Oxygen Desaturation Is Associated With Fibrocyte Activation via Epidermal Growth Factor Receptor/ Hypoxia-Inducible Factor-1α Axis in Chronic Obstructive Pulmonary Disease

Abstract

Background: Fibrocytes are bloodborne mesenchymal progenitors which accumulate and differentiate at disease site. We investigated whether hypoxemia activates fibrocytes, accelerating airflow limitation and exercise intolerance in chronic obstructive pulmonary disease (COPD) patients. Methods: Flow cytometry was used to determine collagen I+/CD45+ fibrocytes and α-smooth muscle actin+ differentiating fibrocytes within peripheral blood and cultured cells, as well as the expression of CXC chemokine receptor 4 (CXCR4), epidermal growth factor receptor (EGFR), connective tissue growth factor (CTGF) and hypoxia-inducible factor (HIF)-1α. Fibrocytes in lung specimens were identified by confocal microscopy. Findings: Compared to non-desaturators, COPD desaturators (peripheral blood oxygen saturation ≤88% during exercise) had greater number of fibrocytes in peripheral blood and lung specimens, paralleled with faster yearly lung function decline and 6-minute walk distance. Fibrocytes from desaturators expressed more EGFR, CXCR4, CTGF and HIF-1α, with a higher capacity to proliferation and myofibroblastic differentiation. Hypoxia (5% oxygen) increased the expression of EGFR, CXCR4, CTGF and HIF-1α, the number and differention in fibrocytes. These effects were attenuated by EGFR inhibitor gefitinib, HIF-1α gene silencing, and anti-CTGF antibody. Interpretation: These data elucidate that hypoxaemia triggers fibrocyte activation through the EGFR/HIF-1α axis, aggravating airflow obstruction in COPD. Funding Information: This work was supported by the National Medical Research Program (NMRP) grant 99-2314-B-182-043-MY3, 108-2314-B-182A-128-MY2 and the Chang Gung Medical Research Project (CMRP) grant CMRPG390041-2. Declaration of Interests: The authors have declared that no competing interest exists. Ethics Approval Statement: The study was approved by the Ethics Committee of Chang Gung Memorial Hospital (IRB: 98-3950B, 201801979A3). Written informed consents were obtained from all participants.