Severgnini Mariano, Takahashi Satoe, Rozo Liliana M, Homer Robert J, Kuhn Charles, Jhung Jhung W, Perides George, Steer Michael, Hassoun Paul M, Fanburg Barry L, Cochran Brent H, Simon Amy R
Pulmonary and Critical Care Division, Tufts-New England Medical Center, Boston, MA 02111, USA.
Am J Physiol Lung Cell Mol Physiol. 2004 Jun;286(6):L1282-92. doi: 10.1152/ajplung.00349.2003. Epub 2004 Jan 16.
Acute lung injury (ALI) is a devastating clinical problem with a mortality as high as 60%. It is now appreciated that ALI represents a cytokine excess state that involves the microvasculature of multiple organs. The signal transducers and activators of transcription (STAT) family of transcription factors activate critical mediators of cytokine responses, but there is limited knowledge about their role in mediating ALI. In the present study, we demonstrate that the STAT transcription factors are activated rapidly in the lungs after intraperitoneal and intranasal LPS administration in mice. We also demonstrated that LPS activates both the STAT kinases, Src and JAK, in the lung with kinetics that are consistent with STAT activation. LPS treatment resulted in STAT3 activation throughout the resident lung cells, as well as in the recruited inflammatory cells. Whereas direct LPS treatment did not lead to STAT activation in cultured epithelial or endothelial cells, IL-6 activated STAT3 in both of these cell types. Furthermore, IL-6 was induced by LPS in serum and in the lung with kinetics consistent with STAT3 activation, suggesting that IL-6 may be one mechanism of STAT activation by LPS. In addition, STAT activation required reactive oxygen species, as the overexpression of catalase in mice prevented LPS-mediated STAT activation in the lung. STATs may be a common pathway for mediating ALI, regardless of the inciting factor, as STAT activation also occurred in both a gastric acid aspiration and acute pancreatitis model of ALI. Finally, STATs are activated in the lung long before signs of ALI are present, suggesting that the STAT transcription factors may play a role in initiating the inflammatory response seen in the lung.
急性肺损伤（ALI）是一个极具破坏性的临床问题，死亡率高达60%。现在人们认识到，ALI代表一种细胞因子过量状态，涉及多个器官的微血管系统。信号转导和转录激活因子（STAT）家族转录因子激活细胞因子反应的关键介质，但关于它们在介导ALI中的作用了解有限。在本研究中，我们证明在小鼠腹腔内和鼻内给予脂多糖（LPS）后，肺中的STAT转录因子迅速被激活。我们还证明，LPS以与STAT激活一致的动力学激活肺中的STAT激酶Src和JAK。LPS处理导致驻留肺细胞以及募集的炎症细胞中STAT3激活。而直接LPS处理在培养的上皮细胞或内皮细胞中未导致STAT激活，白细胞介素-6（IL-6）在这两种细胞类型中均激活STAT3。此外，LPS在血清和肺中诱导IL-6，其动力学与STAT3激活一致，表明IL-6可能是LPS激活STAT的一种机制。另外，STAT激活需要活性氧，因为小鼠中过氧化氢酶的过表达可防止LPS介导的肺中STAT激活。无论引发因素如何，STAT可能是介导ALI的共同途径，因为在ALI的胃酸吸入和急性胰腺炎模型中也发生了STAT激活。最后，在ALI迹象出现之前很久，肺中的STAT就被激活，这表明STAT转录因子可能在引发肺中所见的炎症反应中起作用。
