Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan.
PLoS One. 2011;6(6):e21207. doi: 10.1371/journal.pone.0021207. Epub 2011 Jun 20.
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.
H5N1 禽流感病毒和 2009 年甲型 H1N1 流感病毒已知可引起病毒性肺炎，并随后引发弥漫性肺泡损伤（DAD）所致的急性呼吸窘迫综合征（ARDS）。ARDS/DAD 的死亡率极高，约为 60%，目前尚未建立有效的 ARDS/DAD 治疗方法。我们检测了感染流感病毒的小鼠肺部的连续病理变化，以确定从病毒性肺炎发展为 ARDS/DAD 的过程。小鼠经鼻腔感染甲型流感病毒 A/Puerto Rico/8/34（PR8）病毒，每隔 2 天对其肺部进行宏观和微观病理检查。我们还评估了一般状况、存活率、体重、肺部病毒载量和血清表面活性剂蛋白。结果，所有感染的小鼠均在感染后 9 天内死亡。感染后 2 天，在细支气管周围观察到肺泡隔炎症，即间质性肺炎。从 4 天到 6 天，伴有肺泡塌陷的间质性肺炎在整个肺部扩展。从 6 天到 9 天，所有濒死和死亡小鼠的肺部均观察到严重的肺泡塌陷性 DAD。相比之下，在感染后 2 天到 6 天，虽然感染的活鼠一般状况较差，但未观察到 DAD。此外，在为期 20 天的观察期内，用 50%的致死剂量 PR8 病毒感染小鼠进行了组织病理学分析。所有死亡小鼠均观察到伴有肺泡塌陷的 DAD。然而，在存活的小鼠中，没有 DAD，而是广泛观察到肺部的腺性化生。本研究表明，在这种流感病毒感染的小鼠模型中，伴有严重肺泡塌陷的 DAD 与死亡相关。抑制伴有严重肺泡塌陷的 DAD 的发展可能会降低流感病毒感染引起的严重病毒性肺炎的死亡率。
