title: Hyperoxia exaggerates bacterial dissemination and lethality in Pseudomonas aeruginosa pneumonia.
abstract: Effects of hyperoxia on lethality in mice with Pseudomonas aeruginosa pneumonia were defined, and protective roles of macrolides were examined both in vitro and in vivo. Sub-lethal hyperoxia accelerated lethality of mice with P. aeruginosa pneumonia. Bacterial number was not different in the lungs, but higher in the liver of mice in hyperoxic conditions. Filter-sterilized culture supernatants of bacteria induced loss of viability of alveolar epithelial cells, which was exaggerated in hyperoxia. Metalloprotease blocking by inhibitor or gene-disruption in bacteria resulted in partial reduction of cytotoxic activity in culture supernatants. Co-culture of bacteria with sub-inhibitory concentrations of macrolides, such as azithromycin, reduced cytotoxic activity in the culture supernatants. Azithromycin provided significant survival benefit in hyperoxia-pneumonia model, which was associated with suppression of bacterial dissemination to extra-pulmonary organs. These results suggest that hyperoxia serves as an important cofactor for bacterial dissemination and lethality of P. aeruginosa pneumonia. Our data identify the potential of macrolides to protect individuals with P. aeruginosa pneumonia in the setting of hyperoxia.
authors.affiliation: Department of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Ohmorinishi, Ohtaku, Tokyo, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tateda
authors.forename: Etsu T
authors.initials: ET
authors.lastname: Fuse
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Naomasa
authors.initials: N
authors.lastname: Gotoh
authors.forename: Jun
authors.initials: J
authors.lastname: Fukushima
authors.forename: Hajime
authors.initials: H
authors.lastname: Takizawa
authors.forename: Takahide
authors.initials: T
authors.lastname: Nagase
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
authors.forename: Keizo
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D017963:Azithromycin / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D006657:Histones / Q000378:metabolism; D006801:Humans; D018496:Hyperoxia / Q000382:microbiology*; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000382:microbiology; D018942:Macrolides / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D010100:Oxygen / Q000633:toxicity; D018410:Pneumonia, Bacterial / Q000382:microbiology* / Q000401:mortality; D011480:Protease Inhibitors / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000382:microbiology* / Q000401:mortality; D011550:Pseudomonas aeruginosa / Q000235:genetics* / Q000472:pathogenicity*; D037521:Virulence Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D006657:Histones; D018942:Macrolides; D011480:Protease Inhibitors; D037521:Virulence Factors; D017963:Azithromycin; D053148:Caspase 3; D010100:Oxygen