Nature and Science of Sleep (Aug 2022)

Severe Intermittent Hypoxia Modulates the Macrophage Phenotype and Impairs Wound Healing Through Downregulation of HIF-2α

  • Chen L,
  • Gao Y,
  • Li Y,
  • Wang C,
  • Chen D,
  • Gao Y,
  • Ran X

Journal volume & issue
Vol. Volume 14
pp. 1511 – 1520

Abstract

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Lihong Chen,1 Yunyi Gao,2 Yan Li,1 Chun Wang,1 Dawei Chen,1 Yun Gao,1 Xingwu Ran1 1Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Medical Affairs, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Xingwu Ran, Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, 37 Guo Xue Lane, Chengdu, 610041, People’s Republic of China, Tel +86 028-85422046, Email [email protected]: Obstructive sleep apnea is prevalent in patients with diabetic foot ulcers, while the effect of intermittent hypoxia on wound healing is unclear. The objective of this study was to investigate the effect of severe intermittent hypoxia on wound healing.Methods: C57BL/6 mice were exposed to 5 weeks of severe intermittent hypoxia or normoxia. The wound healing rate were assessed. The gene expression of CD206 and HIF-2α was tested in vivo and in vitro. Inflammatory factors in RAW264.7 macrophages were measured to investigate the effect of intermittent hypoxia on macrophage polarization. The proliferation of HUVECs and HaCaT cells was also assessed after exposure to intermittent hypoxia.Results: Severe intermittent hypoxia decreased wound healing at day 3. The expression of CD206 and HIF-2α was significantly decreased after exposure to severe intermittent hypoxia. In vitro, severe intermittent hypoxia significantly promoted M1 phenotype polarization of RAW264.7 macrophages and increased the expression of proinflammatory factors (IL-1β and TNF-α). Severe intermittent hypoxia also decreased the proliferation of HUVECs cultured in endothelial cell medium and HaCaT cells cultured in high glucose DMEM.Conclusion: Severe intermittent hypoxia could lead to M1 but not M2 macrophage polarization through downregulation of HIF-2α, and then lead to impaired wound healing.Keywords: wound and injuries, intermittent hypoxia, wound healing, inflammation, hypoxia inducible factor

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