title: Sublethal hyperoxia impairs pulmonary innate immunity.
abstract: Supplemental oxygen is often required in the treatment of critically ill patients. The impact of hyperoxia on pulmonary host defense is not well-established. We hypothesized that hyperoxia directly impairs pulmonary host defense, beyond effects on alveolar wall barrier function. C57BL/6 mice were kept in an atmosphere of >95% O(2) for 4 days followed by return to room air. This exposure does not lead to mortality in mice subsequently returned to room air. Mice kept in room air served as controls. Mice were intratracheally inoculated with Klebsiella pneumoniae and followed for survival. Alveolar macrophages (AM) were harvested by bronchoalveolar lavage after 4 days of in vivo hyperoxia for ex vivo experiments. Mortality from pneumonia increased significantly in mice exposed to hyperoxia compared with infected mice in room air. Burden of organisms in the lung and dissemination of infection were increased in the hyperoxia group whereas accumulation of inflammatory cells in the lung was impaired. Hyperoxia alone had no impact on AM numbers, viability, or ability to phagocytize latex microbeads. However, following in vivo hyperoxia, AM phagocytosis and killing of Gram-negative bacteria and production of TNF-alpha and IL-6 in response to LPS were significantly reduced. AM surface expression of Toll-like receptor-4 was significantly decreased following in vivo hyperoxia. Thus sublethal hyperoxia increases Gram-negative bacterial pneumonia mortality and has a significant adverse effect on AM host defense function. Impaired AM function due to high concentrations of supplemental oxygen may contribute to the high rate of ventilator-associated pneumonia seen in critically ill patients.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Veterans Affairs Medical Center, University of Michigan, Ann Arbor, MI 48105, USA.
authors.forename: Carlos E O
authors.initials: CE
authors.lastname: Baleeiro
authors.forename: Steven E
authors.initials: SE
authors.lastname: Wilcoxen
authors.forename: Susan B
authors.initials: SB
authors.lastname: Morris
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
authors.forename: Robert
authors.initials: R
authors.lastname: Paine
mesh_terms: D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis; D018496:Hyperoxia / Q000276:immunology* / Q000401:mortality*; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007710:Klebsiella Infections / Q000276:immunology / Q000382:microbiology / Q000401:mortality / Q000503:physiopathology; D007711:Klebsiella pneumoniae / Q000254:growth & development / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D010587:Phagocytosis / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000382:microbiology / Q000401:mortality / Q000503:physiopathology; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018925:Chemokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10