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

BackgroundThe 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 methodsSprague-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)-1β, and HO-1 was assessed by Western blot.ResultsInhibition 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-α, IL-6, and IL-8 in the bronchoalveolar lavage, and reduced Egr-1, IL-1β, 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.ConclusionsEgr-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.