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<p>High-altitude retinopathy (HAR) arises under acute hypobaric hypoxia (AHH), yet the temporal coupling of oxidative stress, apoptosis and cytokine signaling in the retina remains unclear. We exposed healthy male C57BL/6 mice to a hypobaric chamber (≈5,000&#xa0;m) for 2–72&#xa0;h, with normoxic controls at 1,500&#xa0;m (<i>n</i> = 3 eyes/group). Haematoxylin–eosin sections quantified total and laminar thickness; at 24&#xa0;h, bulk RNA-seq profiled transcripts. Reactive oxygen species (ROS) were assayed by dihydroethidium, and Western blotting/immunofluorescence evaluated Bax, Bcl-2/Bcl-xL, cleaved caspase-3, cytochrome c, poly(ADP-ribose) polymerase-1, tumour necrosis factor-α, phosphorylated Janus kinase-1 (p-JAK1), phosphorylated signal transducer and activator of transcription-3 (p-STAT3), leukemia inhibitory factor (LIF) and LIF receptor (LIFR). Total retinal thickness increased from 173.10 ± 0.36&#xa0;μm (control) to 227.99 ± 0.33&#xa0;μm at 24&#xa0;h and 234.61 ± 0.39&#xa0;μm at 72&#xa0;h, with concordant GCL/INL/ONL thickening. RNA-seq showed enrichment of hypoxia/oxidative-stress, apoptotic, and JAK–STAT pathways with <i>Lif/Lifr</i> up-regulation. ROS rose from 12&#xa0;h and peaked at 72&#xa0;h (<i>p</i> &lt; 0.05). Pro-apoptotic indices (Bax/Bcl-2, Bax/Bcl-xL, cleaved caspase-3/total) and cytochrome c, PARP-1, and TNF-α increased with exposure. p-JAK1 rose from 12 to 72&#xa0;h, whereas p-STAT3 peaked at 48&#xa0;h and remained elevated at 72&#xa0;h. LIF/LIFR protein accumulated from 2–72&#xa0;h (48&#xa0;h apex). These time-resolved data reveal progressive oedema with sustained oxidative burden and a LIF–JAK1–STAT3 activation peak, suggesting a therapeutic window in AHH-induced retinal injury.</p>

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Time-Resolved Oxidative Stress and Apoptosis in Murine Retina under Acute Hypobaric Hypoxia with Parallel Activation of the LIF–JAK–STAT3 Axis

  • 期刊论文

  • 发表日期：

    2026年1月16日

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  • Hao Wang,
  • Qiang Ye,
  • Songjian Huang,
  • Keke Ge,
  • Cong Han,
  • Huan Xi,
  • Junyi Qiao,
  • Jingrong Feng,
  • Peirun Wu,
  • Yuhan Bao,
  • Yi Yang,
  • Wenfang Zhang

摘要

High-altitude retinopathy (HAR) arises under acute hypobaric hypoxia (AHH), yet the temporal coupling of oxidative stress, apoptosis and cytokine signaling in the retina remains unclear. We exposed healthy male C57BL/6 mice to a hypobaric chamber (≈5,000 m) for 2–72 h, with normoxic controls at 1,500 m (n = 3 eyes/group). Haematoxylin–eosin sections quantified total and laminar thickness; at 24 h, bulk RNA-seq profiled transcripts. Reactive oxygen species (ROS) were assayed by dihydroethidium, and Western blotting/immunofluorescence evaluated Bax, Bcl-2/Bcl-xL, cleaved caspase-3, cytochrome c, poly(ADP-ribose) polymerase-1, tumour necrosis factor-α, phosphorylated Janus kinase-1 (p-JAK1), phosphorylated signal transducer and activator of transcription-3 (p-STAT3), leukemia inhibitory factor (LIF) and LIF receptor (LIFR). Total retinal thickness increased from 173.10 ± 0.36 μm (control) to 227.99 ± 0.33 μm at 24 h and 234.61 ± 0.39 μm at 72 h, with concordant GCL/INL/ONL thickening. RNA-seq showed enrichment of hypoxia/oxidative-stress, apoptotic, and JAK–STAT pathways with Lif/Lifr up-regulation. ROS rose from 12 h and peaked at 72 h (p < 0.05). Pro-apoptotic indices (Bax/Bcl-2, Bax/Bcl-xL, cleaved caspase-3/total) and cytochrome c, PARP-1, and TNF-α increased with exposure. p-JAK1 rose from 12 to 72 h, whereas p-STAT3 peaked at 48 h and remained elevated at 72 h. LIF/LIFR protein accumulated from 2–72 h (48 h apex). These time-resolved data reveal progressive oedema with sustained oxidative burden and a LIF–JAK1–STAT3 activation peak, suggesting a therapeutic window in AHH-induced retinal injury.