Stimulation of Wnt/β-catenin signaling pathway with Wnt agonist reduces organ injury after hemorrhagic shock.
Stimulation of Wnt/β-catenin signaling pathway with Wnt agonist reduces organ injury after hemorrhagic shock.
复制标题
DOI：
10.1097/ta.0000000000000566
复制
发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Wang P
中科院分区：
文献类型：
--
作者：
Kuncewitch M;Yang WL;Jacob A;Khader A;Giangola M;Nicastro J;Coppa GF;Wang P
失血性休克是外科和创伤患者发病和死亡的主要原因。尽管进行了大量的临床前试验来制定针对失血性休克的治疗策略，但对出血患者的有效治疗仍然存在未满足的需求。由于Wnt/β-连环蛋白在细胞存活和增殖中的核心作用，它控制着发育过程和细胞再生。因此，我们假设Wnt信号的激活可以减少失血性休克引起的全身损伤。成年雄性Sprague-Dawley大鼠进行失血性休克，控制股动脉出血，使平均动脉压（MAP）维持30 mmHg 90分钟，然后用相当于两倍血流量的晶体液复苏。复苏后，给动物注射Wnt激动剂（5mg /kg）或Vehicle （20% DMSO盐水）。复苏后6 h采集血液和组织标本进行分析。失血性休克使血清中AST、乳酸和LDH水平升高。使用Wnt激动剂治疗后，这些水平分别显著降低了40%、36%和77%。Wnt激动剂也使BUN和肌酐分别降低34%和56%。治疗分别降低了55%和68%的髓过氧化物酶活性和IL-6 mRNA，并显著改善了肺组织学。Wnt激动剂治疗使Bcl-2蛋白升高至Sham值，并使cleaved - caspase-3降低46%，表明肺出血诱导的细胞凋亡减弱。出血导致肺中β-catenin蛋白水平显著降低，以及Wnt靶基因cyclind1的下调，而Wnt激动剂治疗保持了这些水平。Wnt激动剂可减轻出血性器官损伤、炎症和细胞凋亡。这与Wnt信号通路的保存有关。因此，Wnt/β-连环蛋白激活可能对失血性休克具有保护作用。
Hemorrhagic shock is a leading cause of morbidity and mortality in surgery and trauma patients. Despite a large number of preclinical trials conducted to develop therapeutic strategies against hemorrhagic shock, there is still an unmet need exist for effective therapy for hemorrhage victims. Wnt/β-catenin signaling controls developmental processes and cellular regeneration owing to its central role in cell survival and proliferation. We therefore hypothesized that the activation of Wnt signaling reduces systemic injury caused by hemorrhagic shock. Adult male Sprague-Dawley rats underwent hemorrhagic shock by controlled bleeding of the femoral artery to maintain a mean arterial pressure (MAP) of 30 mmHg for 90 min, followed by resuscitation with crystalloid equal to two times the shed blood volume. After resuscitation, animals were infused with Wnt agonist (5 mg/kg) or Vehicle (20% DMSO in saline). Blood and tissue samples were collected 6 h after resuscitation for analysis. Hemorrhagic shock increased serum levels of AST, lactate, and LDH. Treatment with Wnt agonist significantly reduced these levels by 40%, 36%, and 77%, respectively. Wnt agonist also decreased BUN and creatinine by 34% and 56%, respectively. Treatment reduced lung myeloperoxidase activity and IL-6 mRNA by 55% and 68% respectively and, significantly improved lung histology. Wnt agonist treatment increased Bcl-2 protein to Sham values and decreased cleaved caspase-3 by 46% indicating attenuation of hemorrhage-induced apoptosis in the lungs. Hemorrhage resulted in significant reductions of β-catenin protein levels in the lungs as well as down-regulation of a Wnt target gene, Cyclin-D1, while Wnt agonist treatment preserved these levels. The administration of Wnt agonist attenuated hemorrhage-induced organ injury, inflammation and apoptosis. This was correlated with preservation of the Wnt signaling pathway. Thus, Wnt/β-catenin activation could be protective in hemorrhagic shock.