BML-111 通过抑制 MAPK 通路抑制失血性休克大鼠肾组织的炎症反应和细胞凋亡。
BML-111 inhibits the inflammatory response and apoptosis of renal tissue in rats with hemorrhagic shock by inhibiting the MAPK pathway.
机构信息
Department of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
出版信息
Eur Rev Med Pharmacol Sci. 2018 Jun;22(11):3439-3447. doi: 10.26355/eurrev_201806_15168.
OBJECTIVE
The effect of lipoxin receptor agonist BML-111 on acute kidney injury and AKI in rats with hemorrhagic shock (HS) and its mechanism were investigated.
MATERIALS AND METHODS
A model of hemorrhagic shock in Sprague-Dawley (SD) rats was established, and recovered after 30 min of shock. 1 mg/kg BML-111 was intraperitoneally injected at the beginning of resuscitation in group BML-111. The concentration of serum creatinine, serum KIM-1 content, NGAL and inflammatory factors were detected. Renal tissue injury was examined by HE staining; TUNEL staining was used to detect the apoptosis of rat kidney cells. Western blot was performed for the detection of the expression level of MAPK (mitogen-activated protein kinase), Bax, cytochrome C and caspase-3,9 in rat renal tissue.
RESULTS
HE staining showed pathological changes in groups group comparing to sham group. BML-111 group had a significant decrease in renal tissue injury. The scores of renal injury in each group were in accordance with the histological changes. The expression level of inflammatory factors in HS group was significantly higher than that in sham group (p<0.05). After BML-111 intervention, the levels of inflammatory factors in renal tissue were significantly lower than those in HS group (p<0.05). Meanwhile, NGAL and KIM-1 also showed the same trend. TUNEL staining showed that compared with sham group, the number of apoptotic cells in renal tissue of HS group increased significantly, and the apoptosis rate of renal tissue cells in group BML-111 decreased significantly. Western blot showed that the expression level of JNK, p38MAPK, and apoptosis-related protein in HS group was significantly increased, whereas the expression level of p38MAPK and JNK in group BML-111 was significantly decreased.
CONCLUSIONS
BML-111 can reduce the inflammatory response and apoptosis of renal tissue by inhibiting the activation of MAPK signaling pathway in acute renal injury induced by hemorrhagic shock.
目的
研究脂氧素受体激动剂 BML-111 对失血性休克（HS）大鼠急性肾损伤（AKI）及 AKI 的作用及其机制。
材料与方法
建立 Sprague-Dawley（SD）大鼠失血性休克模型，休克 30min 后复苏，BML-111 组于复苏开始时腹腔注射 1mg/kg BML-111。检测血清肌酐浓度、血清 KIM-1 含量、NGAL 和炎症因子。HE 染色观察肾组织损伤；TUNEL 染色检测大鼠肾细胞凋亡情况。Western blot 检测大鼠肾组织 MAPK（丝裂原活化蛋白激酶）、Bax、细胞色素 C 和 caspase-3、9 的表达水平。
结果
HE 染色显示各实验组与 sham 组相比均有组织病理学改变。BML-111 组肾组织损伤明显减轻。各组肾损伤评分与组织学变化一致。HS 组炎症因子表达水平明显高于 sham 组（p<0.05）。BML-111 干预后，肾组织中炎症因子水平明显低于 HS 组（p<0.05）。同时，NGAL 和 KIM-1 也呈现相同的趋势。TUNEL 染色显示与 sham 组相比，HS 组肾组织细胞凋亡数明显增加，BML-111 组肾组织细胞凋亡率明显降低。Western blot 显示 HS 组 JNK、p38MAPK 和凋亡相关蛋白表达水平明显升高，而 BML-111 组 p38MAPK 和 JNK 表达水平明显降低。
结论
BML-111 通过抑制 MAPK 信号通路的激活，减少失血性休克诱导的急性肾损伤时肾组织的炎症反应和细胞凋亡。
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