title: Role for inducible nitric oxide synthase in protection from chronic Chlamydia trachomatis urogenital disease in mice and its regulation by oxygen free radicals.
abstract: It has been previously reported that although inducible nitric oxide synthase (iNOS) gene knockout (NOS2(-/-)) mice resolve Chlamydia trachomatis genital infection, the production of reactive nitrogen species (RNS) via iNOS protects a significant proportion of mice from hydrosalpinx formation and infertility. We now report that higher in vivo RNS production correlates with mouse strain-related innate resistance to hydrosalpinx formation. We also show that mice with a deletion of a key component of phagocyte NADPH oxidase (p47(phox-/-)) resolve infection, produce greater amounts of RNS in vivo, and sustain lower rates of hydrosalpinx formation than both wild-type (WT) NOS2(+/+) and NOS2(-/-) controls. When we induced an in vivo chemical block in iNOS activity in p47(phox-/-) mice using N(G)-monomethyl-L-arginine (L-NMMA), a large proportion of these mice eventually succumbed to opportunistic infections, but not before they resolved their chlamydial infections. Interestingly, when compared to WT and untreated p47(phox-/-) controls, L-NMMA-treated p47(phox-/-) mice resolved their infections more rapidly. However, L-NMMA-treated p47(phox-/-) mice lost resistance to chronic chlamydial disease, as evidenced by an increased rate of hydrosalpinx formation that was comparable to that for NOS2(-/-) mice. We conclude that phagocyte oxidase-derived reactive oxygen species (ROS) regulate RNS during chlamydial urogenital infection in the mouse. We further conclude that while neither phagocyte oxidase-derived ROS nor iNOS-derived RNS are essential for resolution of infection, RNS protect from chronic chlamydial disease in this model.
authors.affiliation: Microbiology Department, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, Illinois 60515, USA. kramse@.midwestern.edu
authors.forename: K H
authors.initials: KH
authors.lastname: Ramsey
authors.forename: I M
authors.initials: IM
authors.lastname: Sigar
authors.forename: S V
authors.initials: SV
authors.lastname: Rana
authors.forename: J
authors.initials: J
authors.lastname: Gupta
authors.forename: S M
authors.initials: SM
authors.lastname: Holland
authors.forename: G I
authors.initials: GI
authors.lastname: Byrne
mesh_terms: D000818:Animals; D002690:Chlamydia Infections / Q000209:etiology / Q000276:immunology*; D002692:Chlamydia trachomatis; D002908:Chronic Disease; D005260:Female; D052776:Female Urogenital Diseases / Q000209:etiology / Q000276:immunology*; D007113:Immunity, Innate; D007247:Infertility, Female; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000172:deficiency; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010586:Phagocytes / Q000201:enzymology; D010750:Phosphoproteins / Q000172:deficiency; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D014591:Uterine Diseases / Q000209:etiology / Q000276:immunology*
chemical_list: D010750:Phosphoproteins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1