have been observed in some relatives of patients with colonic polyps or cancers who themselves do not have any demonstrable colonic lesion. Calcium, vitamins A, C, and E, and other agents have been shown to reverse the abnormalities in proliferation in some experimental and clinical conditions, which raises the question of whether some of these agents can be used to reduce the risk of development of cancer in patients with known premalignant conditions of the GI tract.

The constant, rapid renewal of the gastroduodenal epithelium is an important mechanism of mucosal protection because it maintains the functional integrity of the epithelium. It also is necessary for the repair of mucosal injury. Aspirin, indomethacin, and ethanol all have been shown to stimulate epithelial proliferation in the experimental setting. The stimulatory effects of these agents may be a compensatory reaction to mild injury and may contribute to the process of mucosal adaptation. On the other hand, corticosteroids, physiologic stress, and smoking appear to depress epithelial proliferation, which could render the mucosa susceptible to the effects of other ulcerogens as well as retard the healing of existing mucosal lesions. Epithelial proliferation in mucosa adjacent to active duodenal ulcers as well as from nonulcerated duodenitis is increased when compared to normal-appearing mucosa. This stimulation of epithelial proliferation may be caused by inflammation; it is not known whether ulcer patients have a defect in epithelial proliferation that precedes ulceration. Although prostaglandins (PGs) protect ulceration. Although prostaglandins (PGs) protect the gastroduodenal mucosa, the weight of evidence indicates that PGs do not have a primary effect on epithelial proliferation but rather retard senescence and loss of epithelial cells. The result is thickening of the mucosa, which may contribute to the protective effects of PGs. Ulcerogenic agents or conditions may either depress epithelial proliferation, which predisposes to ulceration or the ulcerogenic effects of other ulcerogens, or result in a hyperproliferative response, which may contribute to the process of mucosal adaptation and protection.

We have previously shown that chronic steroid administration delays the healing of experimental gastric ulcers in rats. This study was designed to test the beneficial effects of 16,16-dimethylprostaglandin E2 or TRY-200, a stable prostaglandin I2 analogue, on the delayed healing by hydrocortisone (HC) of chronic gastric ulcers in rats. Chronic gastric ulcers were produced in male Wistar rats, weighing 180 g, by serosal application of 100% acetic acid. The rats were randomly divided into six groups: (1) saline, (2) saline, HC-treated, (3) 10 micrograms/kg of 16,16-dimethylprostaglandin E2, (4) TRY-200, a stable prostaglandin I2 analogue, at 5 micrograms/kg, or (5) 10 micrograms/kg, or (6) 30 micrograms/kg. All rats, except for control, were given daily intraperitoneal injection of 2.5 mg/kg of HC sodium phosphate. Tested drugs were administered intragastrically twice a day for 2 weeks. Rats were killed 14 days later and ulcer size was measured. Chronic administration of HC sodium phosphate resulted in a significant delay of ulcer healing induced by acetic acid. Treatment with TRY-200 at 10 or 30 micrograms/kg abolished the deleterious effect of steroids, whereas 16,16-dimethylprostaglandin E2 had no effect. These results indicate that prostaglandin I2 is more effective than prostaglandin E2 in reversing the delayed healing by steroids of chronic gastric ulcers in the rat.

To study the effects of a single parenteral dose of indomethacin on gastric epithelial proliferation, we performed the following study. Male Wistar rats weighing about 200 g were divided into two groups and given single intraperitoneal injections of indomethacin 5 mg/kg, either suspended in 0.5% carboxymethyl cellulose sodium salt or vehicle alone, after an overnight fast. After 6 h, all rats were injected by tail vein with tritiated thymidine, 1 microCi/g body weight, to label proliferating cells and were killed 1 h later. Sections from fundic and antral mucosae were processed for light autoradiography. Parenteral indomethacin resulted in spotty erosions in fundic mucosa. Histologically, there was congestion with or without epithelial disruption. These areas were excluded in the proliferation measurements. There was a significant decrease not only in the number of labeled cells but also in the thickness of the proliferative zone with the thinning of the entire mucosal thickness in the fundic mucosa. None of the measurements in antral mucosa showed significant difference. These results showed that a single parenteral injection of indomethacin inhibits epithelial proliferation and decreases mucosal thickness in fundic, but not antral mucosa of the rat.

