Progressive Activation of TGF-β after Lung Transplantation Drives Progenitor Fate Arrest and Fibrotic Airway Remodeling

Chronic lung allograft dysfunction (CLAD) leads to significant mortality in lung transplant recipients. The pathogenesis involves a failure of epithelial regeneration and subsequent fibrosis, yet the molecular drivers remain elusive. This study investigates the role of progressive TGF-β activation in disrupting airway progenitor cell function. We utilized a ferret /human orthotopic lung transplant model prone to developing CLAD pathology. Our data indicate that alloimmune injury triggers a localized, progressive activation of TGF-β in the airway niche. This high-TGF-β environment induces a "fate arrest" in resident airway basal cells (BCs), preventing them from differentiating into functional mucociliary epithelium. Instead, these progenitors adopt a pro-fibrotic and EMT phenotype. We identify that specific integrin-mediated activation of TGF-β is the upstream driver of this arrest. Crucially, interrupting this signaling axis restores the regenerative potential of BCs and prevents fibrous obliteration of the airway lumen. These findings highlight the restoration of progenitor efficiency as a potential therapeutic strategy for CLAD. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.