Glasser Stephan W, Witt Teah L, Senft Albert P, Baatz John E, Folger Dusti, Maxfield Melissa D, Akinbi Henry T, Newton Danforth A, Prows Daniel R, Korfhagen Thomas R
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
Am J Physiol Lung Cell Mol Physiol. 2009 Jul;297(1):L64-72. doi: 10.1152/ajplung.90640.2008. Epub 2009 Mar 20.
Patients with mutations in the pulmonary surfactant protein C (SP-C) gene develop interstitial lung disease and pulmonary exacerbations associated with viral infections including respiratory syncytial virus (RSV). Pulmonary infection with RSV caused more severe interstitial thickening, air space consolidation, and goblet cell hyperplasia in SP-C-deficient (Sftpc(-/-)) mice compared with SP-C replete mice. The RSV-induced pathology resolved more slowly in Sftpc(-/-) mice with lung inflammation persistent up to 30 days postinfection. Polymorphonuclear leukocyte and macrophage counts were increased in the bronchoalveolar lavage (BAL) fluid of Sftpc(-/-) mice. Viral titers and viral F and G protein mRNA were significantly increased in both Sftpc(-/-) and heterozygous Sftpc(+/-) mice compared with controls. Expression of Toll-like receptor 3 (TLR3) mRNA was increased in the lungs of Sftpc(-/-) mice relative to Sftpc(+/+) mice before and after RSV infection. Consistent with the increased TLR3 expression, BAL inflammatory cells were increased in the Sftpc(-/-) mice after exposure to a TLR3-specific ligand, poly(I:C). Preparations of purified SP-C and synthetic phospholipids blocked poly(I:C)-induced TLR3 signaling in vitro. SP-C deficiency increases the severity of RSV-induced pulmonary inflammation through regulation of TLR3 signaling.
肺表面活性蛋白C（SP-C）基因突变的患者会患上间质性肺病以及与包括呼吸道合胞病毒（RSV）在内的病毒感染相关的肺部加重。与SP-C充足的小鼠相比，RSV肺部感染在SP-C缺陷（Sftpc(-/-)）小鼠中导致更严重的间质增厚、气腔实变和杯状细胞增生。RSV诱导的病理变化在Sftpc(-/-)小鼠中消退更慢，肺部炎症在感染后持续长达30天。Sftpc(-/-)小鼠支气管肺泡灌洗（BAL）液中的多形核白细胞和巨噬细胞计数增加。与对照组相比，Sftpc(-/-)和杂合Sftpc(+/-)小鼠的病毒滴度以及病毒F和G蛋白mRNA均显著增加。在RSV感染前后，Sftpc(-/-)小鼠肺中Toll样受体3（TLR3）mRNA的表达相对于Sftpc(+/+)小鼠增加。与TLR3表达增加一致，暴露于TLR3特异性配体聚肌胞苷酸（poly(I:C)）后，Sftpc(-/-)小鼠的BAL炎症细胞增加。纯化的SP-C制剂和合成磷脂在体外阻断了poly(I:C)诱导的TLR3信号传导。SP-C缺陷通过调节TLR3信号传导增加了RSV诱导的肺部炎症的严重程度。
