Ikegami Machiko, Falcone Angelica, Whitsett Jeffrey A
Cincinnati Children's Hospital, Div. of Pulmonary Biology, Cincinnati, OH 45229-3039, USA.
J Appl Physiol (1985). 2008 Jun;104(6):1753-60. doi: 10.1152/japplphysiol.00875.2007. Epub 2008 Mar 27.
Acute lung injury associated with surfactant deficiency remains a major cause of pulmonary morbidity and mortality. Since signal transducer and activator of transcription-3 (STAT-3) plays an important role in protecting respiratory epithelial cells during injury, we hypothesized that STAT-3 may regulate gene expression in type II cells that mediate surfactant phospholipid synthesis. Conditional deletion of Stat-3 in respiratory epithelial cells in the lung of transgenic mice (Stat-3(Delta/Delta) mice) decreased surfactant phospholipid synthesis and secretion. Deletion of Stat-3 was associated with decreased expression of Akt2, Srebf-1, and other genes expressed in type II cells that may influence surfactant phospholipid synthesis (Glut-1, Slc34a2, Gpam, Acox2, and Cds2). Stat-3(Delta/Delta) mice were more susceptible to intratracheal lipopolysaccharide (LPS). Saturated phosphatidylcholine and surfactant protein B levels were significantly decreased in bronchoalveolar lavage fluid from LPS-treated Stat-3(Delta/Delta) mice. Alveolar capillary leak, proinflammatory cytokine expression, and perturbations of lung mechanics caused by LPS were exacerbated after deletion of STAT-3. STAT-3 plays a critical role in the regulation of surfactant lipid synthesis in the normal lung and during lung injury caused by LPS.
与表面活性剂缺乏相关的急性肺损伤仍然是肺部发病和死亡的主要原因。由于信号转导和转录激活因子3（STAT-3）在损伤期间保护呼吸道上皮细胞中起重要作用，我们推测STAT-3可能调节II型细胞中介导表面活性剂磷脂合成的基因表达。转基因小鼠肺中呼吸道上皮细胞中Stat-3的条件性缺失（Stat-3(Delta/Delta)小鼠）降低了表面活性剂磷脂的合成和分泌。Stat-3的缺失与Akt2、Srebf-1以及II型细胞中表达的可能影响表面活性剂磷脂合成的其他基因（Glut-1、Slc34a2、Gpam、Acox2和Cds2）的表达降低有关。Stat-3(Delta/Delta)小鼠对气管内脂多糖（LPS）更敏感。LPS处理的Stat-3(Delta/Delta)小鼠支气管肺泡灌洗液中的饱和磷脂酰胆碱和表面活性剂蛋白B水平显著降低。STAT-3缺失后，LPS引起的肺泡毛细血管渗漏、促炎细胞因子表达和肺力学紊乱加剧。STAT-3在正常肺以及LPS引起的肺损伤期间表面活性剂脂质合成的调节中起关键作用。
