Ischemic postconditioning downregulates Egr-1 expression and attenuates postischemic pulmonary inflammatory cytokine release and tissue injury in rats

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• 作者：Huozhi Wu ; MD ; PhD^a ; ¹ ; Shaoqing Lei ; MD ; PhD^b ; ¹ ; Jiang Yuan ; MD^a ; Xin Liu ; MD ; MSc^c ; Dayong Zhang ; MD^a ; Xiaoxia Gu ; MD^c ; Liangqing Zhang ; MD ; PhD^c ; ^{zhanglq1970@163.com} ; Zhengyuan Xia ; MD ; PhD^c ; ^d ; ^zyxia@hku.hk
• 关键词：Ischemic postconditioning ; Lung ischemia reperfusion ; Egr-1 ; Heme oxygenase 1
• 刊名：Journal of Surgical Research
• 出版年：2013
• 出版时间：15 May, 2013
• 年：2013
• 卷：181
• 期：2
• 页码：204-212
• 全文大小：1183 K

文摘

Background

The early growth response-1 (Egr-1) gene is upregulated after an ischemia-reperfusion (IR) challenge and upregulates target genes, such as proinflammatory cytokines. Ischemic postconditioning (IPostC) attenuates lung IR injury and reduces the systemic inflammatory response by activating heme oxygenase-1 (HO-1). However, the role of Egr-1 in IPostC protection against lung IR injury and inflammation and its interplay with HO-1 in IPostC protection is unknown.

Materials and methods

Sprague-Dawley rats or cultured A549 cells were subjected to IR or hypoxia/reoxygenation with or without IPostC or hypoxic postconditioning in the presence or absence of Egr-1 inhibition using Egr-1 antisense oligodeoxyrinonucleotide or Egr-1 small interfering RNA transfection. Lung injury was assessed by measuring the lung wet/dry weight ratio, histologic change, and malondialdehyde content. The amount of lactate dehydrogenase release in culture medium was detected to evaluate cell injury. The protein expression of Egr-1, interleukin (IL)-1¦Â, and HO-1 was assessed by Western blot.

Results

Inhibition of Egr-1 significantly attenuated lung IR injury and the inflammation response caused by IR or hypoxia/reoxygenation, as shown by the alleviated lung pathologic changes, decreased pulmonary malondialdehyde content, wet/dry ratio, reduced release of the cytokines tumor necrosis factor-¦Á, IL-6, and IL-8 in the bronchoalveolar lavage, and reduced Egr-1, IL-1¦Â, and HO-1 protein expression and HO-1 activity. IPostC or hypoxic postconditioning reduced the postischemic Egr-1 expression and conferred similar protection against lung IR injury as Egr-1 inhibition.

Conclusions

Egr-1 plays an important role in regulating the HO-1 production induced by IR or hypoxia/reoxygenation. Thus, downregulation of Egr-1 expression might represent one of the major mechanisms whereby IPostC confers protection against pulmonary IR insult.