GastricHelicobacterInfection Induces a Th2 Phenotype but Does Not Elevate Serum Cholesterol in Mice Lacking Inducible Nitric Oxide Synthase

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Abstract
PersistentHelicobacter felisinfection in (C57BL/6 × 129SvEv)F1mice induces chronic gastritis. Expression of inducible nitric oxide synthase (iNOS) is upregulated in response toHelicobacterinfection. In this study, 20 10-week-old iNOS−/−mice and 20 wild-type [(C57BL/6 × 129SvEv)F1] mice were infected withH. felisby oral gavage and were assessed histologically and serologically at 32 weeks postinfection. Equal numbers of uninfected controls were sham inoculated. The mice were scored for severity of gastric inflammation, hyperplasia, glandular atrophy, and mucous metaplasia in the corpus and for the level of helicobacter colonization. The immunoglobulin G1 (IgG1), IgG2a, and IgG2c antibody responses toH. feliswere determined. As a secondary measure, serum cholesterol levels were assessed. iNOS−/−mice have a propensity for increased serum cholesterol, and although controversial, several human epidemiologic studies have demonstrated an association betweenHelicobacterinfection and several risk factors for cardiovascular disease, including elevated serum cholesterol. Nevertheless, no differences in serum cholesterol levels were observed between theH. felis-infected and -uninfected iNOS−/−mice in this study. The uninfected animals had minimal to no gastric pathology. The gastric pathology scores for the infected animals were reduced significantly in the iNOS-deficient mice relative to those for the wild-type mice (allP< 0.01).Helicobacter-infected iNOS−/−mice had chronic lymphoid infiltration and negligible to mild glandular atrophy and mucous metaplasia in the fundic mucosa, whileH. felis-infected wild-type mice had severe atrophic and metaplastic mucosal changes. The atrophic gastritis in the infected wild-type mice, particularly the female mice, was also accompanied by greater granulocytic infiltration, antral hyperplasia, and diminished antral colonization, unlike that in the infected iNOS−/−mice. iNOS−/−mice developed significantly lower Th1-associated IgG2c antibody responses toH. felis(P< 0.0003); the Th2-associated IgG1 responses were similar (P= 0.09), suggesting a greater effect of the iNOS defect on Th1 responses.H. feliscolonization was significantly greater in the iNOS-deficient mice. These findings are indicative of an impaired Th1 component of theH. felis-induced inflammatory response when the influence of iNOS is removed.