High-Altitude Oral Ulcers: Immune Dysregulation And Cell Death Mechanisms

This study investigates the molecular mechanisms linking hypobaric hypoxia to recurrent oral ulcers, focusing on oxidative stress-mediated crosstalk between pyroptosis, ferroptosis, and immune dysregulation in mucosal epithelial damage. We established an in vitro hypoxia/low-pressure model and used H₂O₂/LPS-induced oxidative stress as a control. Key inflammatory factors (IL-6, TNF-α, IL-1β) and markers of ferroptosis (PTGS2, ACSL4) and pyroptosis (NLRP3, caspase-1, GSDMD) were analyzed using qPCR, Western blot, and ELISA. Additionally, a mouse model of oral ulcers under hypoxic conditions was developed. Histopathological changes were assessed via immunohistochemistry (IL-8, TNF-α, SOD) and HE staining, while flow cytometry was employed to evaluate CD4⁺/CD8⁺ T-cell ratios. Our findings demonstrate that hypoxia significantly upregulated key mediators of pyroptosis (NLRP3, caspase-1, IL-1β) and ferroptosis (PTGS2, ACSL4), leading to reduced cell viability and increased levels of malondialdehyde and lactate dehydrogenase. Hypoxia also caused thinning of the mucosal layer, elevated pro-inflammatory cytokines (IL-8, TNF-α), decreased superoxide dismutase (SOD) activity, and disrupted CD4⁺/CD8⁺ T-cell ratios. Notably, inhibiting NLRP3 or administering the ferroptosis inhibitor LIP-1 effectively mitigated pyroptosis and ferroptosis, promoting mucosal repair. In summary, our study reveals that hypoxia triggers oxidative stress, which drives pyroptosis, ferroptosis, and immune dysregulation in mucosal epithelial cells. Targeting NLRP3, employing antioxidants, or inhibiting ferroptosis may hold significant therapeutic potential for treating oral ulcers. These findings warrant further clinical validation and could pave the way for innovative treatment strategies in this challenging condition.