Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School, Boston, MA 02115, USA.
FASEB J. 2011 Dec;25(12):4292-300. doi: 10.1096/fj.11-187955. Epub 2011 Aug 22.
Growing evidence suggests that transcription factor signal transducer and activator of transcription (Stat) 3 may play an important regulatory role during inflammation. However, the function of Stat3 in acute lung injury (ALI) is largely unknown. In the current study, by using an adenoviral vector expressing a dominant-negative Stat3 isoform (Ad-Stat3-EVA), we determined the role of Stat3 in IgG immune complex (IC)-induced inflammatory responses and injury in the lung from C57BL/6J mice. We show that IgG IC-induced DNA binding activity of Stat3 in the lung was significantly inhibited by Stat3-EVA. We demonstrate that both lung vascular permeability (albumin leak) and lung myeloperoxidase accumulation in the Ad-Stat-EVA treated mice were substantially reduced when compared with values in mice receiving control virus (Ad-GFP) during the injury. Furthermore, intratracheal administration of Ad-Stat3-EVA caused significant decreases in the contents of neutrophils, inflammatory cytokines (TNF-α and IL-6), chemokines [keratinocyte cell-derived chemokine, macrophage inflammatory protein (MIP)-1α, and MIP-1β], and complement component C5a in bronchoalveolar lavage fluids. Using Stat3-specific small interfering RNA, we show that knocking down Stat3 expression in alveolar macrophages (MH-S cells) significantly reduced the production of proinflammatory mediators on IgG IC stimulation. These data suggest that Stat3 plays an essential role in the pathogenesis of IgG IC-induced ALI by mediating the acute inflammatory responses in the lung and alveolar macrophages.
越来越多的证据表明，转录因子信号转导子和转录激活子（Stat）3 可能在炎症过程中发挥重要的调节作用。然而，Stat3 在急性肺损伤（ALI）中的功能在很大程度上是未知的。在本研究中，我们使用表达显性失活 Stat3 同工型（Ad-Stat3-EVA）的腺病毒载体，确定了 Stat3 在 IgG 免疫复合物（IC）诱导的肺部炎症反应和损伤中的作用来自 C57BL/6J 小鼠。我们表明，Stat3-EVA 显著抑制 IgG IC 诱导的肺 Stat3 的 DNA 结合活性。我们证明，与接受对照病毒（Ad-GFP）的小鼠相比，Ad-Stat-EVA 治疗的小鼠的肺血管通透性（白蛋白渗漏）和肺髓过氧化物酶积聚在损伤期间大大降低。此外，气道内给予 Ad-Stat3-EVA 导致支气管肺泡灌洗液中的中性粒细胞、炎症细胞因子（TNF-α 和 IL-6）、趋化因子[角质形成细胞衍生的趋化因子、巨噬细胞炎症蛋白（MIP）-1α 和 MIP-1β]和补体成分 C5a 的含量显著降低。使用 Stat3 特异性小干扰 RNA，我们表明，肺泡巨噬细胞（MH-S 细胞）中 Stat3 表达的敲低显著减少了 IgG IC 刺激下促炎介质的产生。这些数据表明，Stat3 通过介导肺和肺泡巨噬细胞中的急性炎症反应，在 IgG IC 诱导的 ALI 的发病机制中发挥重要作用。
