Hyperoxia exaggerates bacterial dissemination and lethality in Pseudomonas aeruginosa pneumonia.
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.
Kikuchi
Yoshiaki
Y
Department of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Ohmorinishi, Ohtaku, Tokyo, Japan.
Tateda
Kazuhiro
K
Fuse
Etsu T
ET
Matsumoto
Tetsuya
T
Gotoh
Naomasa
N
Fukushima
Jun
J
Takizawa
Hajime
H
Nagase
Takahide
T
Standiford
Theodore J
TJ
Yamaguchi
Keizo
K
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
D000900:Anti-Bacterial Agents; D006657:Histones; D018942:Macrolides; D011480:Protease Inhibitors; D037521:Virulence Factors; D017963:Azithromycin; D053148:Caspase 3; D010100:Oxygen