Respiratory and Critical Illness Medicine, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, China.
Eur Rev Med Pharmacol Sci. 2018 Sep;22(18):6077-6084. doi: 10.26355/eurrev_201809_15946.
Chronic obstructive pulmonary disease (COPD) is an incomplete, reversible disease with progressive inflammation obstruction in airways. This study aims to explore the regulatory mechanism of hypoxia-inducible factor-1α (HIF-1α) in inflammatory response and progression of COPD.
71 bronchoalveolar lavage fluid (BALF) samples were collected, including 59 samples from COPD patients (COPD group) and 12 from patients with normal pulmonary function (control group). The mRNA and protein levels of HIF-1α and epidermal growth factor receptor (EGFR) in BALF were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot, respectively. Serum levels of interleukin-13 (IL-13), IL-9, IL-1, and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). Hypoxia cell model was constructed by COCl2 induction in human embryonic lung cells. Expression levels of HIF-1α, EGFR and p-AKT in NCI-H1563 cells treated with 740Y-P, the phosphoinositide 3-kinase (PI3K) agonist were detected. Finally, we detected proliferation and apoptosis in NCI-H1563 cells with HIF-1α overexpression by cell counting kit-8 (CCK-8) assay and flow cytometry, respectively.
The mRNA and protein levels of HIF-1α and EGFR were higher in COPD groups compared with those of control group. Serum levels of IL-13, IL-9, IL-1, and TNF-α in COPD patients were elevated. CoCl2 induction in NCI-H1563 cells led to upregulated levels of IL-13, IL-9, IL-1, and TNF-α. 740Y-P treatment remarkably activated EGFR/PI3K/AKT pathway. Overexpressed HIF-1α inhibited proliferation but induced apoptosis of NCI-H1563 cells.
HIF-1α was overexpressed in COPD, which upregulated expressions of inflammatory factors via activating the EGFR/PI3K/AKT pathway. The activated EGFR/PI3K/AKT pathway induced by pulmonary inflammation further upregulated HIF-1α expression in a feedback loop, thus aggravating COPD pathological changes.
慢性阻塞性肺疾病（COPD）是一种不完全、可逆转的气道炎症阻塞性疾病，其具有进行性加重的特点。本研究旨在探讨缺氧诱导因子-1α（HIF-1α）在 COPD 炎症反应和进展中的调控机制。
收集 71 例支气管肺泡灌洗液（BALF）标本，包括 COPD 患者 59 例（COPD 组）和肺功能正常患者 12 例（对照组）。采用实时定量聚合酶链反应（qRT-PCR）和 Western blot 检测 BALF 中 HIF-1α和表皮生长因子受体（EGFR）的 mRNA 和蛋白水平。采用酶联免疫吸附试验（ELISA）检测血清白细胞介素-13（IL-13）、IL-9、IL-1 和肿瘤坏死因子-α（TNF-α）水平。采用 COCl2 诱导人胚肺细胞构建缺氧细胞模型。采用 740Y-P（PI3K 激动剂）处理 NCI-H1563 细胞，检测 HIF-1α、EGFR 和磷酸化 AKT（p-AKT）的表达水平。最后，通过细胞计数试剂盒-8（CCK-8）检测和流式细胞术分别检测 HIF-1α过表达对 NCI-H1563 细胞增殖和凋亡的影响。
COPD 组 HIF-1α和 EGFR 的 mRNA 和蛋白水平均高于对照组。COPD 患者血清中 IL-13、IL-9、IL-1 和 TNF-α水平升高。NCI-H1563 细胞中 CoCl2 诱导导致 IL-13、IL-9、IL-1 和 TNF-α水平上调。740Y-P 处理显著激活 EGFR/PI3K/AKT 通路。过表达 HIF-1α抑制 NCI-H1563 细胞增殖，但诱导其凋亡。
COPD 中 HIF-1α表达上调，通过激活 EGFR/PI3K/AKT 通路上调炎症因子表达。肺部炎症激活的 EGFR/PI3K/AKT 通路进一步以反馈环的方式上调 HIF-1α表达，从而加重 COPD 病理变化。
