Han Shuangyu, Huang Jie, Yang Changqing, Feng Jing, Wang Yubao
Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, China.
FASEB J. 2025 Jan 15;39(1):e70306. doi: 10.1096/fj.202402813R.
Obstructive sleep apnea (OSA) is increasingly recognized for its link to idiopathic pulmonary fibrosis (IPF), though the underlying mechanisms remain poorly understood. Histone lysine demethylase 6B (KDM6B) may either prevent or promote organ fibrosis, but its specific role in IPF is yet to be clarified. This study aimed to investigate the function and mechanisms of KDM6B in IPF and the exacerbating effects of OSA. We assessed KDM6B levels in lung tissues from IPF patients, IPF mouse models, and a dual-hit model combining OSA-associated intermittent hypoxia (IH) with bleomycin (BLM) or TGF-β1. We evaluated pulmonary fibrosis, myofibroblast activation, and oxidative stress. KDM6B levels were elevated in lung tissues from IPF patients and BLM-treated mice, as well as in TGF-β1-stimulated myofibroblasts. Importantly, IH significantly worsened BLM-induced pulmonary fibrosis and TGF-β1-induced myofibroblast activation, further amplifying KDM6B expression both in vivo and in vitro. Inhibition of KDM6B reduced pulmonary fibrosis and decreased fibroblast activation and migration in IPF and dual-hit models. Mechanistically, KDM6B inhibition led to decreased NOX4 expression and reduced oxidative stress. KDM6B plays a critical role in promoting pulmonary fibrosis and mediating the exacerbating effects of OSA on this condition. Our findings identify KDM6B as a novel potential therapeutic target for IPF.
阻塞性睡眠呼吸暂停（OSA）与特发性肺纤维化（IPF）的关联日益受到关注，但其潜在机制仍不清楚。组蛋白赖氨酸去甲基化酶6B（KDM6B）可能预防或促进器官纤维化，但其在IPF中的具体作用尚待阐明。本研究旨在探讨KDM6B在IPF中的功能和机制以及OSA的加剧作用。我们评估了IPF患者、IPF小鼠模型以及将OSA相关间歇性缺氧（IH）与博来霉素（BLM）或转化生长因子-β1（TGF-β1）相结合的双打击模型的肺组织中KDM6B水平。我们评估了肺纤维化、肌成纤维细胞活化和氧化应激。IPF患者和BLM处理小鼠的肺组织以及TGF-β1刺激的肌成纤维细胞中KDM6B水平升高。重要的是，IH显著加重了BLM诱导的肺纤维化和TGF-β1诱导的肌成纤维细胞活化，在体内和体外进一步放大了KDM6B的表达。抑制KDM6B可减轻IPF和双打击模型中的肺纤维化，并减少成纤维细胞活化和迁移。机制上，抑制KDM6B导致NOX4表达降低和氧化应激减轻。KDM6B在促进肺纤维化和介导OSA对这种疾病的加剧作用中起关键作用。我们的研究结果确定KDM6B是IPF的一个新的潜在治疗靶点。
