Alanazi Abdulaziz H, Selim Mohamed S, Zhu Yin, Zhang Duo, Narayanan S Priya, Somanath Payaningal R
Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA, USA.
Research Department, Health Care System, Augusta, GA, USA.
Tissue Barriers. 2025 Jun 20:2521136. doi: 10.1080/21688370.2025.2521136.
Diabetes mellitus is a systemic disease characterized by chronic hyperglycemia, persistent inflammation, and oxidative stress. While the vascular complications of diabetes are well-documented, their impact on lung barrier integrity remains underexplored. In this study, we investigated the molecular mechanisms by which advanced glycation end-products (AGE) compromise the integrity of lung endothelial and epithelial barriers. Using human lung microvascular endothelial cells and epithelial (A549) cells, we assessed the impact of AGE on the tight junction protein claudin-5, adherens junction protein VE-cadherin, and key signaling molecules including the receptor for AGE (RAGE), phosphorylated Akt, and p38 MAPK as well as a panel of pro-inflammatory cytokines. Our findings demonstrated that AGE exposure (50 μg/mL) significantly activated Akt and p38 MAPK, upregulated Claudin-5 and RAGE, and downregulated VE-cadherin, correlating with reduced transendothelial electrical resistance . Notably, we observed similar effects on lung epithelial cells. Moreover, AGE-treated conditioned media from THP-1 macrophages induced a pronounced increase in inflammatory cytokines, amplifying the disruption of lung barrier integrity. These findings reveal a potential mechanism linking diabetes-induced vascular dysfunction and immune activation to compromised lung barrier function, emphasizing the need for further research into diabetes-associated lung complications.
糖尿病是一种以慢性高血糖、持续性炎症和氧化应激为特征的全身性疾病。虽然糖尿病的血管并发症已有充分记录，但其对肺屏障完整性的影响仍未得到充分研究。在本研究中，我们调查了晚期糖基化终产物（AGE）损害肺内皮和上皮屏障完整性的分子机制。使用人肺微血管内皮细胞和上皮（A549）细胞，我们评估了AGE对紧密连接蛋白claudin-5、黏附连接蛋白VE-钙黏蛋白以及包括AGE受体（RAGE）、磷酸化Akt和p38丝裂原活化蛋白激酶（p38 MAPK）在内的关键信号分子以及一组促炎细胞因子的影响。我们的研究结果表明，暴露于AGE（50μg/mL）显著激活了Akt和p38 MAPK，上调了Claudin-5和RAGE，并下调了VE-钙黏蛋白，这与跨内皮电阻降低相关。值得注意的是，我们在肺上皮细胞上观察到了类似的效应。此外，来自THP-1巨噬细胞的经AGE处理的条件培养基诱导炎性细胞因子显著增加，加剧了肺屏障完整性的破坏。这些发现揭示了一种潜在机制，将糖尿病诱导的血管功能障碍和免疫激活与受损肺屏障功能联系起来，强调了对糖尿病相关肺部并发症进行进一步研究的必要性。
