Mechanical Forces and Mechanotransduction in COPD: Pathogenesis, Clinical Phenotypes, and Therapeutic Implications

Abstract: Chronic obstructive pulmonary disease (COPD) remains a leading cause of global morbidity and mortality. Despite advances in therapy, its complex pathogenesis involves mechanisms beyond the traditional paradigms of inflammation and protease–antiprotease imbalance. Emerging evidence indicates that COPD is also shaped by important mechanobiological processes, in which altered airway mechanics, parenchymal destruction, and respiratory muscle dysfunction create a pathological physical environment. In this narrative review, we synthesize current knowledge on how abnormal mechanical forces are sensed by key mechanosensors—including integrins, Piezo channels, and YAP/TAZ—and transduced into biochemical signals that drive chronic inflammation, fibrosis, and defective repair. We further discuss how these mechanotransduction feedback loops perpetuate structural injury and may help explain the clinical heterogeneity observed across airflow obstruction, emphysema, and exacerbation-prone phenotypes. Furthermore, we discuss therapeutic strategies, positioning pulmonary rehabilitation, lung volume reduction, and ventilation as interventions that restore mechanical homeostasis. Finally, we highlight the emerging possibility of targeting mechanosensitive pathways (e.g. ROCK and YAP/TAZ inhibitors) and utilizing mechanobiology-informed regenerative medicine. By integrating biomechanics with clinical management, this review provides a conceptual framework that may inform future efforts to move beyond symptomatic palliation toward more mechanism-based and potentially disease-modifying strategies in COPD. Keywords: chronic obstructive pulmonary disease, COPD, mechanotransduction, extracellular matrix remodeling, YAP/TAZ, mechanical homeostasis