Airway epithelial cells and asthma: from barrier disruption to alarmin-driven inflammation and remodeling

Asthma is a highly heterogeneous chronic inflammatory airway disease whose pathophysiology is determined by a combination of genetic, environmental, and immune factors. As the largest interface between the host and the environment, airway epithelial cells serve not only as a physical barrier against exogenous stimuli but also as central cells in sensing environmental threats and initiating immune responses. Among their functions, the release of epithelial-derived alarmins is a key step in initiating type 2 inflammation. Under the long-term interaction of genetic susceptibility and environmental factors, persistent structural and functional alterations occur in the airway epithelium of asthma patients. These include disruption of the barrier integrity, skewed cell differentiation, aberrant repair programs, and dysregulated alarmin release. These alterations not only exacerbate airway inflammation but can also directly drive the process of airway remodeling through mechanisms such as epithelial-mesenchymal transition, ciliary dysfunction, mucus hypersecretion, and paracrine regulation of smooth muscle. Remodeling also involves biochemical and mechanical alterations, including dysregulated expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), increased extracellular matrix (ECM) stiffness, and enhanced collagen crosslinking. Given the central role of the airway epithelium in asthma pathogenesis, targeting its alarmins and related signaling pathways holds promise for providing precise intervention strategies for patients with specific endotypes. This article systematically reviews the structural and functional changes in the asthmatic airway epithelium, analyzes the intrinsic links between barrier dysfunction, alarmin release, and airway pathological changes, and summarizes recent advances in interventions targeting the airway epithelium, aiming to provide a new theoretical basis for the precise diagnosis and treatment of asthma.