Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan.
PLoS One. 2012;7(8):e42419. doi: 10.1371/journal.pone.0042419. Epub 2012 Aug 1.
Patients with influenza virus infection can develop severe pneumonia and acute respiratory distress syndrome (ARDS) which have a high mortality. Influenza virus infection is treated worldwide mainly by neuraminidase inhibitors (NAIs). However, monotherapy with NAIs is insufficient for severe pneumonia secondary to influenza virus infection. We previously demonstrated that mice infected with a lethal dose of influenza virus develop diffuse alveolar damage (DAD) with alveolar collapse similar to that seen in ARDS in humans. Additionally, pulmonary surfactant proteins were gradually increased in mouse serum, suggesting a decrease in pulmonary surfactant in the lung. Therefore, the present study examined whether combination therapy of NAI with exogenous artificial surfactant affects mortality of influenza virus-infected mice.
METHODOLOGY/PRINCIPAL FINDINGS: BALB/c mice were inoculated with several viral doses of influenza A/Puerto Rico/8/34 (PR8) virus (H1N1). The mice were additionally administered exogenous artificial surfactant in the presence or absence of a new NAI, laninamivir octanoate. Mouse survival, body weight and general condition were observed for up to 20 days after inoculation. Viral titer and cytokine/chemokine levels in the lungs, lung weight, pathological analysis, and blood O(2) and CO(2) pressures were evaluated. Infected mice treated with combination therapy of laninamivir octanoate with artificial surfactant showed a significantly higher survival rate compared with those that received laninamivir octanoate monotherapy (p = 0.003). However, virus titer, lung weight and cytokine/chemokine responses were not different between the groups. Histopathological examination, a hydrostatic lung test and blood gas analysis showed positive results in the combination therapy group.
CONCLUSIONS/SIGNIFICANCE: Combination therapy of laninamivir octanoate with artificial surfactant reduces lethality in mice infected with influenza virus, and eventually suppresses DAD formation and preserves lung function. This combination could be effective for prevention of severe pneumonia secondary to influenza virus infection in humans, which is not improved by NAI monotherapy.
流感病毒感染患者可发展为严重肺炎和急性呼吸窘迫综合征（ARDS），死亡率较高。全球范围内，流感病毒感染的治疗主要采用神经氨酸酶抑制剂（NAI）。然而，对于流感病毒感染引起的严重肺炎，NAI 单药治疗是不够的。我们之前的研究表明，感染致死剂量流感病毒的小鼠会出现弥漫性肺泡损伤（DAD），肺泡塌陷类似于人类 ARDS。此外，小鼠血清中肺表面活性蛋白逐渐增加，表明肺中肺表面活性物质减少。因此，本研究探讨了 NAI 联合外源性人工表面活性物质治疗对流感病毒感染小鼠死亡率的影响。
方法/主要发现：BALB/c 小鼠接种了几种剂量的流感 A/Puerto Rico/8/34（PR8）病毒（H1N1）。在存在或不存在新型 NAI 拉尼那米韦辛酸酯的情况下，向小鼠额外给予外源性人工表面活性物质。接种后，观察小鼠的存活、体重和一般状况，最长可达 20 天。评估病毒滴度、肺部细胞因子/趋化因子水平、肺重、病理分析以及血氧和二氧化碳压。与接受拉尼那米韦辛酸酯单药治疗的感染小鼠相比，接受拉尼那米韦辛酸酯联合人工表面活性物质治疗的感染小鼠的存活率显著提高（p = 0.003）。然而，两组之间的病毒滴度、肺重和细胞因子/趋化因子反应没有差异。组织病理学检查、静水肺试验和血气分析显示联合治疗组有阳性结果。
结论/意义：拉尼那米韦辛酸酯联合人工表面活性物质治疗可降低感染流感病毒小鼠的死亡率，并最终抑制 DAD 形成和维持肺功能。这种联合治疗可能对预防 NAI 单药治疗不能改善的流感病毒感染引起的严重肺炎有效。
