Redox Signaling in Chronic Airway Diseases: Pathogenic Mechanisms and Therapeutic Implications

Mario Cazzola^1*Paola Rogliani¹Luigino Calzetta²Frank M.P. Van Haren³Clive P Page⁴Maria Gabriella Matera⁵

• ¹Universita degli Studi di Roma Tor Vergata Dipartimento di Medicina Sperimentale, Rome, Italy
• ²Universita degli Studi di Parma Dipartimento di Medicina e Chirurgia, Parma, Italy
• ³Australian National University School of Medicine and Psychology, Canberra, Australia
• ⁴King's College London, London, United Kingdom
• ⁵Universita degli Studi della Campania Luigi Vanvitelli Dipartimento di Medicina Sperimentale, Naples, Italy

Chronic airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis, impose a significant global health burden. A central unifying feature of these diseases is redox imbalance, which is characterized by an excess of reactive oxygen and nitrogen species (ROS/RNS) that overwhelms the body's antioxidant defenses, causing cellular dysfunction, inflammation, and tissue damage. Physiological ROS/RNS are essential for immune regulation and transcriptional control, but chronic oxidative stress disrupts these processes, driving disease progression. In asthma, eosinophil-and epithelial-derived ROS worsen airway hyperresponsiveness, mucus overproduction, and reduce steroid effects. COPD involves neutrophil-dominated inflammation, mitochondrial dysfunction, protease-and oxidant-mediated extracellular matrix degradation, and accelerated senescence. Bronchiectasis features persistent neutrophilic oxidative injury, microbial colonization, impaired mucociliary clearance, and progressive airway destruction. Exogenous oxidants, cigarette smoke, biomass fuels, pollutants, and pathogens further burden antioxidant systems, including superoxide dismutases, catalase, glutathione peroxidase, and Nrf2-regulated pathways. Redox dysregulation also contributes to post-COVID sequelae, promoting ongoing airway inflammation, fibrosis, and systemic complications. Therapeutic strategies targeting redox imbalance, mainly thiol-based antioxidants, Nrf2 activators, NADPH oxidase inhibitors, and mitochondria-targeted antioxidants, show mechanistic promise but face challenges in specificity, bioavailability, and clinical translation. Advancing precision redox medicine requires biomarker-guided patient stratification, high-resolution redox proteomics, single-cell and organoid models, and spatial imaging to identify disease-specific redox endotypes. Modulating pathological oxidative stress while preserving physiological signaling offers a novel avenue to improve outcomes. Understanding redox biology in airway disease highlights the potential of precision antioxidant strategies as adjuncts to 3 conventional therapies, representing a paradigm shift in managing chronic airway disorders.