Advanced glycation endproducts induce cytokine dysregulation and weaken lung epithelial and endothelial barrier integrity.

IF 4 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Abdulaziz H Alanazi, Mohamed S Selim, Yin Zhu, Duo Zhang, S Priya Narayanan, Payaningal R Somanath
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Abstract

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 in vitro. 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.

晚期糖基化终产物诱导细胞因子失调,削弱肺上皮和内皮屏障的完整性。
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有充分的文献记载,但它们对肺屏障完整性的影响仍未得到充分探讨。在这项研究中,我们研究了晚期糖基化终产物(AGE)破坏肺内皮和上皮屏障完整性的分子机制。利用人肺微血管内皮细胞和上皮细胞(A549),我们评估了AGE对紧密连接蛋白cladin -5、粘附连接蛋白VE-cadherin、AGE受体(RAGE)、磷酸化Akt和p38 MAPK等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,AGE暴露(50 μg/mL)可显著激活Akt和p38 MAPK,上调cladin -5和RAGE,下调VE-cadherin,并与体外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类似的作用。此外,经age处理的THP-1巨噬细胞条件培养基诱导炎症细胞因子显著增加,放大了肺屏障完整性的破坏。这些发现揭示了糖尿病诱导的血管功能障碍和免疫激活与肺屏障功能受损之间的潜在机制,强调了对糖尿病相关肺并发症的进一步研究的必要性。
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来源期刊
Tissue Barriers
Tissue Barriers MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.60
自引率
6.50%
发文量
25
期刊介绍: Tissue Barriers is the first international interdisciplinary journal that focuses on the architecture, biological roles and regulation of tissue barriers and intercellular junctions. We publish high quality peer-reviewed articles that cover a wide range of topics including structure and functions of the diverse and complex tissue barriers that occur across tissue and cell types, including the molecular composition and dynamics of polarized cell junctions and cell-cell interactions during normal homeostasis, injury and disease state. Tissue barrier formation in regenerative medicine and restoration of tissue and organ function is also of interest. Tissue Barriers publishes several categories of articles including: Original Research Papers, Short Communications, Technical Papers, Reviews, Perspectives and Commentaries, Hypothesis and Meeting Reports. Reviews and Perspectives/Commentaries will typically be invited. We also anticipate to publish special issues that are devoted to rapidly developing or controversial areas of research. Suggestions for topics are welcome. Tissue Barriers objectives: Promote interdisciplinary awareness and collaboration between researchers working with epithelial, epidermal and endothelial barriers and to build a broad and cohesive worldwide community of scientists interesting in this exciting field. Comprehend the enormous complexity of tissue barriers and map cross-talks and interactions between their different cellular and non-cellular components. Highlight the roles of tissue barrier dysfunctions in human diseases. Promote understanding and strategies for restoration of tissue barrier formation and function in regenerative medicine. Accelerate a search for pharmacological enhancers of tissue barriers as potential therapeutic agents. Understand and optimize drug delivery across epithelial and endothelial barriers.
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