Superoxide anion and nitric oxide in high-grade esophagitis induced by acid and pepsin in rabbits.

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.

Nitric oxide and superoxide anion in low-grade esophagitis induced by acid and pepsin in rabbits.

It has been suggested that free radicals are involved in esophagitis. To study the role and potential interaction of superoxide anion and nitric oxide (NO) in low-grade esophagitis, we perfused acidified pepsin (30 min every 12 hr) for seven days in rabbits treated with different agents to modulate the generation of these radicals. Measurements included macroscopic and microscopic damage, superoxide anion generation, mucosal nitric oxide synthase activity, and peroxynitrite formation. Low-grade esophagitis was associated with increased nitric oxide synthase mucosal activity and mucosal damage was dose-dependently increased by treatment with the NO synthase inhibitor NG-nitro-L-arginine. Superoxide anion was scarcely generated in the mucosa, but this was not accompanied by any change in the activity of mucosal superoxide dismutase. Treatment with superoxide dismutase did not improve mucosal damage. Generation of peroxynitrites was not detected. In conclusion, nitric oxide is involved in the mucosal defense of the esophagus against acid- and pepsin-induced damage. Superoxide anion generation seems irrelevant in the induction of low-grade esophagitis and not sufficient to interact with nitric oxide to generate measurable mucosal peroxynitrite radicals.

Experimental esophagitis induced by acid and pepsin in rabbits mimicking human reflux esophagitis.

BACKGROUND & AIMS: The lack of appropriate animal models might explain the paucity of information on the mechanisms of mucosal damage and defense in reflux esophagitis. The aim of this study was to develop a model of esophagitis in rabbits mimicking human reflux esophagitis. METHODS: New Zealand white rabbits underwent surgery for placement of a plastic tube into the cervical esophagus. Acidified pepsin (AP) was intermittently perfused for different periods. Esophageal injury was assessed by macroscopic and microscopic examination, including the cell proliferation immunohistochemical parameter mib1. RESULTS: Rabbit losses (20%) were attributable mostly to postsurgical mortality and tube displacement. Perfusion of AP for 60 min/12 h or 45 min/12 h induced high-grade esophagitis by days 3 and 5, respectively, characterized by diffuse erosion/ulceration, inflammation, bleeding, and reactive epithelial changes. Perfusion of acidified pepsin for 60 min/day, especially at 30 min/12 h, induced low-grade esophagitis characterized by superficial epithelial loss, mild/absent inflammation, and epithelial reactive changes including increased cell proliferation, basal hyperplasia, and papillomatosis, which reached maximal expression by day 7. This perfusion regimen induced mucosal adaptation to damage. CONCLUSIONS: Different and highly reproducible esophageal mucosal lesions mimicking human reflux esophagitis can be induced in rabbits with repetitive acid and pepsin exposure.