Laninamivir Octanoate and Artificial Surfactant Combination Therapy Significantly Increases Survival of Mice Infected with Lethal Influenza H1N1 Virus
Laninamivir Octanoate and Artificial Surfactant Combination Therapy Significantly Increases Survival of Mice Infected with Lethal Influenza H1N1 Virus
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DOI：
10.1371/journal.pone.0042419
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发表时间：
2012-08-01
期刊：
影响因子：
3.7
通讯作者：
Kudo, Koichiro
中科院分区：
文献类型：
--
作者：
Fukushi, Masaya;Yamashita, Makoto;Kudo, Koichiro
背景资料：流感病毒感染可导致重症肺炎和急性呼吸窘迫综合征（ARDS），死亡率高。流感病毒感染在世界范围内主要通过神经氨酸酶抑制剂（NAIs）治疗。然而，NAIs单药治疗不足以治疗继发于流感病毒感染的重症肺炎。我们先前证明，感染致死剂量流感病毒的小鼠会发生弥漫性肺泡损伤（DAD），肺泡塌陷与人类ARDS相似。此外，小鼠血清中肺表面活性物质蛋白逐渐增加，表明肺表面活性物质减少。因此，本研究探讨是否与外源性人工表面活性剂的联合治疗NAI影响流感病毒感染mice.Methodology/Principal Findings的死亡率：BALB/c小鼠接种了几个病毒剂量的流感A/波多黎各/8/34（PR 8）病毒（H1N1）。在存在或不存在新的NAI，辛酸拉尼米韦的情况下，另外向小鼠施用外源性人工表面活性剂。接种后观察小鼠存活率、体重和一般状况长达20天。评价了肺中的病毒滴度和细胞因子/趋化因子水平、肺重量、病理学分析以及血液O-2和CO2压力。与接受辛酸拉尼米韦单药治疗的小鼠相比，辛酸拉尼米韦与人工表面活性剂联合治疗的感染小鼠显示出显著更高的存活率（p = 0.003）。然而，病毒滴度、肺重量和细胞因子/趋化因子反应在组间无差异。组织病理学检查，肺静水压试验和血气分析显示，在联合治疗group.Conclusions/Significance阳性结果：联合治疗的拉尼米韦辛酸酯与人工表面活性剂降低流感病毒感染小鼠的致死率，并最终抑制DAD的形成，并保留肺功能。这种组合可以有效地预防人类流感病毒感染继发的严重肺炎，而NAI单药治疗不能改善这种情况。
Background: 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 CO2 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.