Hua Feng, Ren Weiying, Zhu Lei
aDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, People's Republic of China.
Blood Coagul Fibrinolysis. 2011 Sep;22(6):480-6. doi: 10.1097/MBC.0b013e328346ef56.
Mice lacking plasminogen activator inhibitor-1 (PAI-1) did not affect lung injury induced by gram-positive bacteria pneumococcal pneumonia but worsened lung injury induced by gram-negative bacteria Klebsiella. The exact mechanisms have not been completely elucidated. In this study, we examined the signaling pathway of Toll-like receptor 4 (TLR4) with/without PAI-1 in acute lung injury (ALI) induced by lipopolysaccharides (LPS) in mice. PAI-1 knockout mice (n=60) and wild-type mice (n=60) were exposed to LPS intratracheal instillation. Different groups of mice were then sacrificed at 0 and 8 h after LPS instillation. PAI-1-/- mice showed increased excess lung water and elevated cytokines production and release. In addition, expression of TLR4 was up-regulated and the phosphorylation activation of extracellular regulating kinase (ERK) and c-Jun N-terminal kinase (JNK) were also increased in PAI-1 knockout mice compared to wild-type mice. Inversely, interleukin (IL)-1 receptor-associated kinase-M (IRAK-M) and suppressor of cytokine signaling 1 (SOCS1) were both significantly reduced in PAI-1-/-mice after LPS challenge. PAI-1 deletion increased lung injury induced by LPS through up-regulation of TLR4, ERK and C-JNK and down-regulation of TLR4 negative regulators.
缺乏纤溶酶原激活物抑制剂-1（PAI-1）的小鼠不会影响革兰氏阳性菌肺炎球菌肺炎所致的肺损伤，但会加重革兰氏阴性菌肺炎克雷伯菌所致的肺损伤。确切机制尚未完全阐明。在本研究中，我们检测了在小鼠脂多糖（LPS）诱导的急性肺损伤（ALI）中，有无PAI-1情况下Toll样受体4（TLR4）的信号通路。将PAI-1基因敲除小鼠（n = 60）和野生型小鼠（n = 60）经气管内滴注LPS。然后在LPS滴注后0小时和8小时处死不同组别的小鼠。PAI-1基因敲除小鼠表现出肺内多余水分增加以及细胞因子产生和释放升高。此外，与野生型小鼠相比，PAI-1基因敲除小鼠中TLR4的表达上调，细胞外调节激酶（ERK）和c-Jun氨基末端激酶（JNK）的磷酸化激活也增加。相反，LPS攻击后，PAI-1基因敲除小鼠中的白细胞介素（IL）-1受体相关激酶-M（IRAK-M）和细胞因子信号转导抑制因子1（SOCS1）均显著降低。PAI-1缺失通过上调TLR4、ERK和C-JNK以及下调TLR4负调节因子，增加了LPS诱导的肺损伤。
