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α2A -AR antagonism by BRL-44408 maleate attenuates acute lung injury in rats with downregulation of ERK1/2, p38MAPK, and p65 pathway.

马来酸 BRL-44408 拮抗 α 2a-AR 可减轻 ERK1/2 、 p38MAPK 和 p65 通路下调的大鼠急性肺损伤。

  • 影响因子:3.89
  • DOI:10.1002/jcp.29586
  • 作者列表:"Cong Z","Li D","Tao Y","Lv X","Zhu X
  • 发表时间:2020-01-31
Abstract

:Acute respiratory distress syndrome (ARDS), characterized by acute hypoxic respiratory dysfunction or failure, is a manifestation of multiple organ failure in the lung, and the most common risk factor is sepsis. We previously showed that blocking α2 -adrenoceptor (α2 -AR) could attenuate lung injury induced by endotoxin in rats. α2A -adrenoceptor (α2A -AR), a subtype of α2 -AR plays a key role in inflammatory diseases, but the mechanism remains unknown. Here, we explored the effect of BRL-44408 maleate (BRL), a specific α2A -AR antagonist, on cecal ligation puncture (CLP)-induced ARDS in rats and the underlying mechanism. Preadministration of BRL-44408 maleate significantly alleviated CLP-induced histological injury, macrophage infiltration, inflammatory response, and wet/dry ratio in lung tissue. However, there was no statistical difference in survival rate between the CLP and CLP+BRL groups. Extracellular regulated protein kinase (ERK1/2), p38MAPK, and p65 were activated in the CLP group, and BRL-44408 maleate inhibited the activation of these signal molecules, c-Jun N-terminal kinase (JNK) and protein kinase A (PKA) showed no changes in activation between these two groups. BRL-44408 maleate decreased lipopolysaccharide (LPS)-induced expression of cytokines in NR8383 rat alveolar macrophages and reduced phosphorylation of ERK1/2, p38MAPK, and p65. JNK and PKA were not influenced by LPS. Together, these findings suggest that antagonism of α2A -AR improves CLP-induced acute lung injury and involves the downregulation of ERK1/2, p38MAPK, and p65 pathway independent of the activation of JNK and PKA.

摘要

急性呼吸窘迫综合征 (ARDS) 以急性缺氧性呼吸功能障碍或衰竭为特征,是肺部多器官功能衰竭的表现,最常见的危险因素是脓毒症。我们以前的研究表明,阻断 α 2-肾上腺素受体 (α 2-AR) 可以减轻内毒素诱导的大鼠肺损伤。 α 2-AR 亚型 α 2a-肾上腺素受体 (α 2a-AR) 在炎症性疾病中起关键作用,但其机制尚不清楚。在此,我们探讨了特异性 α 2a-AR 拮抗剂马来酸 BRL-44408 (BRL) 对盲肠结扎穿孔 (CLP) 诱导的大鼠 ARDS 的影响及其机制。术前给予马来酸 BRL-44408 可明显减轻 CLP 诱导的肺组织损伤、巨噬细胞浸润、炎症反应及肺组织湿/干重比。但 CLP 组和 CLP + BRL 组生存率无统计学差异。CLP 组细胞外调节蛋白激酶 (ERK1/2) 、 p38MAPK 和 p65 被激活,马来酸 BRL-44408 抑制这些信号分子的激活。 c-6月 N 末端激酶 (JNK) 和蛋白激酶 A (PKA) 在这两组之间的激活没有变化。马来酸 BRL-44408 降低脂多糖 (LPS) 诱导的 NR8383 大鼠肺泡巨噬细胞细胞因子的表达,降低 ERK1/2 、 p38MAPK 和 p65 的磷酸化。JNK 和 PKA 不受 LPS 的影响。总之,这些研究结果表明,α 2a-AR 的拮抗作用改善了 CLP 诱导的急性肺损伤,并涉及 ERK1/2 、 p38MAPK 和 p65 通路的下调,而不依赖于 JNK 和 PKA 的激活。

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相关文献
影响因子:3.89
发表时间:2020-01-31
DOI:10.1002/jcp.29586
作者列表:["Cong Z","Li D","Tao Y","Lv X","Zhu X"]

METHODS::Acute respiratory distress syndrome (ARDS), characterized by acute hypoxic respiratory dysfunction or failure, is a manifestation of multiple organ failure in the lung, and the most common risk factor is sepsis. We previously showed that blocking α2 -adrenoceptor (α2 -AR) could attenuate lung injury induced by endotoxin in rats. α2A -adrenoceptor (α2A -AR), a subtype of α2 -AR plays a key role in inflammatory diseases, but the mechanism remains unknown. Here, we explored the effect of BRL-44408 maleate (BRL), a specific α2A -AR antagonist, on cecal ligation puncture (CLP)-induced ARDS in rats and the underlying mechanism. Preadministration of BRL-44408 maleate significantly alleviated CLP-induced histological injury, macrophage infiltration, inflammatory response, and wet/dry ratio in lung tissue. However, there was no statistical difference in survival rate between the CLP and CLP+BRL groups. Extracellular regulated protein kinase (ERK1/2), p38MAPK, and p65 were activated in the CLP group, and BRL-44408 maleate inhibited the activation of these signal molecules, c-Jun N-terminal kinase (JNK) and protein kinase A (PKA) showed no changes in activation between these two groups. BRL-44408 maleate decreased lipopolysaccharide (LPS)-induced expression of cytokines in NR8383 rat alveolar macrophages and reduced phosphorylation of ERK1/2, p38MAPK, and p65. JNK and PKA were not influenced by LPS. Together, these findings suggest that antagonism of α2A -AR improves CLP-induced acute lung injury and involves the downregulation of ERK1/2, p38MAPK, and p65 pathway independent of the activation of JNK and PKA.

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