Hypoxia Impacts Injury and Repair in Submucosal Glands

Long-term lung transplant survival remains challenging due to the development of chronic lung allograft dysfunction (CLAD). Submucosal glands (SMGs) are a critical stem cell niche in the airways that supports surface airway epithelial homeostasis. The destruction of SMGs has been associated with aberrant injury repair and fibrosis. Our laboratory has identified depletion of SMGs within 21 days post-transplant in a ferret model, consistent with observations in human CLAD. A potential etiology for SMG destruction is ischemia-reperfusion injury (IRI), in which prolonged ischemia followed by re-oxygenation can lead to hypoxic stress, oxidative injury, and cellular damage. We hypothesize that IRI drives SMG destruction by impairing SMG cell viability and disrupting pathways essential for their regenerative capacity. We further propose that hypoxia-mediated HIF-1α activation contributes to SMG gland depletion. To investigate the IRI-associated hypoxia, we have utilized a novel AirTech technique to culture ferret trachea explants on a Matrigel matrix and expose them to controlled hypoxic conditions. Preliminary findings demonstrated a decrease in SMG viability under hypoxic conditions, which may contribute to SMG injury as well as their limited capacity for regeneration. These results will advance our understanding of how hypoxia and reperfusion affect airway epithelial regeneration. Additionally, this framework will facilitate mechanistic studies aimed at deciphering hypoxia-responsive pathways and identifying potential targets to preserve SMG function in lung allografts, thereby maintaining airway epithelial regeneration and potentially preventing or delaying 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.