HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells
HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells
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DOI：
10.1016/j.freeradbiomed.2005.03.026
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发表时间：
2005-08-01
影响因子：
7.4
通讯作者：
Forman, HJ
中科院分区：
文献类型：
--
作者：
Iles, KE;Dickinson, DA;Forman, HJ
血红素加氧酶-I（HO-1）是一种重要的细胞保护酶，也是氧化应激的标志物。吸烟者肺泡腔中的巨噬细胞中HO-1表达增加。支气管和肺泡上皮细胞中的脂质过氧化产物4-羟基壬烯醛（FINE）也因吸烟而增加。这表明慢性环境应激、HNE形成和HO-1诱导之间存在联系。FINE既是体内氧化应激的试剂，也是有效的细胞信号分子。我们假设FINE作为内源性产生的肺信号分子，激发适应性反应，最终诱导HO-1。在这里，我们证明了FINE增加肺上皮细胞中HO-1 mRNA、蛋白和活性，并确定ERK是参与的关键途径。用FINE处理增加ERK磷酸化、c-Fos蛋白、JNK磷酸化、c-Jun磷酸化和AP-1结合。然而，用MEK抑制剂PD 98059抑制ERK通路可显著降低HNE介导的ERK磷酸化、c-Fos蛋白诱导、AP-1结合和HO-1蛋白诱导，抑制ERK通路对HNE诱导的HO-1 mRNA无影响。这表明ERK通过调节翻译而不是转录参与HO-1的增加。(c)2005年爱思唯尔公司All rights reserved.
Heme oxygenase-I (HO-1) is a key cytoprotective enzyme and an established marker of oxidative stress. Increased HO-1 expression has been found in the resident macrophages in the alveolar spaces of smokers. The lipid peroxidation product 4-hydroxynonenal (FINE) is also increased in the bronchial and alveolar epithelium in response to cigarette smoke. This suggests a link between a chronic environmental stress, HNE formation, and HO-1 induction. FINE is both an agent of oxidative stress in vivo and a potent cell signaling molecule. We hypothesize that FINE acts as an endogenously produced pulmonary signaling molecule that elicits an adaptive response culminating in the induction of HO-1. Here we demonstrate that FINE increases HO-1 mRNA, protein, and activity in pulmonary epithelial cells and identify ERK as a key pathway involved. Treatment with FINE increased ERK phosphorylation, c-Fos protein, JNK phosphorylation, c-Jun phosphorylation, and AP-1 binding. Whereas inhibiting the ERK pathway with the MEK inhibitor PD98059 significantly decreased HNE-mediated ERK phosphorylation, c-Fos protein induction, AP-1 binding, and HO-I protein induction, inhibition of the ERK pathway had no effect on HNE-induced HO-1 mRNA. This suggests that ERK is involved in the increase in HO-1 through regulation of translation rather than transcription. (c) 2005 Elsevier Inc. All rights reserved.