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MCT4调解了IPF纤维细胞的缺氧诱导的细胞外乳酸释放

Richard S Nho¹, Lauren Nielsen¹, Jessica Roberts¹

¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, 43210, OH.

American journal of respiratory cell and molecular biology

|February 25, 2026

概括

单碳酸盐载体4 (MCT4) 驱动异常性肺纤维化 (IPF) 纤维细胞中的乳酸出口,促进肺纤维化. 抑制MCT4或乳酸信号减少纤维化,为IPF提供潜在的治疗点.

科学领域:

肺部医学肺部医学
细胞生物学细胞生物学
生物化学生物化学

背景情况:

乳酸盐在异形性肺纤维化 (IPF) 肺部升高,与纤维化病原发生有关.
在缺氧下,IPF纤维细胞通过改变的乳酸脱酶活性产生多余的乳酸盐.
单碳酸盐输送物4 (MCT4),乳酸输出物,在肺纤维化中的作用尚未研究.

研究的目的:

研究MCT4在IPF纤维细胞乳酸生产和肺纤维化中的作用.
为了确定MCT4是否在IPF纤维细胞上调节,并有助于细胞外乳酸积累.
探索在IPF中准MCT4或乳酸信号的治疗潜力.

主要方法:

在控制和IPF纤维细胞中评估了MCT4和MCT1表达在低氧状态下.
利用MCT4的药理抑制和沉默来评估其对乳酸出口的影响.
在肺损伤和IPF患者肺组织的小鼠模型中检查了MCT4表达.
研究了IPF纤维细胞受条件介质对正常纤维细胞分化的影响以及MCT4和GPR-81.1的作用.

主要成果:

在低氧条件下,MCT4在IPF纤维细胞中显著上调,而MCT1水平保持不变.
通过IPF纤维细胞抑制或抑制MCT4减少细胞外乳酸生成.
在白素受伤的小鼠肺部和IPF患者肺部,MCT4表达升高.
来自缺氧IPF纤维细胞的条件介质在正常纤维细胞中诱导了α-光滑肌动蛋白表达,这种效应因MCT4或GPR-81抑制而减弱.

结论:

在低氧环境下,MCT4在促进IPF纤维细胞在细胞外乳酸盐产生方面发挥着关键作用.
通过MCT4增加乳酸出口有助于肺纤维化和纤维细胞分化.
准MCT4或乳酸受体GPR-81为IPF提供了一个新的治疗策略.

关键词:

氧气过低是因为缺氧.异形性肺纤维化 (IPF) 是一种疾病.乳酸脱酶的使用方法 α-平滑肌肉行为蛋白 (α-SMA)

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