Abstract Rationale Chronic obstructive pulmonary disease (COPD) is characterized by progressive alveolar destruction, airway remodeling, and pulmonary vascular alterations. The main pathological factors include chronic oxidative stress and aberrant repair. The dual oxidase 1 (DUOX1), a non-phagocytic NADPH oxidase producing H2O2, contributes to epithelial redox signaling, wound healing, and barrier maintenance. DUOX1 is markedly downregulated in human COPD lungs, but the mechanistic insights in chronic injury and tissue remodeling remain unexplored. Methods Wild-type (Wt) and Duox1 knockout (Duox1−/−) mice were exposed to cigarette smoke (CS) for 3 or 8 months to model emphysema and COPD-associated vascular alterations. Structural and functional changes were assessed by micro-computed tomography (µCT), echocardiography, lung mechanics, and right heart catheterization. Morphometric and molecular analyses were used to examine emphysema, vascular remodeling, mitochondrial dynamics, and autophagy flux. Ex vivo precision-cut lung slices (PCLS) from Wt and Duox1−/− mice were exposed to CS extract to evaluate cytotoxicity, proliferation and capillary pruning. Available single-cell RNA-seq datasets from human COPD and healthy donor lungs were analyzed to assess DUOX1 expression and DUOX1 deficiency-associated signaling pathways in alveolar epithelial cells. Results DUOX1 deficiency conferred protection against acute CS-induced epithelial injury, characterized by reduced apoptosis and necrosis in mouse PCLS. However, chronic CS exposure resulted in markedly aggravated emphysema, increased lung compliance, airway wall thickening, and extracellular matrix remodeling in Duox1−/− mice compared to Wt controls. These animals developed spontaneous pulmonary hypertension, with elevated right ventricular systolic pressure, decreased RV function, and evidence of capillary pruning. Unlike classical inflammation-driven vascular remodeling, DUOX1-deficient lungs displayed limited leukocyte infiltration but marked accumulation of dysfunctional epithelial cells with impaired clearance. Mechanistically, loss of DUOX1 disrupted mitochondrial quality control, increased the fusion/fission ratio, and induced autophagic arrest, reflected by p62 and LC3B accumulation. These defects blunted adaptive inflammatory signaling while permitting persistence of damaged cells, leading to maladaptive tissue degeneration and vascular pruning. Conclusions Epithelial DUOX1 is crucial for redox signaling, mitochondrial homeostasis, and autophagic clearance to maintain lung integrity during chronic stress caused by environmental exposure to noxious factors. DUOX1 deficiency creates a paradoxical state of injury tolerance without effective repair, aggravating emphysema and pulmonary vascular alterations. Targeting DUOX1-dependent epithelial stress adaptation may represent a novel therapeutic avenue to preserve alveolar-vascular integrity in COPD. Funding University Hospital Giessen and Marburg Lung Center (UKGM; 5/2023GI), the German Research Foundation (DFG; CRC 1213 A04), the von Behring-Röntgen Stiftung (72₀014), and the Excellence Cluster Cardio-Pulmonary Institute (CPI). This abstract is funded by: University Hospital Giessen and Marburg Lung Centre (UKGM) Forschungsförderung §2 Abs. 3; Projekt Nr. 5/2023 GI and Projekt Nr. 15/2025 GI, the German Research Foundation (DFG) CRC 1213, A07; Projekt Nr. 268555672, the von-Behring-Röntgen Stiftung Projekt 72₀014, as well as the Excellence Cluster Cardio-Pulmonary Institute (CPI) Projekt Nr. 390649896
Hadzic et al. (Fri,) studied this question.