Histone deacetylase inhibitor treatment attenuates MAP kinase pathway activation and pulmonary inflammation following hemorrhagic shock in a rodent model.
Histone deacetylase inhibitor treatment attenuates MAP kinase pathway activation and pulmonary inflammation following hemorrhagic shock in a rodent model.
复制标题
DOI：
10.1016/j.jss.2011.06.007
复制
发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Alam HB
中科院分区：
文献类型：
--
作者：
Kochanek AR;Fukudome EY;Li Y;Smith EJ;Liu B;Velmahos GC;deMoya M;King D;Alam HB
失血性休克激活细胞应激信号，可导致全身炎症反应、器官损伤和死亡。我们之前已经证明，在致死性出血模型(60%失血)中，组蛋白去乙酰酶抑制剂(HDACIs)的治疗显著提高了存活率。目前这项研究的目的是检查这些保护作用是否由于丝裂原活化蛋白激酶(MAPK)信号通路的减弱而产生，而MAPK信号通路已知促进炎症和凋亡。大鼠体重250-300g，造成40%失血模型，随机分为两组：1)丙戊酸(丙戊酸)(丙戊酸300 mg/kg静脉滴注，体积=0.75ml/kg)，对照组(0.75ml/kg生理盐水)。分别于1、4、20h处死动物(n=3~4个/组/时间点)，用Western blotting分析活化(磷酸化)和失活形式的c-jun氨基末端激酶(JNK)和p38MAPK的表达。出血后20h测定肺组织髓过氧化物酶(MPO)活性，作为中性粒细胞浸润的标志。正常动物3只作为假手术组。与假手术组相比，失血后1小时磷酸化p38、4小时磷酸化JNK和20小时MPO活性显著升高(p<；0.05)。VPA治疗显著减轻了所有这些变化(p<；0.05)。失血性休克激活了促炎症的MAPK信号通路，促进了肺中性粒细胞的浸润，这种影响可被VPA治疗显著减轻。这可能是HDACI在失血性休克中减少器官损伤和提高存活率的关键机制。
Hemorrhagic shock activates cellular stress signals and can lead to systemic inflammatory response, organ injury, and death. We have previously shown that treatment with histone deacetylase inhibitors (HDACIs) significantly improves survival in lethal models (60% blood loss) of hemorrhage. The aim of the current study was to examine whether these protective effects were due to attenuation of mitogen activated protein kinase (MAPK) signaling pathways, which are known to promote inflammation and apoptosis. Wistar-Kyoto rats (250–300g) were subjected to 40% blood loss and randomized to treatment with: 1) HDACI valproic acid (VPA 300mg/kg IV; volume = 0.75 ml/kg), or 2) vehicle control (0.75 ml/kg of 0.9% saline). Animals were sacrificed at 1, 4 and 20 hours (n=3–4/group/timepoint), and lung samples were analyzed by Western blotting for expression of active (phosphorylated) and inactive forms of c-Jun N terminal Kinase (JNK) and p38 MAPK. Myeloperoxidase (MPO) activity was measured in lung tissue 20 hours after hemorrhage as a marker of neutrophil infiltration. Normal animals (n=3) served as shams. Hemorrhaged animals demonstrated significant increases in phosphorylated p38 at 1 hour, phosphorylated JNK at 4 hours, and increased MPO activity at 20 hours (p<0.05 compared to sham). VPA treatment significantly (p <0.05) attenuated all of these changes. Hemorrhagic shock activates pro-inflammatory MAPK signaling pathways and promotes pulmonary neutrophil infiltration, affects that are significantly attenuated by VPA treatment. This may represent a key mechanism through which HDACIs decrease organ damage and promote survival in hemorrhagic shock.
登录
查看更多内容
影响因子：
3.8
作者：
Hsu, Jun-Te;Kan, Wen-Hong;Chaudry, Irshad H.
通讯作者：
Chaudry, Irshad H.
影响因子：
3.8
作者：
Alam, Hasan B.;Shuja, Fahad;Velmahos, George C.
通讯作者：
Velmahos, George C.
DOI：
10.1097/01.ta.0000057151.02906.27
发表时间：
2003-05-01
影响因子：
--
作者：
Champion, HR;Bellamy, RF;Leppaniemi, A
通讯作者：
Leppaniemi, A
DOI：
10.1084/jem.20071728
发表时间：
2008-06-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cao W;Bao C;Padalko E;Lowenstein CJ
通讯作者：
Lowenstein CJ
影响因子：
5.8
作者：
Chanteux H;Guisset AC;Pilette C;Sibille Y
通讯作者：
Sibille Y