TIR/BB环状拟似物AS-1对创伤失血性休克大鼠再灌注后肝损伤的影响

TIR /BB-loop mimetic AS-1 attenuates ischemia /reperfusion-triggered liver injury after traumatic hemorrhagic shock and resuscitation

目的：创伤失血性休克患者常常合并肝损伤，白细胞介素1β（ interleukin-1β， IL-1β）是参与该过程的重要炎性因子。文中通过制备创伤失血性休克模型，观察肝组织损伤相关指标，研究IL-1β通路重要信号分子髓样分化因子88（ mye-loid differentiation primary response gene 88， Myd88）的Toll IL-1受体同源区域（Toll IL-1 recptor homology， TIR）/BB环状拟似物氢化肉桂基-L-缬氨酰吡咯烷（ hydrocinnamoyl-L-valyl pyrrolidine ， AS-1）对创伤失血性休克大鼠再灌注后肝损伤的影响。方法32只雄性SD大鼠随机分为创伤失血性休克复苏组（模型组）、创伤失血性休克联合AS-1复苏组（ AS-1组）、创伤失血性休克联合溶剂复苏组（溶剂组）、对照组。模型组、AS-1组、溶剂组钳夹胫骨致骨折，股动脉放血将平均动脉压（ mean arterial pressure， MAP）降至30mmHg（1mmHg＝0．133kPa），维持于30～40mmHg 1h，以血液及林格溶液按比例于30min内匀速回输；AS-1组复苏前予AS-1（160 mg/kg）；溶剂组复苏前予等比例溶剂；对照组无处理。模型组、AS-1组、溶剂组大鼠复苏后3 h，对照组保留插管2．5 h后隔3 h，测血清天冬氨酸氨基转移酶（aspartate transaminase， AST）、丙氨酸氨基转移酶（alanine amin-otransferase， ALT）活性及IL-1β、肿瘤坏死因子α（tumor necrosis factor-α， TNF-α）的含量，测肝左叶髓过氧化物酶（myeloperoxi-dase， MPO）活性并光镜下观察其病理改变。结果与对照组比，模型组、AS-1组、溶剂组大鼠血清ALT、AST活性，IL-1β、TNF-α含量，肝组织MPO活性均明显升高（P＜0．05），病理损伤明显；与模型组、溶剂组比，AS-1组大鼠上述指标均降低（P＜0．05），而模型组、溶剂组组间差异无统计学意义（P＞0．05）。结论 TIR/BB环状拟似物AS-1可通过减少IL-1β、TNF-α含量，减少肝组织内中性粒细胞聚集来减轻创伤失血性休克大鼠再灌注后肝损伤。

Objective Traumatic hemorrhagic shock （ THS） is frequently complicated by liver injury , and IL-1βis one of the important inflammatory factors involved in this process .We ob-served changes of liver injury-related indexes in the rat model of THS and investigated the effects of AS-1, the mimic of the TIR/BB loop of Myd88, an important molecule of the IL-1βsignal pathway, on liver injury triggered by ischemia/reperfusion following THS and resuscita-tion （ THSR） in rats. Methods Thirty-two healthy male SD rats 〈br〉 were randomly divided into groups A （THSR）, B （ THSR＋AS-1）, C （THSR＋dissolution medium）, and D （control）.For those of the first three groups , fracture was induced in the left tibia , the mean arterial pressure reduced to 30 mmHg by bloodletting from the femoral artery and maintained at 30-40 mmHg for an hour , and then the rats resuscitated by infusion of blood and Ringer′s solution in proportion at a uniform speed in 30 min.Before resuscitation, the rats in group B were treated with AS-1 （160 mg/kg）, group C with dissolution medium, and group D left untreated .At 3 hours after resuscitation in groups A , B and C, and at 3 hours after 2.5h-our in-tubation in group D , we detected the activity of ALT , the levels of AST , IL-1βand TNF-α, and the activity of MPO in the left liver , and observed pathological changes in the liver by light microscopy . Results Compared with group D, groups A, B and C showed ev-ident liver injury and significant increases in the activity of ALT （87.55 ±6.8 vs 206.13 ±23.67, 110.45 ±18.20 and 210.73 ± 28.43）, AST （327.03 ±36.23 vs 621.00 ±40.61, 409.13 ±63.53 and 600.25 ±44.05）, the levels of IL-1β（327.03 ±36.23 vs 621.00 ±40.61, 409.13 ±63.53 and 600.25 ±44.05） and TNF-α（93.51 ±9.86 vs 214.13 ±21.24, 145.25 ±12.42 and 206.50 ± 36.97）, and the activity of MPO （0.90 ±0.21 vs 1.72 ±0.12, 1.20 ±0.11 and 1.67 ±0.14） （all P＆lt;0.05）.The above indexes were remarkably lower in group B than in A and C, （all P＆lt;0.05）, but with no significant differences between the latter two groups （P＆gt;0.05）.Conclusion TIR/BB-loop mimetic AS-1 can attenuate ischemia/reperfusion-induced liver injury after THSR in rats by decrea -sing the levels of IL1-βand TNF-αin the serum.