Legionella-induced acute lung injury in the setting of hyperoxia: protective role of tumour necrosis factor-alpha.
Among the main characteristics of Legionella pneumophila pneumonia are acute lung injury and severe hypoxemia. Although high oxygen supplementation is a valuable supportive therapy in these patients, oxygen itself is known to be a risk factor for acute lung injury. The effects of hyperoxia on lung injury of mice with Legionella pneumonia were examined. Hyperoxia treatment reduced survival of the infected mice in an oxygen concentration- and exposure time-dependent manner. The enhanced lethality was associated with an increase in total lung weight and apoptosis markers, but not with bacterial burden in the lungs. Hyperoxia decreased the levels of the antioxidant glutathione (GSH) in infected lungs. Exogenous tumour necrosis factor-alpha (TNF-alpha) improved the survival of infected mice kept under hyperoxia. TNF-alpha effects were associated with restoration of total lung weight and histone DNA and GSH levels on day 2, whereas the lung bacterial burden did not differ significantly. Moreover, upregulation of GSH by TNF-alpha was observed in the lungs of mice without infection. These results demonstrate that hyperoxia exacerbates L. pneumophila pneumonia. The data suggest that TNF-alpha may be a potential therapeutic candidate for these individuals, not only through modulating host antibacterial systems, but also by mediating induction of the antioxidant GSH.
Departments of Microbiology1 and Pediatrics2, Toho University School of Medicine, Tokyo 143-8540, Japan 3Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109-0360, USA.
Chiharu
C
Nara
Departments of Microbiology1 and Pediatrics2, Toho University School of Medicine, Tokyo 143-8540, Japan 3Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109-0360, USA.
Kazuhiro
K
Tateda
Departments of Microbiology1 and Pediatrics2, Toho University School of Medicine, Tokyo 143-8540, Japan 3Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109-0360, USA.
Tetsuya
T
Matsumoto
Departments of Microbiology1 and Pediatrics2, Toho University School of Medicine, Tokyo 143-8540, Japan 3Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109-0360, USA.
Akira
A
Ohara
Departments of Microbiology1 and Pediatrics2, Toho University School of Medicine, Tokyo 143-8540, Japan 3Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109-0360, USA.
Shuichi
S
Miyazaki
Departments of Microbiology1 and Pediatrics2, Toho University School of Medicine, Tokyo 143-8540, Japan 3Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109-0360, USA.
Theodore J
TJ
Standiford
Departments of Microbiology1 and Pediatrics2, Toho University School of Medicine, Tokyo 143-8540, Japan 3Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109-0360, USA.
Keizo
K
Yamaguchi
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D015169:Colony Count, Microbial; D004247:DNA / Q000032:analysis; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D018496:Hyperoxia / Q000503:physiopathology*; D015850:Interleukin-6 / Q000494:pharmacology; D016952:Legionella pneumophila / Q000472:pathogenicity*; D007877:Legionnaires' Disease / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
D000975:Antioxidants; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione