title: Serial histopathological examination of the lungs of mice infected with influenza A virus PR8 strain.
abstract: Avian influenza H5N1 and pandemic (H1N1) 2009 viruses are known to induce viral pneumonia and subsequent acute respiratory distress syndrome (ARDS) with diffuse alveolar damage (DAD). The mortality rate of ARDS/DAD is extremely high, at approximately 60%, and no effective treatment for ARDS/DAD has been established. We examined serial pathological changes in the lungs of mice infected with influenza virus to determine the progress from viral pneumonia to ARDS/DAD. Mice were intranasally infected with influenza A/Puerto Rico/8/34 (PR8) virus, and their lungs were examined both macro- and micro-pathologically every 2 days. We also evaluated general condition, survival rate, body weight, viral loads in lung, and surfactant proteins in serum. As a result, all infected mice died within 9 days postinfection. At 2 days postinfection, inflammation in alveolar septa, i.e., interstitial pneumonia, was observed around bronchioles. From 4 to 6 days postinfection, interstitial pneumonia with alveolar collapse expanded throughout the lungs. From 6 to 9 days postinfection, DAD with severe alveolar collapse was observed in the lungs of all of dying and dead mice. In contrast, DAD was not observed in the live infected-mice from 2 to 6 days postinfection, despite their poor general condition. In addition, histopathological analysis was performed in mice infected with a dose of PR8 virus which was 50% of the lethal dose for mice in the 20-day observation period. DAD with alveolar collapse was observed in all dead mice. However, in the surviving mice, instead of DAD, glandular metaplasia was broadly observed in their lungs. The present study indicates that DAD with severe alveolar collapse is associated with death in this mouse infection model of influenza virus. Inhibition of the development of DAD with alveolar collapse may decrease the mortality rate in severe viral pneumonia caused by influenza virus infection.
authors.affiliation: Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan. mfukushi@ri.ncgm.go.jp
authors.forename: Masaya
authors.initials: M
authors.lastname: Fukushi
authors.forename: Tateki
authors.initials: T
authors.lastname: Ito
authors.forename: Teruaki
authors.initials: T
authors.lastname: Oka
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitazawa
authors.forename: Tohru
authors.initials: T
authors.lastname: Miyoshi-Akiyama
authors.forename: Teruo
authors.initials: T
authors.lastname: Kirikae
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamashita
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kudo
mesh_terms: D000818:Animals; D002460:Cell Line; D004285:Dogs; D005260:Female; D009980:Influenza A virus / Q000472:pathogenicity*; D008168:Lung / Q000473:pathology* / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000473:pathology* / Q000821:virology