The role of the epidermal growth factor receptor in sustaining neutrophil inflammation in severe asthma
The role of the epidermal growth factor receptor in sustaining neutrophil inflammation in severe asthma
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DOI：
10.1046/j.1365-2222.2003.01593.x
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发表时间：
2003-02-01
影响因子：
6.1
通讯作者：
Davies, DE
中科院分区：
文献类型：
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作者：
Hamilton, LM;Torres-Lozano, C;Davies, DE
背景 哮喘中上皮损伤的程度通过表皮生长因子受体（EGFR）的表达来反映，其表达与疾病严重程度成比例增加，并且是皮质类固醇难治性的。虽然 EGFR 参与上皮生长和分化，但尚不清楚它是否也有助于哮喘的炎症反应。 目的 由于严重哮喘以中性粒细胞炎症为特征，我们使用体外培养模型研究了 EGFR 激活与 IL-8 和巨噬细胞抑制蛋白 1 α (MIP-1α) 产生之间的关系，并检查了哮喘受试者支气管活检中 IL-8 和 EGFR 上皮表达之间的关联。 方法 H292 或原发性将支气管上皮细胞暴露于EGF或H-2 O-2以实现配体依赖性和配体非依赖性EGFR激活；通过实时PCR测量IL-8 mRNA，通过酶联免疫吸附测定（ELISA）测量IL-8和MIP-1α蛋白。通过免疫组织化学检查哮喘受试者支气管活检中的上皮 IL-8 和 EGFR 表达，并通过图像分析进行定量。结果使用 H292 细胞，EGF 和 H-2 O-2 增加了 IL-8 基因表达和释放，并且这种情况被 EGFR 选择性酪氨酸激酶抑制剂 AG1478 完全抑制，但仅部分被地塞米松抑制。 MIP-1α 的释放不受 EGF 的刺激，而 H-2 O-2 则导致 1.8 倍的增加，并且这对 AG1478 不敏感。 EGF 还显着刺激支气管刷检建立的哮喘或正常原代上皮细胞培养物中 IL-8 的释放。在支气管活检中，与轻度疾病相比，重度疾病的上皮 IL-8、MIP-1α、EGFR 和粘膜下中性粒细胞均显着增加，并且 EGFR 和 IL-8 表达之间存在很强的相关性（r = 0.70，P < 0.001）。 结论 这些结果表明，在严重哮喘中，上皮损伤有可能通过 EGFR 依赖性机制增加 IL-8 的产生，从而导致中性粒细胞炎症。
Background The extent of epithelial injury in asthma is reflected by expression of the epidermal growth factor receptor (EGFR), which is increased in proportion to disease severity and is corticosteroid refractory. Although the EGFR is involved in epithelial growth and differentiation, it is unknown whether it also contributes to the inflammatory response in asthma.Objectives Because severe asthma is characterized by neutrophilic inflammation, we investigated the relationship between EGFR activation and production of IL-8 and macrophage inhibitory protein-1 alpha (MIP-1alpha) using in vitro culture models and examined the association between epithelial expression of IL-8 and EGFR in bronchial biopsies from asthmatic subjects.Methods H292 or primary bronchial epithelial cells were exposed to EGF or H-2 O-2 to achieve ligand-dependent and ligand-independent EGFR activation; IL-8 mRNA was measured by real-time PCR and IL-8 and MIP-1alpha protein measured by enzyme-linked immunosorbent assay (ELISA). Epithelial IL-8 and EGFR expression in bronchial biopsies from asthmatic subjects was examined by immunohistochemistry and quantified by image analysis.Results Using H292 cells, EGF and H-2 O-2 increased IL-8 gene expression and release and this was completely suppressed by the EGFR-selective tyrosine kinase inhibitor, AG1478, but only partially by dexamethasone. MIP-1alpha release was not stimulated by EGF, whereas H-2 O-2 caused a 1.8-fold increase and this was insensitive to AG1478. EGF also significantly stimulated IL-8 release from asthmatic or normal primary epithelial cell cultures established from bronchial brushings. In bronchial biopsies, epithelial IL-8, MIP-1alpha, EGFR and submucosal neutrophils were all significantly increased in severe compared to mild disease and there was a strong correlation between EGFR and IL-8 expression (r = 0.70, P < 0.001).Conclusions These results suggest that in severe asthma, epithelial damage has the potential to contribute to neutrophilic inflammation through enhanced production of IL-8 via EGFR- dependent mechanisms.