Antagonist of the Type-1 ANG II receptor prevents against LPS-induced septic shock in rats
Antagonist of the Type-1 ANG II receptor prevents against LPS-induced septic shock in rats
复制标题
DOI：
10.1007/s00134-009-1545-x
复制
发表时间：
2009-08-01
影响因子：
38.9
通讯作者：
Noguchi, Takayuki
中科院分区：
文献类型：
--
作者：
Hagiwara, Satoshi;Iwasaka, Hideo;Noguchi, Takayuki
1型血管紧张素II（AT 1）受体拮抗剂在体外和患者中具有抗炎作用。本研究的目的是探讨氯沙坦（LOS），一种AT 1受体拮抗剂，是否通过抑制高迁移率族蛋白1（HMGB 1）蛋白和细胞因子的诱导脂多糖（LPS;血清型：O 127：B8）在大鼠模型中减少肺损伤。对照组大鼠接受0.9%NaCl溶液。LOS + LPS组大鼠在给予LPS（7.5mg·kg-1）前给予LOS（50 mg·kg-1）。LPS组大鼠腹腔注射LPS（7.5mg·kg ~（-1）），采用免疫组化、ELISA和western blot方法检测LOS对LPS诱导的细胞因子产生的抑制作用。与LPS组相比，LOS + LPS组中细胞因子（IL-6和TNF-α）和HMGB 1的血浆浓度显著降低（p < 0.05）。LOS还抑制LPS介导的血管紧张素转换酶2（ACE 2）活性的降低（p < 0.05）。免疫组化分析显示对照组和LOS + LPS组肺组织中ACE 2染色阳性。与对照组和LOS + LPS组相比，LPS组肺组织切片中ACE 2标记的强度和程度显著降低（p < 0.05）。另外，用LPS刺激RAW 264.7鼠巨噬细胞，同时进行或不进行LOS处理，导致I κ B磷酸化的抑制。
Type 1 angiotensin II (AT1) receptor antagonists have anti-inflammatory effects in vitro and in patients. The purpose of this study was to investigate whether losartan (LOS), an AT1 receptor antagonist, reduces lung damage by inhibiting the induction of high mobility group box 1 (HMGB1) protein and cytokines by lipopolysaccharide (LPS; serotype: O127:B8) in a rat model.We used male Wistar rats. Control group rats received a 0.9% NaCl solution. The LOS + LPS group rats received LOS (50 mg kg(-1)) before LPS (7.5 mg kg(-1)) administration. LPS group rats received injection of LPS (7.5 mg kg(-1)).We performed immunohistochemistry, ELISA, and western blot analysis to examine the suppressive effects of LOS on LPS-induced cytokine induction. Plasma concentrations of cytokines (IL-6 and TNF-alpha) and HMGB1 (p < 0.05) were markedly reduced in the LOS + LPS group compared to the LPS group. LOS also inhibited the LPS-mediated decrease in angiotensin-converting enzyme 2 (ACE2) activity (p < 0.05). Immunohistochemical analysis revealed positive staining for ACE2 in lungs from both control and LOS + LPS groups. The intensity and degree of ACE2 labeling in lung tissue sections from the LPS group were markedly reduced compared to the control and LOS + LPS groups (p < 0.05). Additionally, RAW264.7 murine macrophages were stimulated with LPS, with or without simultaneous LOS treatment, resulting in inhibition of I kappa B phosphorylation.Treatment with LOS improved lung injury in an endotoxin shock model system by an anti-inflammatory action that inhibits reduction of ACE2.