title: Hyperoxia mediates acute lung injury and increased lethality in murine Legionella pneumonia: the role of apoptosis.
abstract: Legionella pneumophila is a major cause of life-threatening pneumonia, which is characterized by a high incidence of acute lung injury and resultant severe hypoxemia. Mechanical ventilation using high oxygen concentrations is often required in the treatment of patients with L. pneumophila pneumonia. Unfortunately, oxygen itself may propagate various forms of tissue damage, including acute lung injury. The effect of hyperoxia as a cofactor in the course of L. pneumophila pneumonia is poorly understood. In this study, we show that exposure to hyperoxic conditions during the evolution of pneumonia results in a marked increase in lethality in mice with Legionella pneumonia. The enhanced lethality was associated with an increase in lung permeability, but not changes in either lung bacterial burden or leukocyte accumulation. Interestingly, accelerated apoptosis as evidenced by assessment of histone-DNA fragments and caspase-3 activity were noted in the infected lungs of mice exposed to hyperoxia. TUNEL staining of infected lung sections demonstrated increased apoptosis in hyperoxic mice, predominantly in macrophages and alveolar epithelial cells. In vitro exposure of primary murine alveolar epithelial cells to Legionella in conjunction with hyperoxia accelerated apoptosis and loss of barrier function. Fas-deficient mice demonstrated partial resistance to the lethal effects of Legionella infection induced by hyperoxia, which was associated with attenuated apoptosis in the lung. These results demonstrate that hyperoxia serves as an important cofactor for the development of acute lung injury and lethality in L. pneumophila pneumonia. Exaggerated apoptosis, in part through Fas-mediated signaling, may accelerate hyperoxia-induced acute lung injury in Legionella pneumonia.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tateda
authors.forename: Jane C
authors.initials: JC
authors.lastname: Deng
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Moore
authors.forename: Michael W
authors.initials: MW
authors.lastname: Newstead
authors.forename: Robert
authors.initials: R
authors.lastname: Paine
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Keizo
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D004847:Epithelial Cells / Q000382:microbiology / Q000473:pathology; D005260:Female; D018496:Hyperoxia / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D007877:Legionnaires' Disease / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D008168:Lung / Q000382:microbiology / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018410:Pneumonia, Bacterial / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D011650:Pulmonary Alveoli / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000235:genetics
chemical_list: D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor