Role of α-SMA, NOX4, Fibronectin, and HIF-1α in Pulmonary Microvascular Remodeling in COPD Patients Without Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a severe chronic obstructive pulmonary disease (COPD) complication, with vascular remodeling occurring early in disease progression. Oxidative stress, particularly NADPH oxidase subunit 4 (NOX4) activity, drives vascular smooth muscle differentiation, vasoconstriction, and proliferation, while Hypoxia-inducible factor-1α (HIF-1α), activated by NOX4-derived hydrogen peroxide (H2O2), plays a key contributory role in early pulmonary vascular remodeling. This study explores the roles of α-smooth muscle actin (α-SMA), NOX4, fibronectin (FN), and HIF-1α roles in pulmonary microvascular remodeling in COPD patients without PAH. METHODS: Lung tissue samples from patients undergoing resection at General Hospital of Ningxia Medical University (Oct 2022-Dec 2023) were analyzed. Participants included COPD (n = 20) and control (n = 17) groups. NOX4, HIF-1α, α-SMA, and fibronectin expression in the pulmonary microvasculature (< 500 μm) were assessed via immunohistochemistry and Western blot. Smooth muscle remodeling (pulmonary vascular smooth muscle thickness percentage, WT%; pulmonary vascular smooth muscle area percentage, WA%) and serum vascular endothelial growth factor (VEGF) levels were evaluated. RESULTS: COPD patients exhibited significant thickening of the pulmonary microvascular smooth muscle layer, with endothelial cell swelling, degeneration, and necrosis. The WT% and WA% values of COPD patients were elevated compared to controls, alongside increased FN expression in the pulmonary microvasculature. NOX4, HIF-1α, and α-SMA expression levels were higher in COPD patients, particularly within endothelial cells and macrophages surrounding pulmonary vessels. The peripheral blood neutrophil count in the COPD group was higher than in the control group. Compared to the control group, COPD patients showed high expression of NOX4 and HIF-1α in macrophages surrounding the pulmonary microvessels. Serum VEGF concentrations were significantly elevated in COPD patients and positively correlated with HIF-1α expression in lung tissue homogenates. CONCLUSIONS: Pulmonary microvascular remodeling occurs in COPD patients even without PAH, characterized by smooth muscle thickening, extracellular matrix deposition, and endothelial alterations. The NOX4-HIF-1α oxidative stress pathway, coupled with inflammatory cell activation, may contribute to microvascular remodeling in COPD.