Integrated airway epithelial signaling networks linking allergen-driven inflammation to airway remodeling in asthma

Asthma is a chronic inflammatory airway disease characterized by persistent immune activation, airway hyperresponsiveness, and progressive structural remodeling. The airway epithelium functions as the primary sensor of inhaled allergens and actively orchestrates both innate and adaptive immune responses through alarmin and chemokine release, while directly driving structural changes via epithelial-mesenchymal transition and profibrotic mediator production. Upon allergen challenge, exemplified by house dust mite, airway epithelial cells activate an integrated network of signaling pathways, including epidermal growth factor receptor, mitogen-activated protein kinase, PI3K/protein kinase B, nuclear factor kappa B (NF-κB), Janus kinase/signal transducer and activator of transcription (STAT), and transforming growth factor-β/SMAD, which converge on key transcription factors, including NF-κB/RelA, AP-1, STAT6, SMAD2/3, and CCAAT/enhancer-binding protein beta, to coordinately induce the production of acute inflammatory factors, including alarmins (thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, IL-25), and chemokines (C-C motif chemokine ligand 20, C-X-C motif chemokine ligand 8), as well as chronic cellular remodeling, including goblet cell hyperplasia, subepithelial fibrosis, and smooth muscle expansion. This review provides a comprehensive, network-centered synthesis of these mechanisms, with a particular focus on the molecular basis of asthma endotype heterogeneity, amplifying role of viral exacerbations, epigenetic regulation of epithelial inflammatory programs, and signaling basis of corticosteroid resistance. Further, we map the mechanistic basis of the phenotypic heterogeneity across eosinophilic, neutrophilic, and mixed asthma endotypes onto specific network configurations and then discuss therapeutic implications spanning approved biologics, kinase inhibitors, barrier-restoration strategies, and combinatorial approaches.