Hui Liu, Yao Yongming, Wang Songbai, Yu Yan, Dong Ning, Li Hongyun, Sheng Zhiyong
Department of Microbiology and Immunology, Burns Institute, First Hospital Affiliated to Chinese PLA General Hospital (formerly 304th Hospital), Beijing 100037, People's Republic of China.
J Trauma. 2009 Mar;66(3):859-65. doi: 10.1097/TA.0b013e318164d05f.
Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway plays an important role in sepsis, transducing a multitude of inflammatory signals. To date, knowledge of JAK/STAT pathway in sepsis is limited. This study was to investigate the potential role of JAK/STAT pathway in mediating multiple organ damage and mortality in septic rats. Our data showed that inhibition of JAK2/STAT3 attenuated cecal ligation and puncture-induced multiple organ damage and mortality in 48 hours in rats.
A total of 98 male Wistar rats were randomly divided into 4 groups as follows: (1) normal control group (n = 10); (2) cecal ligation and puncture (CLP) group (n = 40), which was further divided into 2, 6, 24, 48-hour post-CLP groups; (3) AG490 (8.0 mg/kg, Calbiochem, La Jolla, CA) treatment group (n = 24), which was further divided into 2, 6, 24, 48-hour post-CLP groups; (4) rapamycin (0.4 mg/kg, Calbiochem, Calbiochem, La Jolla, CA) treatment group (n = 24), which was further divided into 2, 6, 24, 48-hour post-CLP groups; CLP was performed to induce experimental sepsis. AG490 (8 mg/kg) or rapamycin (0.4 mg/kg) was injected subcutaneously 0.5 hour before CLP in respective group. Animals were killed at destined time after CLP (not including the death rate observation group), and specimens of serum, liver, and lungs were harvested and stored in liquid nitrogen for subsequent analyses. In an additional experiment, 88 animals were randomly divided into three groups to compare the survival rate, including CLP group (n = 40), AG490 treatment group (8 mg/kg, n = 24), and rapamycin treatment group (0.4 mg/kg, n = 24). Mortality of rats in each group was recorded up to 48 hours after the procedure.
After CLP challenge, myeloperoxidase (MPO), aspartate transaminase, and alanine aminotransferase levels, as well as activation of JAK2 and STAT3, were markedly increased. Administration of AG490 or rapamycin significantly decreased activation of JAK2 and STAT3, as well as high mobility group box-1 protein, MPO, alanine aminotransferase levels (p < 0.05 or p < 0.01). In addition, treatment with AG490 or rapamycin significantly improved the 48-hour survival rate from 37.5% (15 of 40) to 66.7% (16 of 24) and 70.8% (17 of 24), respectively (both p < 0.05).
JAK2/STAT3 pathway might play a role in the development of multiple organ damage in septic rats, which suggested a potential strategy to control sepsis.
Janus激酶/信号转导子和转录激活子（JAK/STAT）通路在脓毒症中发挥重要作用，可传导多种炎症信号。迄今为止，关于脓毒症中JAK/STAT通路的认识有限。本研究旨在探讨JAK/STAT通路在介导脓毒症大鼠多器官损伤及死亡中的潜在作用。我们的数据表明，抑制JAK2/STAT3可减轻盲肠结扎穿孔术诱导的大鼠48小时内多器官损伤及死亡。
总共98只雄性Wistar大鼠随机分为4组如下：（1）正常对照组（n = 10）；（2）盲肠结扎穿孔术（CLP）组（n = 40），该组进一步分为CLP术后2、6、24、48小时组；（3）AG490（8.0 mg/kg，Calbiochem，拉霍亚，加利福尼亚州）治疗组（n = 24），该组进一步分为CLP术后2、6、24、48小时组；（4）雷帕霉素（0.4 mg/kg，Calbiochem，Calbiochem，拉霍亚，加利福尼亚州）治疗组（n = 24），该组进一步分为CLP术后2、6、24、48小时组；行CLP诱导实验性脓毒症。在各自组中，于CLP前0.5小时皮下注射AG490（8 mg/kg）或雷帕霉素（0.4 mg/kg）。在CLP后预定时间处死动物（不包括死亡率观察组），采集血清、肝脏和肺组织标本并储存于液氮中以备后续分析。在另一项实验中，88只动物随机分为三组比较生存率，包括CLP组（n = 40）、AG490治疗组（8 mg/kg，n = 24）和雷帕霉素治疗组（0.4 mg/kg，n = 24）。记录每组大鼠术后48小时内的死亡率。
CLP攻击后，髓过氧化物酶（MPO）、天冬氨酸转氨酶和丙氨酸转氨酶水平以及JAK2和STAT3的激活均显著增加。给予AG490或雷帕霉素可显著降低JAK2和STAT3的激活以及高迁移率族蛋白B1、MPO、丙氨酸转氨酶水平（p < 0.05或p < 0.01）。此外，AG490或雷帕霉素治疗分别将48小时生存率从37.5%（40只中的15只）显著提高至66.7%（24只中的16只）和70.8%（24只中的17只）（均p < 0.05）。
JAK2/STAT3通路可能在脓毒症大鼠多器官损伤的发生发展中起作用，这提示了一种控制脓毒症的潜在策略。