Unlabelled: To study the effects of (a) cold restraint stress and (b) adrenalectomy in association with cold restraint stress on gastric mucosal ulceration and prostaglandin generation, we performed two experiments. In the first, 40 rats were divided into four groups of 10 rats each: (a) unstressed and (b) stressed for 0.5 h, (c) stressed for 2 h, and (d) stressed for 4 h. In the second experiment, another 80 rats were divided into four groups of 20 rats each: (a) adrenalectomy plus cold restraint stress for 2 h, (b) adrenalectomy plus no stress, (c) sham operated plus 2 h of stress, and (d) sham operated plus no stress. In both experiments we recorded an ulcer index and measured mucosal generation of prostaglandin E2 (PGE2) and prostaglandin I2 (6-keto-PGF1a)., In Conclusion: (a) Cold restraint stress is associated with a time-dependent decrease in gastric mucosal PGE2 generation, but no change in 6-keto-PGF1a generation, and an increase in mucosal injury that is maximal by 2 h. (b) Adrenalectomy augments the effects of stress on mucosal injury but has no effect on prostaglandin generation; thus, the ulcerogenic effect of adrenalectomy appears to be independent of an effect on prostaglandin generation.

The natural history of peptic ulcer disease shows a high rate of recurrence over the short term, with the recurrence rate decreasing over a period of many years. Drug therapy does not appear to alter the natural history of the disease. Smoking increases the risk of ulcer recurrence by increasing the rate of gastric emptying, diminishing the secretion of pancreatic bicarbonate, decreasing duodenal luminal pH, reducing mucosal blood flow, and inhibiting mucosal prostaglandin synthesis. There is a probable role for routine maintenance therapy in patients with known recurrent ulcer disease.

A 65-year-old woman suffered from both chronic gastroesophageal reflux, which was complicated by columnar metaplasia (Barrett's epithelium), and profound hypothyroidism. An esophageal motility tracing showed absence of peristalsis in the lower esophagus and the lower esophageal sphincter (LES) could not be identified. Thyroid replacement therapy, in conjunction with antacid and cimetidine treatment, was associated not only with improvement in the gastroesophageal reflux symptoms, but also with a return of esophageal peristalsis and LES pressure to normal. To support our clinical observations, we rendered four cats hypothyroid with 131I and documented a fall in LES pressure. We propose that abnormal smooth-muscle function of the esophagus may be another manifestation of the gastrointestinal motility disturbances which are associated with hypothyroidism.

Three aspects of the esophageal mucosal injury that occur in gastroesophageal reflux disease are discussed in this article. First, the histologic changes in the squamous epithelium-lined esophagus are variable. Some patients with reflux symptoms do not have histologic evidence of inflammatory cell infiltration within the mucosa, but rather may have more subtle effects of mucosal injury, namely, thickening of the basal regenerative layer, elongation of the papillae, or intraepithelial eosinophils. However, these more subtle findings often are merely confirmatory of other clinical indicators of gastro-esophageal reflux; they may have their most practical application to the research investigation of reflux disease. Second, the presence of esophageal mucosal inflammation may adversely affect lower esophageal sphincter function. This phenomenon can be demonstrated in the cat model. Whether it is operative in humans is unclear. Finally, the development of columnar metaplasia (Barrett's epithelium) is more than a histologic curiosity because this condition confers an increased risk of developing adenocarcinoma of the esophagus. Among several unanswered questions about Barrett's epithelium is what is an appropriate surveillance program for patients with Barrett's epithelium to detect the presence of, or predict the development of, cancer?

Cigarette smoking appears to be a risk factor for the development, maintenance, and recurrence of peptic ulcer disease. Smoking has an inconsistent effect on gastric acid secretion, but it does have other effects on upper gastrointestinal function that could contribute to the pathogenesis of peptic ulcer disease. These include (a) interference with the action of histamine-2 antagonists, (b) acceleration of gastric emptying of liquids, (c) promotion of duodenogastric reflux, (d) inhibition of pancreatic bicarbonate secretion, (e) reduction in mucosal blood flow, and (f) inhibition of mucosal prostaglandin production. Because these effects are related directly to the act of smoking and cessation of smoking is associated with the prompt recovery of the respective functions, smokers will benefit immediately by stopping or reducing cigarette consumption.

We performed upper gastrointestinal endoscopy in 60 rural Haitian patients who complained of chronic upper abdominal pain. Twenty-five of 37 men (68%) and 5 of 23 women (22%) had abnormal findings. In men the predominant abnormalities were severe duodenal ulcer, duodenitis, and pyloroduodenal obstruction; duodenal ulcer or duodenitis appeared to precede obstructive disease by about 20 years. In women the abnormal findings invariably were milder than in men and consisted of duodenal ulcer, duodenitis, and gastritis. These observations as well as the observations of others indicate that peptic ulcer disease is common in developing countries, particularly among men. We hypothesize that this familiar abnormality reported from unfamiliar places represents the ordinary spectrum of peptic ulcer disease, but that inadequate treatment of recurrent episodes over time leads to obstruction. Physicians need to learn more about the epidemiology of peptic disease in developing countries and to devise better methods of effective treatment to prevent the late complication of gastric outlet obstruction.