老龄小鼠的呼吸功能障碍可能与高磷血症诱发的炎症和肺纤维化有关。

IF 4.4 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL European Journal of Clinical Investigation Pub Date : 2024-08-18 DOI:10.1111/eci.14302
Ana Asenjo-Bueno, Elena Alcalde-Estévez, Gemma Olmos, Patricia Martínez-Miguel, María Piedad Ruiz-Torres, Susana López-Ongil
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引用次数: 0

摘要

背景:随着年龄的增长,肺部会发生典型的变化,导致呼吸功能衰退。我们的目的是评估与年龄相关的高磷血症在这些变化中的作用:方法:我们使用 C57BL6 小鼠研究体内老化模型,并用磷酸盐供体--β-甘油磷酸酯(BGP)处理人肺成纤维细胞,以探索相关机制。呼吸功能由双腔式胸透仪记录。用不同的染色法分析肺部结构,用比色试剂盒分析磷酸盐和细胞因子水平,用 Western 印迹或 RT-PCR 分析纤维化、炎症和 ET-1 系统的表达:结果:老龄小鼠表现为高磷血症、肺纤维化、弹性蛋白丧失、促炎细胞因子表达增加和呼吸功能受损。BGP 通过激活 NFkB 并使其与 MCP-1 或 FN 启动子结合,诱导成纤维细胞发生炎症和纤维化。BGP 通过诱导 NFkB 与 ECE-1 启动子结合,增加了 ECE-1 的表达。NFkB抑制剂QNZ阻断了这些作用。当用磷酰氨抑制 ECE-1 时,BGP 诱导的炎症和纤维化明显减轻,这表明 ET-1 在 BGP 介导的效应中发挥作用。ET-1 产生的效应与 BGP 相似,也依赖于 NFkB。为了研究高磷血症在体内的病理生理相关性,给一组老年动物喂食低磷饮食,结果显示,与食用标准饮食的老年小鼠相比,纤维化、炎症和呼吸功能均有所改善:这些结果表明,与年龄相关的高磷血症会诱发老年小鼠的炎症、纤维化和呼吸功能受损;这些影响似乎是由 ET-1 和 NFkB 激活介导的。
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Respiratory dysfunction in old mice could be related to inflammation and lung fibrosis induced by hyperphosphatemia

Background

With age, lungs undergo typical changes that lead to a deterioration of respiratory function. Our aim was to assess the role of age-associated hyperphosphatemia in these changes.

Methods

We used C57BL6 mice to study an ageing model in vivo and human lung fibroblasts were treated with a phosphate donor, beta-glycerophosphate (BGP), to explore mechanisms involved. Respiratory function was registered with a double chamber plethysmograph. Lung structure was analysed by different staining, phosphate and cytokines levels by colorimeric kits, expression of fibrosis, inflammation and ET-1 system by western blot or RT-PCR.

Results

Old mice showed hyperphosphatemia, along with lung fibrosis, loss of elastin, increased expression of pro-inflammatory cytokines and impaired respiratory function. BGP induced inflammation and fibrosis in fibroblasts through the activation and binding of NFkB to the MCP-1 or FN promoters. BGP increased ECE-1 expression by inducing NFkB binding to the ECE-1 promoter. QNZ, an NFkB inhibitor, blocked these effects. When ECE-1 was inhibited with phosphoramidon, BGP-induced inflammation and fibrosis were significantly reduced, suggesting a role for ET-1 in BGP-mediated effects.ET-1 produced effects similar to those of BGP, which were also dependent on NFkB. To study the pathophysiological relevance of hyperphosphatemia in vivo, a low-P diet was administered to a group of old animals, showing an improvement in fibrosis, inflammation and respiratory function compared to old mice on a standard diet.

Conclusion

These results suggest that age-related hyperphosphatemia induces inflammation, fibrosis, and impaired respiratory function in old mice; these effects appear to be mediated by ET-1 and NFkB activation.

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来源期刊
CiteScore
9.50
自引率
3.60%
发文量
192
审稿时长
1 months
期刊介绍: EJCI considers any original contribution from the most sophisticated basic molecular sciences to applied clinical and translational research and evidence-based medicine across a broad range of subspecialties. The EJCI publishes reports of high-quality research that pertain to the genetic, molecular, cellular, or physiological basis of human biology and disease, as well as research that addresses prevalence, diagnosis, course, treatment, and prevention of disease. We are primarily interested in studies directly pertinent to humans, but submission of robust in vitro and animal work is also encouraged. Interdisciplinary work and research using innovative methods and combinations of laboratory, clinical, and epidemiological methodologies and techniques is of great interest to the journal. Several categories of manuscripts (for detailed description see below) are considered: editorials, original articles (also including randomized clinical trials, systematic reviews and meta-analyses), reviews (narrative reviews), opinion articles (including debates, perspectives and commentaries); and letters to the Editor.
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