The Role of Hypoxia-Inducible Factor in Wound Healing
Open accessAbstract
Significance: Poor wound healing remains a significant health issue for a large number of patients in the United States. The physiologic response to local wound hypoxia plays a critical role in determining the success of the normal healing process. Hypoxia-inducible factor-1 (HIF-1), as the master regulator of oxygen homeostasis, is an important determinant of healing outcomes. HIF-1 contributes to all stages of wound healing through its role in cell migration, cell survival under hypoxic conditions, cell division, growth factor release, and matrix synthesis throughout the healing process. Recent Advances: Positive regulators of HIF-1, such as prolyl-4-hydroxylase inhibitors, have been shown to be beneficial in enhancing diabetic ischemic wound closure and are currently undergoing clinical trials for treatment of several human-ischemia-based conditions. Critical Issues: HIF-1 deficiency and subsequent failure to respond to hypoxic stimuli leads to chronic hypoxia, which has been shown to contribute to the formation of nonhealing ulcers. In contrast, overexpression of HIF-1 has been implicated in fibrotic disease through its role in increasing myofibroblast differentiation leading to excessive matrix production and deposition. Both positive and negative regulators of HIF-1 therefore provide important therapeutic targets that can be used to manipulate HIF-1 expression where an excess or deficiency in HIF-1 is known to correlate with pathogenesis. Future Directions: Targeting HIF-1 during wound healing has many important clinical implications for tissue repair. Counteracting the detrimental effects of excessive or deficient HIF-1 signaling by modulating HIF-1 expression may improve future management of poorly healing wounds.
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Positive regulators of HIF-1, such as prolyl-4-hydroxylase inhibitors, have been shown to be beneficial in enhancing diabetic healing.
“positive regulators of HIF-1, such as prolyl-4-hydroxylase inhibitors, have been shown to be beneficial in enhancing diabetic healing (Hong et al., 2014).”
From The role of iron in the skin and cutaneous wound healing (2014) · cites this paper as Hong et al., 2014
The Abstract says prolyl-4-hydroxylase inhibitors enhanced diabetic ischemic wound closure. The Discussion reports improved healing of diabetic ischemic wounds in mice. The claim omits those conditions and presents the benefit as applying to diabetic healing generally. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCurrent evidence favors a key role for hypoxia in the mechanisms by which iron deficiency may impair wound healing.
“Current evidence favors a key role played by hypoxia.”
From The role of iron in the skin and cutaneous wound healing (2014) · cites this paper as Hong et al., 2014
The Translational Relevance section says hypoxia is an important determinant of wound repair, and the Discussion links persistent hypoxia to impaired healing. These passages support the printed sentence’s general point, but our copy does not link iron deficiency to hypoxia as a mechanism of impaired wound healing (searched: iron deficiency, anemia). (LLM, conf=0.84)
Experimental — accuracy not yet measuredHypoxia-inducible factor-1 contributes to all stages of wound healing through its role in cell migration, cell survival under hypoxic conditions, cell division, growth factor release, and matrix synthesis.
“Hypoxia-inducible factor-1 (HIF-1) contributes to all stages of wound healing (through its role in cell migration, cell survival under hypoxic conditions, cell division, growth factor release, and matrix synthesis)”
From The role of iron in the skin and cutaneous wound healing (2014) · cites this paper as Hong et al., 2014
Hypoxia may be the single most important event following tissue injury, and adaptation to hypoxic stress via HIF signaling plays a critical role in promoting wound healing.
“Thus, hypoxia may well be viewed as the single most important event following tissue injury, and, indeed, adaptation to hypoxic stress via HIF signaling plays a critical role in promoting wound healing processes [74,75].”
From The Pathogenesis of Adenomyosis vis-à-vis Endometriosis (2020) · cites this paper as [75]
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“…(through its role in cell migration, cell survival under hypoxic conditions, cell division, growth factor release, and matrix synthesis) and positive regulators of HIF-1, such as prolyl-4-hydroxylase inhibitors, have been shown to be beneficial in enhancing diabetic healing (Hong et al., 2014).”
BackgroundThe Pathogenesis of Adenomyosis vis-à-vis Endometriosis
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“Thus, hypoxia may well be viewed as the single most important event following tissue injury, and, indeed, adaptation to hypoxic stress via HIF signaling plays a critical role in promoting wound healing processes [74,75].”
BackgroundA tissue injury sensing and repair pathway distinct from host pathogen defense
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- Authors
- Hong, W. X., Hu, M. S., Esquivel, M., Liang, G. Y., Rennert, R. C., McArdle, A., Paik, K. J., Duscher, D., Gurtner, G. C., Lorenz, H. P., & Longaker, M. T.
- Affiliations
- University of Central Florida (US)
- University of Hawaiʻi at Mānoa (US)
- Stanford Medicine (US)
- ORCID
- Venue
- Advances in Wound Care
- Publisher
- SAGE Publications
- Published
- 2014-05
- Volume
- 3
- Issue
- 5
- Pages
- 390-399
- ISSN
- 2162-1918 (ISSN-L)
- 2162-1934
- PMC
- PMC4005494
- OpenAlex
- W2119778962
- Cited by
- 448
- References
- 55
- Citations by year
- 2026: 61 · 2025: 55 · 2024: 60 · 2023: 57 · 2022: 51 · 2021: 47 · 2020: 29 · 2019: 28 · 2018: 18 · 2017: 21 · 2016: 7 · 2015: 7 · 2014: 5
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Advances in Wound Care (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- California Institute for Regenerative Medicine
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetic Foot Ulcer Assessment and Management
- Keywords
- HIF-1, wound healing, wound hypoxia, oxygen homeostasis, chronic wounds, chronic ulcers, fibrosis, myofibroblast differentiation, extracellular matrix synthesis, cell migration
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