HIF-1α promotes inflammatory response of chronic obstructive pulmonary disease by activating EGFR/PI3K/AKT pathway

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.