Blanchet Sophie, Ramgolam Kiran, Baulig Augustin, Marano Francelyne, Baeza-Squiban Armelle
Laboratoire de Cytophysiologie et Toxicologie Cellulaire, Université Paris 7-Denis Diderot, Paris, France.
Am J Respir Cell Mol Biol. 2004 Apr;30(4):421-7. doi: 10.1165/rcmb.2003-0281RC. Epub 2003 Dec 30.
Particulate matter (PM) is thought to be responsible for respiratory health problems. Epithelial cells exposed to particles release pro-inflammatory cytokines leading to inflammation of airways. However, the signaling cascades triggered by particles are poorly understood. We demonstrate that PM with an aerodynamic diameter < 2.5 microm (PM2.5) or diesel exhaust particles upregulate the expression of amphiregulin (AR), a ligand of the epidermal growth factor receptor (EGFR), in human bronchial epithelial cells. AR secretion was blocked by an inhibitor of the EGFR tyrosine kinase (AG1478), or a selective mitogen-activated protein (MAP) kinase/extracellular regulated kinase (Erk) inhibitor (PD98059), but not by the p38 MAP kinase inhibitor (SB203580). Thus, AR secretion is mediated through the activation of the EGFR and Erk MAP kinase pathway. In addition, AR secretion was inhibited by the antioxidant N-acetyl cysteine, but not by a neutralizing anti-EGFR, suggesting an EGFR transactivation via oxidative stress. AR may be involved in cytokine secretion, as AR can induce granulocyte macrophage-colony-stimulating factor (GM-CSF) release and a neutralizing anti-EGFR reduces the particle-induced GM-CSF release. This study indicates that PM2.5 induces the expression and secretion of AR, an EGFR ligand contributing to GM-CSF release, which may reflect an important mechanism for sustaining the proinflammatory response.
颗粒物（PM）被认为是导致呼吸道健康问题的原因。暴露于颗粒物的上皮细胞会释放促炎细胞因子，导致气道炎症。然而，由颗粒物触发的信号级联反应却知之甚少。我们证明，空气动力学直径小于2.5微米的颗粒物（PM2.5）或柴油废气颗粒可上调人支气管上皮细胞中双调蛋白（AR）的表达，AR是表皮生长因子受体（EGFR）的一种配体。EGFR酪氨酸激酶抑制剂（AG1478）或选择性丝裂原活化蛋白（MAP）激酶/细胞外调节激酶（Erk）抑制剂（PD98059）可阻断AR的分泌，但p38 MAP激酶抑制剂（SB203580）则不能。因此，AR的分泌是通过EGFR和Erk MAP激酶途径的激活介导的。此外，抗氧化剂N-乙酰半胱氨酸可抑制AR的分泌，但中和性抗EGFR则不能，这表明EGFR通过氧化应激发生反式激活。AR可能参与细胞因子的分泌，因为AR可诱导粒细胞巨噬细胞集落刺激因子（GM-CSF）的释放，而中和性抗EGFR可减少颗粒物诱导的GM-CSF释放。这项研究表明，PM2.5可诱导AR的表达和分泌，AR作为一种EGFR配体有助于GM-CSF的释放，这可能反映了维持促炎反应的一个重要机制。
