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Although certain factors appear to predispose the host to infection by Helicobacter pylori, clearly the bacterium possesses a well-defined battery of virulence factors that allow the organism to: (1) colonize the gastric mucosa (urease, flagella, adhesins, acid-inhibitory protein, iron acquisition proteins, and heat shock proteins); (2) evade host defense (shedding of surface proteins, catalase, superoxide dismutase, and poorly reactive lipopolysaccharide); and (3) damage host tissue (vacuolating cytotoxin, protease, CagA-related factors, inducers of cytokines, and chemotaxins). Together these factors allow H. pylori to persist in the host, establishing a chronic infection. Although many of these virulence factors are produced by all strains of H. pylori, there are also well-defined pathogenicity islands (contiguous stretches of chromosomal DNA) present in some strains that encode additional proteins including CagA that potentiate virulence. Strains possessing these "virulence cassettes" are isolated more frequently from patients with the more serious clinical manifestations associated with duodenal ulcer than from patients with gastritis alone or nonulcer dyspepsia.

BACKGROUND & AIMS: Helicobacter pylori uniquely colonizes the human stomach and produces gastric mucosal inflammation. High-output nitric oxide production by inducible nitric oxide synthase (iNOS) is associated with immune activation and tissue injury. Because mononuclear cells comprise a major part of the cellular inflammatory response to H. pylori infection, the ability of H. pylori to induce iNOS in macrophages was assessed. METHODS: H. pylori preparations were added to RAW 264.7 murine macrophages, and iNOS expression was assessed by Northern blot analysis, enzyme activity assay, and NO2- release. RESULTS: Both whole H. pylori and French press lysates induced concentration-dependent NO2- production, with peak levels 20-fold above control. These findings were paralleled by marked increases in iNOS messenger RNA and enzyme activity levels. iNOS expression was synergistically increased with interferon gamma, indicating that the H. pylori effect can be amplified by other macrophage-activating factors. Studies of lipopolysaccharide (LPS) content and polymyxin B inhibition of LPS suggested that the H. pylori effect was attributable to both LPS- dependent and -independent mechanisms. CONCLUSIONS: iNOS expression in macrophages is activated by highly stable H. pylori products and may play an important role in the pathogenesis of H. pylori-associated gastric mucosal disease. (Gastroenterology 1996 Dec;111(6):1524-33)

BACKGROUND & AIMS: Helicobacter pylori surface proteins induce the production of proinflammatory mediators by mononuclear phagocytes, but the protein responsible for this stimulation has not been identified. This study determined whether urease, the major component of the soluble proteins extracted from H. pylori grown in culture, activates mononuclear phagocytes and stimulates them to produce proinflammatory cytokines. METHODS: Primary human blood monocytes were incubated with column-purified H. pylori urease and assayed by flow cytometry, Immunoassay, and reverse-transcription polymerase chain reaction for phenotypic, functional, and molecular evidence of activation. RESULTS: H. pylori urease induced monocyte expression of surface interleukin 2 receptors and increased expression of HLA-DR, phenotypic changes consistent with activation. Urease also stimulated dose-dependent production of interleukin 1 beta, interleukin 6, interleukin 8, and tumor necrosis factor alpha peptides and messenger RNA. These urease- induced phenotypic and functional changes were inhibited by preincubation of the urease with antisera to H. pylori whole bacteria, purified urease, or the 31-kilodalton subunit of urease. CONCLUSIONS: Among the soluble proteins released by H. pylori, urease is capable of activating monocytes for proinflammatory cytokines production. The local production of cytokines by urease-stimulated mononuclear phagocytes may play a central role in the development of H. pylori gastroduodenal inflammation. (Gastroenterology 1996 Aug;111(2):419-25)

with histologically proven BE were offered entry into the protocol. After initiating acid suppression with omeprazole (confirmed by gastric analysis), the patients were treated monthly with ELT. An Nd:YAG laser (SLT, Montgomeryville, PA) using free beam and contact tip technology was used. Treatments were continued until all tissue was ablated. Acid exposure was reduced by fundoplication or continued omeprazole therapy. Re-endoscopy to evaluate remission was performed after 2, 6 and 12 months. Results: 20 pts. were entered into the protocol from 6/94 to 12197; 11 males and 9 females (all Caucasian). Age was 55.3 -+ .6 years (range 32-71). The length of Barrett's was 5.1 -+ 0.7 cm (range 1-12). 3 pts. were dropped from the study because of lack of conversion; one was dropped after a complication. At entry, 4 had low grade and 2 had high grade dysplasia. A total of 107 treatments were performed with a mean of 5.3 -+ 1.2 per patient. For the 11 completed pts., at total of 66 treatments were performed (x=6.0 2.0 per patient). The duration of treatment was 11.3-+2.7 months. 3 pts. are still "in progress". 5/11 completed pts. had a Nissen fundoplication. At 2 month follow-up 11/11 (100%) were negative for BE. At 6 months, 3/5 evaluable pts. were negative for BE. At 12 months, the only evaluable patient had a recurrence of BE. In all cases of recurrence, there was substantially less BE tissue at the time of recurrence than at the time of treatment initiation. Complications included one performation (managed medically), one stricture, and one patient each with "anxiety" and agitation. Conclusions: This study demonstrates that BE can be successfully obliterated with ELT, although several treatment sessions are required. The conversion of BE to normal squamous epithelium can be maintained in most pts. by reduction of acid exposure by omeprazole or a fundoplication. However, in patients undergoing endoscopic ablation of BE, ongoing monitoring for recurrence is necessary. This work was supported in part by GCRC grant RR00349, from the NCRR/NIH.