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Epidemiological studies have shown that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduction of gastrointestinal cancer risk. Since up-regulation of COX-2 has been reported in different stages of the esophageal and gastric carcinogenic sequence, the cyclooxygenase-2 selective inhibitors (COXIBs) were considered a good alternative to traditional NSAIDs since they cause less injury to the gastrointestinal mucosa. However, recent chemoprevention trial data reporting an increased risk of cardiovascular events have raised serious concerns on the safety of COXIBs in chemoprevention strategies. Moreover, low expression of COX-2 has been reported in a subset of gastrointestinal cancers due to COX-2 methylation, indicating that these patients could be less responsive to treatment by specific COX-2 inhibitors. Furthermore, the COX-1 isoform may have a potential role in the angiogenic process associated with esophageal adenocarcinoma, which suggests that inhibition of COX-1 may be another effective therapeutic target in upper gastrointestinal cancer. Finally, lipoxygenase-derived products may be increased following COX-inhibition due to shunting of the arachidonic acid metabolism. Specifically, the 5-LOX pathway seems to be relevant in gastrointestinal cancer development. Taken together, these data indicate that a re-evaluation of potential chemoprevention strategies for cancers of the upper gastrointestinal tract needs to be considered.

Nitric oxide (NO) exerts both protective and proinflammatory actions in the gastrointestinal tract. Enhanced gastric NO synthase (NOS) activity has been shown in duodenal ulcer patients. Recently, intron-4 polymorphism of the endothelial constitutive (ec) NOS gene has been associated with some pathological conditions. Our aim was to determine the genotype and allele frequencies of the ecNOS4 polymorphism in peptic ulcer patients. The distribution of the polymorphism ecNOS4a/b was studied in 188 ulcer patients and 120 healthy controls, from genomic DNA. Genotypes ab, bb, and aa and allele frequency were similar in both peptic ulcer patients and controls, and no differences were found when patients and controls were analyzed according to the presence of several etiological factors. However, alelle “a” carrier status was associated with decreased risk of bleeding in duodenal ulcer patients (OR = 0.49; 95% CI = 0.25–0.95; P = 0.03). In conclusion, this ecNOS4 polymorphism gene could be related to susceptibility of duodenal ulcer patients to bleeding.

It has been proposed that free radicals are involved in the pathogenesis of esophageal mucosal damage induced by acid and pepsin. Recent data have suggested that nitric oxide (NO) is involved in the mucosal defense of the esophagus and that superoxide anion plays a minor role in low-grade esophagitis. To study the role and potential interaction of NO and superoxide anion in an experimental model of high-grade esophagitis, acidified pepsin was perfused (45 min/12 hr) for five days in rabbits with different agents to modulate the generation of these radicals. Measurements included both macroscopic and microscopic mucosal damage, superoxide anion generation, NO synthase mucosal activity, and peroxynitrite formation. High-grade esophagitis was associated with mucosal superoxide anion generation. Treatment with exogenous superoxide dismutase completely prevented mucosal damage. The perfusion of acidified pepsin in the lumen of the esophagus was initially associated with increased NO synthase mucosal activity but decreased with the progression of damage. Generation of peroxynitrites was present in those cases with severe damage. Treatment with NO-modifying agents did not induce consistent modification of mucosal damage. It is concluded that superoxide anion is involved in the induction of high-grade esophagitis and that it interacts with nitric oxide to generate peroxynitrite radicals in this model. Superoxide dismutase but not NO-donor-modifying agents might have a therapeutic role in preventing severe esophageal mucosal damage induced by acid and pepsin.

Factors and mechanisms involved in esophagealmucosal injury and repair are not well known. The aim ofthis study was to assess the effects of growth factorsand prostaglandins on esophageal mucosal cell repair activities. Rabbit esophageal cells wereisolated, cultured, and exposed to different growthfactors and prostaglandin E2. Subconfluentcell cultures were used to study proliferative responsesdetermined by [3H]thymidine incorporation intoDNA. Restitution was studied in confluent monolayerswounded by mechanical denudation. Restitution was themain mechanism involved in wound repair within the first24 hr. HGF, IGF-I, and EGF dose-dependentlystimulated cell proliferation but did not affectrestitution. TGF-β1inhibited bothproliferation and restitution while PDGF-BB andprostaglandin E2had no effect. Esophageal epithelial cell restitution andproliferation are affected by growth factors. HGF,IGF-I, EGF (stimulation), and TGF-β1(inhibition) are major growth factors affecting in vitroesophageal wound repair activities, which, unlike those ofother areas of the digestive tract, are not affected byprostaglandins.

Unlike gastric mucosa, it has been considered that lipoxygenase metabolites protect the esophageal mucosa and that prostaglandins are only secreted in the presence of esophageal inflammation. The aim of this study was to determine the profile of arachidonic acid metabolites and their response to regulatory compounds in rabbit esophageal mucosal cells in culture. Eicosanoids secreted into the medium were extracted and identified by HPLC and RIA. Esophageal mucosal cells in culture metabolized arachidonic acid mainly through the cycloxygenase pathway and PGE2was the major arachidonic acid metabolite secreted. The addition of IL-1β and A23187 (calcium ionophore) stimulated PGE2synthesis. In basal conditions neither leukotrienes nor HETEs were detected. However, the addition of the NDGA induced the secretion of lipoxygenase metabolites identified as 12–15 HETEs. In conclusion, rabbit esophageal epithelial cells in culture metabolize arachidonic acid via both cycloxygenase and lipoxygenase pathways. In our system, PGE2was the main arachidonic acid metabolite.

Erythroid atrophy developed rapidly in Cebus monkeys when they were fed a protein-free diet. When refed, there was an initial erythroid hyperplasia followed by a return to control normoblast counts. The findings confirm the observations previously made in patients with kwashiorkor and marasmus and support the postulate that the basic mechanism producing the anemia of protein deficiency is an atrophy of the erythropoietic tissue.

Erythroid atrophy developed rapidly in Cebus monkeys when they were fed a protein-free diet. When refed, there was an initial erythroid hyperplasia followed by a return to control normoblast counts. The findings confirm the observations previously made in patients with kwashiorkor and marasmus and support the postulate that the basic mechanism producing the anemia of protein deficiency is an atrophy of the erythropoietic tissue.