Abstract
The molecular mechanisms whereby hyperbaric oxygen (HBO) improves ischemic wound healing remain elusive. In this study, a rat model of wound ischemia was used to test the hypothesis that HBO enhances wound healing by modulating hypoxia-inducible factor-1alpha (HIF-1alpha) signaling. Male Sprague-Dawley rats underwent creation of a previously validated ischemic flap. Three groups underwent daily treatment: HBO (90 minutes, 2.4 atm); systemic administration of the free radical scavenger, N-acetylcysteine (NAC 150 mg kg(-1) intraperitoneal); control (neither HBO nor NAC). HBO treatment improved healing of the ischemic wounds. Analysis of ischemic wound tissue extracts demonstrated significantly reduced expression of HIF-1alpha, p53, and BNip3. Additionally, HBO increased expression of Bcl-2 while decreasing cleaved caspase-3. DNA fragmentation was abolished and the number of TUNEL-positive cells was reduced compared to the other groups. Vascular endothelial growth factor, cyclooxygenase-2, and neutrophil infiltration were reduced in ischemic wounds treated with HBO. These results indicate that HBO improves ischemic wound healing by downregulation of HIF-1alpha and subsequent target gene expression with attenuation of cell apoptosis and reduction of inflammation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / pharmacology
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Acetylcysteine / therapeutic use
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Animals
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Apoptosis / physiology*
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Cyclooxygenase 2 / metabolism
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Free Radical Scavengers / pharmacology
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Free Radical Scavengers / therapeutic use
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Hyperbaric Oxygenation*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Inflammation / physiopathology*
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Inflammation / therapy
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Ischemia / metabolism
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Ischemia / physiopathology*
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Ischemia / therapy
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mitochondrial Proteins
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Models, Animal
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / physiology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Vascular Endothelial Growth Factor A / metabolism
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Wound Healing / drug effects
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Wound Healing / physiology
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Wounds and Injuries / metabolism
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Wounds and Injuries / physiopathology*
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Wounds and Injuries / therapy
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bcl-2-Associated X Protein / metabolism
Substances
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BNIP3 protein, rat
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Free Radical Scavengers
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Hif1a protein, rat
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Hypoxia-Inducible Factor 1, alpha Subunit
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Membrane Proteins
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Mitochondrial Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Protein p53
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Vascular Endothelial Growth Factor A
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bcl-2-Associated X Protein
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Cyclooxygenase 2
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Caspase 3
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Acetylcysteine