Division of Respiratory Medicine, Second Affiliated Hospital, Chongqing Medical University, Yuzhong District, Chongqing, China.
Mol Cell Biochem. 2011 Jun;352(1-2):65-75. doi: 10.1007/s11010-011-0740-6. Epub 2011 Feb 10.
Mucus hypersecretion is an important manifestation in patients with chronic inflammatory airway diseases. Mucin 5AC (MUC5AC) is a major component of airway mucus. MUC5AC expression is regulated by epidermal growth factor receptor (EGFR) which can be activated by reactive oxygen species (ROS). Hyaluronan (HA), a linear glycosaminoglycan with molecular weights ranging from 2 × 10(5) to 1 × 10(7), is expressed in airway epithelium and can be depolymerized by ROS into hyaluronan fragments. The mechanisms through which fragmented HA exerts its biologic functions have been elucidated by interactions with its receptor CD44. The aim of our study was to examine the role of HA and CD44 in ROS-induced EGFR activation and MUC5AC expression. We exposed NCI-H292 cells to ROS generated by xanthine/xanthine oxidase (X/XO). ROS-induced EGFR phosphorylation, which was activated by tissue kallekrein (TK) activation and EGF release. We found ROS promoted CD44 co-immunoprecipitation with EGFR and MUC5AC up-regulation. These effects were mimicked by hyaluronan fragments. All the effects were inhibited by blocking CD44 or EGFR, suggesting that CD44 plays a critical role in ROS-induced MUC5AC up-regulation. These results show that ROS depolymerizes hyaluronan into fragments, and these fragments bind their receptor CD44 to induce TK activation, which cleaves EGF precursors into mature EGF to activate its receptor EGFR. Furthermore, we provide evidence that hyaluronan fragments are sufficient to induce CD44/EGFR interaction and EGFR signaling which lead to MUC5AC expression. The results indicate that the regulation of ROS-induced MUC5AC expression by hyaluronan and CD44 may provide important insights in the mechanism of mucus hypersecretion.
黏液高分泌是慢性炎症性气道疾病患者的重要表现。黏蛋白 5AC（MUC5AC）是气道黏液的主要成分。MUC5AC 的表达受表皮生长因子受体（EGFR）调控，而 EGFR 可被活性氧（ROS）激活。透明质酸（HA）是一种具有线性结构的糖胺聚糖，分子量范围为 2×10(5)到 1×10(7)，在气道上皮细胞中表达，并可被 ROS 解聚成透明质酸片段。ROS 与透明质酸片段与其受体 CD44 相互作用，阐明了其发挥生物学功能的机制。我们的研究目的是研究 HA 和 CD44 在 ROS 诱导的 EGFR 激活和 MUC5AC 表达中的作用。我们使 NCI-H292 细胞暴露于黄嘌呤/黄嘌呤氧化酶（X/XO）产生的 ROS 中。ROS 诱导 EGFR 磷酸化，这是通过组织激肽释放酶（TK）激活和 EGF 释放而被激活的。我们发现 ROS 促进 CD44 与 EGFR 的共免疫沉淀，并上调 MUC5AC。透明质酸片段模拟了这些作用。阻断 CD44 或 EGFR 可抑制所有这些作用，表明 CD44 在 ROS 诱导的 MUC5AC 上调中起关键作用。这些结果表明，ROS 将透明质酸解聚成片段，这些片段与其受体 CD44 结合，诱导 TK 激活，将 EGF 前体切割成熟 EGF，从而激活其受体 EGFR。此外，我们提供的证据表明，透明质酸片段足以诱导 CD44/EGFR 相互作用和 EGFR 信号传导，从而导致 MUC5AC 表达。这些结果表明，HA 和 CD44 对 ROS 诱导的 MUC5AC 表达的调节可能为黏液高分泌的机制提供重要的见解。
