BCL-2 调节 IRE1α 激活,以减轻内分泌网膜压力和肺纤维化
Claude Jourdan Le Saux1, Tsung Che Ho1, Alexis M Brumwell1
1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California; and.
American journal of respiratory cell and molecular biology
|December 20, 2023
概括
在BCL-2蛋白质限制肺损伤和纤维化通过减少内质网膜 (ER) 的压力和细胞外矩阵积累. 抑制BCL-2会加剧ER压力和原积累,损害肺部的修复.
科学领域:
- 细胞生物学 细胞生物学
- 肺部医学 肺部医学
- 分子生物学分子生物学
背景情况:
- BCL-2家族蛋白质是细胞存活的关键调节者.
- 细胞内网膜 (ER) 应激和细胞外基质 (ECM) 积累与肺损伤和纤维化有关.
研究的目的:
- 研究BCL-2在肺损伤和修复过程中的作用.
- 确定BCL-2在减轻ER压力和肺损伤后ECM积累方面的功能.
主要方法:
- 在小鼠中引发肺部损伤的intratracheal bleomycin挑战.
- 用纳维托克拉克斯 (一种BCL-2/BCL-xL抑制剂) 来评估BCL-2抑制效应.
- 分析ER压力标志物 (IRE1α激活),亡,原积累和MRC2表达.
- 使用精密切割的肺切片培养物进行机械学研究.
主要成果:
- 在白素挑战后,BCL-2抑制增加了上皮细胞损失和ER压力标志物 (IRE1α激活).
- 与对照组不同,纳维托克拉克斯治疗导致持续的原积累和纤维化.
- IRE1α的RNAase活性降低了MRC2的调节,这是一种原循环调节剂,有助于纤维化.
- 在肺切片培养中,MRC2缺乏模仿了BCL-2抑制的纤维效应.
结论:
- 除了抗亡,BCL-2在减轻ER压力和限制纤维化方面发挥着至关重要的作用.
- 抑制BCL-2会破坏IRE1α和BAX之间的关联,促进ER压力.
- IRE1α对MRC2的下调有助于持续的原体积累和肺部修复功能受损.
- 向BCL-2可能通过调节ER压力和ECM平衡来为肺纤维性疾病提供治疗潜力.
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