title: Inducible nitric oxide synthase contributes to immune dysfunction following trauma.
abstract: Trauma results in a persistent depression in adaptive immunity, which contributes to patient morbidity and mortality. This state of immune paralysis following trauma is characterized by a change in cell-mediated immunity, specifically a depression in T-cell function and a shift toward TH2 T-cell phenotype. Upregulation of inducible nitric oxide synthase (iNOS) is well recognized after injury and contributes to the inflammatory response and organ damage early after trauma. However, it is unknown whether iNOS plays a role in adaptive immune dysfunction after trauma. This study utilized a murine model of severe peripheral tissue injury to show that iNOS is rapidly upregulated in macrophages and a (Gr-1-CD11b) myeloid-derived suppressor cell subpopulation in the spleen. Through the use of iNOS knockout mice, a specific iNOS inhibitor, and a nitric oxide (NO) scavenger, this study demonstrates that iNOS-derived NO is required for the depression in T-lymphocyte proliferation, interferon γ, and interleukin 2 production within the spleen at 48 h after trauma. These findings support the hypothesis that iNOS regulates immune suppression following trauma and suggest that targeting the sustained production of NO by iNOS may attenuate posttraumatic immune depression.
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Sophie S
authors.initials: SS
authors.lastname: Darwiche
authors.forename: Roman
authors.initials: R
authors.lastname: Pfeifer
authors.forename: Christoph
authors.initials: C
authors.lastname: Menzel
authors.forename: Xiangcai
authors.initials: X
authors.lastname: Ruan
authors.forename: Marcus
authors.initials: M
authors.lastname: Hoffman
authors.forename: Changchun
authors.initials: C
authors.lastname: Cai
authors.forename: R Savanh
authors.initials: RS
authors.lastname: Chanthaphavong
authors.forename: Patricia
authors.initials: P
authors.lastname: Loughran
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pitt
authors.forename: Rosemary
authors.initials: R
authors.lastname: Hoffman
authors.forename: Hans-Christoph
authors.initials: HC
authors.lastname: Pape
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
mesh_terms: D000818:Animals; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D014947:Wounds and Injuries / Q000201:enzymology / Q000235:genetics / Q000276:immunology*
chemical_list: D007376:Interleukin-2; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse