Abstract Rationale Hypoxemia and exercise-induced desaturation are associated with accelerated lung function decline and increased mortality in COPD. Fibrocytes derived from COPD desaturators were activated through the EGFR/HIF-1α axis, aggravating airflow obstruction in COPD. We investigated hypoxia-induced mechanism of airway fibrosis. Methods Serum and lung tissue were obtained from COPD desaturators (defined as SpO2 ≤88 in room air or during exercise) and non-desaturators. Lung fibroblast MRC-5 and bronchial epithelial BEAS-2B cell lines were cultured under normoxic and hypoxic conditions (5% O2). The effects of IL-8 stimulation and EGFR inhibition on fibroblast proliferation, differentiation, and cytokine release were evaluated with analysis of gene and protein expression of HIF-1α, EGFR, vimentin, α-smooth muscle actin (α-SMA), collagen I, connective tissue growth factor (CTGF), IL-8, MMP-9, and vascular endothelial growth factor (VEGF). Results Serum levels of IL-8 of COPD desaturators (25.6±3.4pg/ml, n = 13) were higher compared to those of non-desaturators (12.3±1.9pg/ml, n = 14, p 0.01). Higher expression of IL-8 immunoreactivity in lung tissue from COPD desaturators was also noticed in immunostaing. In MRC-5 fibroblasts, hypoxia induced activation of EGFR and associated downstream signaling pathways (includes ERK, AKT/mTOR, p38 MAPK), all of which were blocked by gefitinib except for p38 MAPK. Hypoxia and IL-8 exposure increased transforming growth factor-β1 (TGF-β1) and IL-8 expression, while gefitinib suppressed IL-8 upregulation. Hypoxia enhanced vimentin expression, a marker of epithelial-mesenchymal transition (EMT), which was blocked by inhibitors of EGFR, mTOR, and p38, but not ERK. α-SMA and collagen I expression were reduced by gefitinib, rapamycin, and SB203580 under both normoxia and hypoxia. In BEAS-2B cells, hypoxia increased HIF-1α protein epression in a time-dependent manner, peaking at 24 hours. Gefitinib attenuated IL-8 and MMP-9 but paradoxically increased CTGF expression under both normoxia and hypoxia. Conclusions Hypoxia-induced activation of EGFR/HIF-1α/IL-8 signaling axis mediates fibroblast proliferation, differentiation, and EMT through ERK, AKT/mTOR, and p38 MAPK pathways. Targeting EGFR or HIF-1α may attenuate hypoxia-driven fibrogenesis and airway remodeling, offering potential therapeutic strategies for COPD. This abstract is funded by: None
Hsieh et al. (Fri,) studied this question.