Obstructive sleep apnea (OSA) has been increasingly recognized as a risk factor for idiopathic pulmonary fibrosis (IPF). The intermittent hypoxia (IH) and re-oxygenation of OSA contribute to poor outcomes of IPF, however, the potential mechanism remains unknown. Here, C57BL/6J mice were administered intratracheal injection of Bleomycin (BLM) or saline and then exposed to IH (alternating cycles of FiO₂ 21% for 60S and FiO₂ 10% for 30 s, 40 cycles/hour, 8 h/day) to mimic OSA or intermittent air (IA) for 4 days, 8 days or 21 days. This study found that pulmonary fibrosis in BLM + IH treated mice was more severe than that in BLM + IA group at day 8 and 21, but not observed at day 4. Besides, the expression of reactive oxygen species (ROS) and hypoxia inducible factor-1α (HIF-1α),which are related to hypoxia reduced oxidative stress and inflammation, were higher in BLM + IH treated mice than BLM + IA mice, and IH increased these indexes in BLM treated mice from day 4 to day 21. Interestingly, a positive linear correlation between the HIF-1α expression and hydroxyproline (HYP) content was observed. We further found some inflammatory cells in bronchoalveolar lavage fluid were increased significantly from day 4 to 21, and there was a positive correlation between inflammation and ROS expression. Our results demonstrated that IH aggravated BLM-induced pulmonary fibrosis, and ROS/HIF-1α related oxidative stress and inflammation involved. The increase of ROS/HIF-1α related oxidative stress and inflammation may be a potential mechanism of moderate-to-severe OSA in potentiating pulmonary fibrosis of IPF, which warrants further study.

阻塞性睡眠呼吸暂停（OSA）越来越被认为是特发性肺纤维化（IPF）的危险因素。 OSA 的间歇性缺氧 (IH) 和再氧合导致 IPF 的不良预后，但其潜在机制仍不清楚。此处，C57BL/6J 小鼠气管内注射博来霉素 (BLM) 或盐水，然后暴露于 IH（FiO ₂ 21% 60 秒和 FiO ₂ 10% 30 秒的交替循环，40 个循环/小时，8 小时/天） ) 模拟 OSA 或间歇空气 (IA) 4 天、8 天或 21 天。本研究发现，第8天和第21天时，BLM+IH治疗组小鼠的肺纤维化程度较BLM+IA组严重，但在第4天时未观察到。此外，活性氧（ROS）和缺氧诱导因子的表达也较BLM+IA组严重。 -1α (HIF-1α) 与缺氧减少氧化应激和炎症有关，在 BLM + IH 处理的小鼠中比 BLM + IA 小鼠更高，并且 IH 从第 4 天到第 21 天增加了 BLM 处理小鼠的这些指标。有趣的是，观察到 HIF-1α 表达与羟脯氨酸（HYP）含量之间呈正线性相关。我们进一步发现支气管肺泡灌洗液中的一些炎症细胞在第4天至第21天显着增加，并且炎症与ROS表达呈正相关。我们的结果表明，IH 加重了 BLM 诱导的肺纤维化，并涉及 ROS/HIF-1α 相关的氧化应激和炎症。 ROS/HIF-1α相关氧化应激和炎症的增加可能是中重度OSA加重IPF肺纤维化的潜在机制，值得进一步研究。