Infectious Diseases Program, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Kent Ridge 117597, Singapore.
Am J Respir Cell Mol Biol. 2010 Jun;42(6):732-43. doi: 10.1165/rcmb.2008-0423OC. Epub 2009 Jul 17.
Recent studies have demonstrated an essential role of alveolar macrophages during influenza virus infection. Enhanced mortalities were observed in macrophage-depleted mice and pigs after influenza virus infection, but the basis for the enhanced pathogenesis is unclear. This study revealed that blocking macrophage recruitment into the lungs in a mouse model of influenza pneumonitis resulted in enhanced alveolar epithelial damage and apoptosis, as evaluated by histopathology, immunohistochemistry, Western blot, RT-PCR, and TUNEL assays. Abrogation of macrophage recruitment was achieved by treatment with monoclonal antibody against monocyte chemoattractant protein-1 (MCP-1) after sub-lethal challenge with mouse-adapted human influenza A/Aichi/2/68 virus. Interestingly, elevated levels of hepatocyte growth factor (HGF), a mitogen for alveolar epithelium, were detected in bronchoalveolar lavage samples and in lung homogenates of control untreated and nonimmune immunoglobulin (Ig)G-treated mice after infection compared with anti-MCP-1-treated infected mice. The lungs of control animals also displayed strongly positive HGF staining in alveolar macrophages as well as alveolar epithelial cell hyperplasia. Co-culture of influenza virus-infected alveolar epithelial cells with freshly isolated alveolar macrophages induced HGF production and phagocytic activity of macrophages. Recombinant HGF added to mouse lung explants after influenza virus infection resulted in enhanced BrdU labeling of alveolar type II epithelial cells, indicating their proliferation, in contrast with anti-HGF treatment showing significantly reduced epithelial regeneration. Our data indicate that inhibition of macrophage recruitment augmented alveolar epithelial damage and apoptosis during influenza pneumonitis, and that HGF produced by macrophages in response to influenza participates in the resolution of alveolar epithelium.
最近的研究表明，肺泡巨噬细胞在流感病毒感染过程中起着至关重要的作用。在流感病毒感染后，巨噬细胞耗竭的小鼠和猪的死亡率明显升高，但增强发病机制的基础尚不清楚。本研究揭示，在流感性肺炎的小鼠模型中，阻断巨噬细胞向肺部募集可导致肺泡上皮损伤和细胞凋亡加剧，这可通过组织病理学、免疫组织化学、Western blot、RT-PCR 和 TUNEL 检测评估。用针对单核细胞趋化蛋白-1（MCP-1）的单克隆抗体在亚致死性用小鼠适应的人源流感 A/Aichi/2/68 病毒攻击后处理，可以实现巨噬细胞募集的阻断。有趣的是，与用抗 MCP-1 处理的感染小鼠相比，在感染后，支气管肺泡灌洗液样本和对照未处理及非免疫性免疫球蛋白（Ig）G 处理的小鼠的肺匀浆中检测到肝细胞生长因子（HGF）水平升高，HGF 是肺泡上皮的有丝分裂原。与用抗 MCP-1 处理的感染小鼠相比，对照动物的肺组织也显示出肺泡巨噬细胞和肺泡上皮细胞增生的强烈的 HGF 染色阳性。流感病毒感染的肺泡上皮细胞与新鲜分离的肺泡巨噬细胞共培养可诱导 HGF 的产生和巨噬细胞的吞噬活性。流感病毒感染后将重组 HGF 添加到小鼠肺外植体中，导致肺泡 II 型上皮细胞的 BrdU 标记增强，表明其增殖，而抗 HGF 处理则显示出明显减少的上皮再生。我们的数据表明，抑制巨噬细胞募集会加剧流感性肺炎中的肺泡上皮损伤和细胞凋亡，并且巨噬细胞对流感的反应产生的 HGF 参与了肺泡上皮的修复。
