右美托咪定通过影响CHOP凋亡通路减轻缺血/再灌注肺损伤

Dexmedetomidine alleviates lung ischemia-reperfusion injury through CHOP pathway in mice

目的：探讨右美托咪定（dexmedetomidine，DEX）能否通过 CCAAT／增强子结合蛋白同源蛋白（CHOP）凋亡通路减轻小鼠缺血再灌注（I／R）性肺损伤。方法：选取雄性8～10周龄C57BL／6J小鼠40只，体重18～22 g，复制在体左肺I／R损伤模型。随机分为4组：假手术组（ sham组），I／R模型组（ I／R组），生理盐水对照组（ I／R＋NS组），右美托咪定干预组（ I／R＋DEX组）。 DEX组在小鼠左肺缺血前30 min腹腔注射DEX 25μg／kg，I／R＋NS组给予与DEX 等体积的生理盐水。实验毕，留取左肺组织。测定肺组织干湿比（ W／D ）及总肺含水量（TLW），行肺组织损伤评估（IQA），光、电镜观察肺组织形态学及超微结构改变。原位末端标记（TUNEL）法检测组织细胞凋亡指数（AI）。 Western blot 和逆转录PCR（RT－PCR）分别检测CHOP、葡萄糖调节蛋白78（GRP78）蛋白和mRNA表达量。结果：与sham组比，I／R组和I／R＋NS组肺W／D、TLW、IQA、AI明显升高（P＜0．01），肺组织形态破坏显著，CHOP、GRP78蛋白和mRNA表达量增加（ P＜0．01）；I／R组与I／R＋NS组相比，上述指标无显著差异。与I／R组比，I／R＋DEX组肺组织W／D、TLW、IQA及AI明显下降（ P＜0．05），组织损伤明显减轻， CHOP蛋白和mRNA表达量下降（ P＜0．01）。结论：DEX可有效减轻小鼠缺血／再灌注性肺损伤，其机制可能与其抑制CHOP通路所致凋亡有关。

AIM：To explore the effect of dexmedetomidine （ DEX） on the CCAAT/enhancer-binding protein-homologous protein （ CHOP） pathway during lung ischemia-reperfusion （ I/R） in mice.METHODS：C57BL/6J male mice were randomly divided into sham operation group （ sham group） , lung ischemia/reperfusion group （ I/R group） , ischemia/reperfusion ＋normal saline group （ I/R＋NS group ） and ischemia/reperfusion＋dexmedetomidine group （ I/R＋DEX group） .Dexmedetomidine was infused intraperitoneally with 25 μg/kg for 30 min prior to the ischemia period in I/R＋DEX group, the normal saline was administrated with the same volume of dexmedetomidine in I/R＋NS group.After fini-shed the 3 h-reperfusion period , the left lung tissues were harvested to determine lung wet/dry weight （ W/D） , the total lung water content （ TLW） , and index of quantitative evaluation for alveolar damage （ IQA） .Morphological observation and terminal-deoxynucleotidyl transferase mediated nick end labeling （ TUNEL） were applied to evaluate the structure changes and the apoptosis index （AI） of the lung tissues.The expression of CHOP and glucose-regulated protein 78 （GRP78） at mRNA and protein levels in the lung tissues was detected by Western blot and RT-PCR.RESULTS：Compared with sham group, the W/D, TLW, IQA, AI, the mRNA and protein expression of CHOP and GRP78 obviously increased, and the left lung tissues structure were damaged more obviously both in I/R group and I/R＋NS group.Compared with I/R group, the W/D, TLW, IQA, AI and the protein and mRNA expression of CHOP in I/R＋DEX group decreased, the injury of the left lung tissue structures induced by I/R in I/R＋DEX group were also alleviated .CONCLUSION：DEX alleviates the 〈br〉 lung I/R injury, which may be related to inhibition of apoptosis mediated by CHOP pathway.