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首页> 外文期刊>American Journal of Physiology >Ultrafine carbon black particles stimulate proliferation of human airway epithelium via EGF receptor-mediated signaling pathway.
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Ultrafine carbon black particles stimulate proliferation of human airway epithelium via EGF receptor-mediated signaling pathway.

机译：超细炭黑颗粒通过EGF受体介导的信号传导途径刺激人气道上皮的增殖。

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摘要

Exposure to ambient ultrafine particles induces airway inflammatory reactions and tissue remodeling. In this experiment, to determine whether ultrafine carbon black (ufCB) affects proliferation of airway epithelium and, if so, what the mechanism of action is, we studied human primary bronchial epithelial cell cultures. Incubation of cells in the serum-free medium with ufCB increased incorporations of [(3)H]thymidine and [(3)H]leucine into cells in a time- and dose-dependent manner. This effect was attenuated by Cu- and Zn-containing superoxide dismutase (Cu/Zn SOD) and apocynin, an inhibitor of NADPH oxidase, and completely inhibited by pretreatment with the epidermal growth factor receptor (EGF-R) tyrosine kinase inhibitors AG-1478 and BIBX-1382, and the mitogen-activated protein kinase kinase inhibitor PD-98059. Transfection of a dominant-negative mutant of H-Ras likewise abolished the effect ufCB. Stimulation with ufCB also induced processing of membrane-anchored proheparin-binding (HB)-EGF, releaseof soluble HB-EGF into the medium, association of phosphorylated EGF-R and Shc with glutathione-S-transferase-Grb2 fusion protein, and phosphorylation of extracellular signal-regulated kinase (ERK). Pretreatment with AG-1478, [Glu(52)]Diphtheria toxin, a specific inhibitor of HB-EGF, neutralizing HB-EGF antibody, Cu/Zn SOD, and apocynin each inhibited ufCB-induced ERK activation. These results suggest that ufCB causes oxidative stress-mediated proliferation of airway epithelium, involving processing of HB-EGF and the concomitant activation of EGF-R and ERK cascade.
机译：暴露于环境超细颗粒会引起气道炎症反应和组织重塑。在此实验中，为了确定超细炭黑（ufCB）是否影响气道上皮的增殖，以及作用机理是什么，我们研究了人原发性支气管上皮细胞培养物。用ufCB在无血清培养基中培养细胞会增加[（3）H]胸苷和[（3）H]亮氨酸以时间和剂量依赖性的方式掺入细胞。含铜和锌的超氧化物歧化酶（Cu / Zn SOD）和Apocynin（NADPH氧化酶的抑制剂）减弱了这种作用，而经表皮生长因子受体（EGF-R）酪氨酸激酶抑制剂AG-1478预处理则完全抑制了这种作用。 BIBX-1382，促分裂原活化的蛋白激酶激酶抑制剂PD-98059。 H-Ras显性阴性突变体的转染同样消除了ufCB效应。用ufCB刺激还诱导了膜锚定的肝素原结合（HB）-EGF的加工，可溶性HB-EGF释放到培养基中，磷酸化的EGF-R和Shc与谷胱甘肽-S-转移酶-Grb2融合蛋白的缔合以及细胞外信号调节激酶（ERK）。用AG-1478，[Glu（52）]白喉毒素，HB-EGF的特异性抑制剂，中和HB-EGF抗体，Cu / Zn SOD和载脂蛋白的预处理均抑制ufCB诱导的ERK活化。这些结果表明，ufCB引起氧化应激介导的气道上皮细胞增殖，涉及HB-EGF的加工以及EGF-R和ERK级联反应的活化。

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