Oxygen in wound healing: More than a nutrient

This article provides an overview of the role of oxygen in wound healing. The understanding of this role has undergone a major evolution from its long-recognized importance as an essential factor for oxidative metabolism, to its recognition as an important cell signal interacting with growth factors and other signals to regulate signal transduction pathways. Our laboratory has been engaged in the study of animal models of skin ischemia to explore in vivo the impact of hypoxia as well as the use of oxygen as a therapeutic agent either alone or in combination with other agents such as growth factors. We have demonstrated a synergistic effect of systemic hyperbaric oxygen and growth factors that has been substantiated by Hunt's group. Within the past 10 years research in the field of wound healing has given new insight into the mechanism of action of hypoxia and hyperoxia as modifiers of the normal time-course of wound healing. The article concludes with a discussion of why hypoxia and hyperoxia intercurrently play an important role in wound healing. Hypoxia-inducible factor 1 is crucial in that interplay.

[1]  D. Faller,et al.  Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells. , 1990, The Journal of clinical investigation.

[2]  Bruce M. Smith,et al.  Transcutaneous oxygen measurements predict healing of leg wounds with hyperbaric therapy , 1996, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[3]  Thomas A. Mustoe, MD, FACS,et al.  Hypoxia increases human keratinocyte motility on connective tissue. , 1997, The Journal of clinical investigation.

[4]  J. West,et al.  Adjuncts to preparing wounds for closure: hyperbaric oxygen, growth factors, skin substitutes, negative pressure wound therapy (vacuum-assisted closure). , 2001, Foot and ankle clinics.

[5]  Thomas A. Mustoe, MD, FACS,et al.  Effect of ischemia on growth factor enhancement of incisional wound healing. , 1995, Surgery.

[6]  T. K. Hunt,et al.  Hydrogen peroxide stimulates macrophage vascular endothelial growth factor release. , 2001, American journal of physiology. Heart and circulatory physiology.

[7]  S H Lee,et al.  Early expression of angiogenesis factors in acute myocardial ischemia and infarction. , 2000, The New England journal of medicine.

[8]  Yanru Wang,et al.  Modification of the Furter equation and correlation of the vapor–liquid equilibrium for mixed-solvent electrolyte systems , 1999 .

[9]  G. Semenza HIF-1: mediator of physiological and pathophysiological responses to hypoxia. , 2000, Journal of applied physiology.

[10]  T. K. Hunt,et al.  Tissue oxygenation, anemia, and perfusion in relation to wound healing in surgical patients. , 1991, Annals of surgery.

[11]  T. K. Hunt,et al.  Role of oxygen in repair processes. , 1972, Acta chirurgica Scandinavica.

[12]  J. Remacle,et al.  Stress-Induced Premature Senescence or Stress-Induced Senescence-Like Phenotype: One In Vivo Reality, Two Possible Definitions? , 2002, TheScientificWorldJournal.

[13]  T. K. Hunt,et al.  Wound tissue oxygen tension predicts the risk of wound infection in surgical patients. , 1997, Archives of surgery.

[14]  G. Semenza,et al.  HIF-1, O2, and the 3 PHDs How Animal Cells Signal Hypoxia to the Nucleus , 2001, Cell.

[15]  Thomas A. Mustoe, MD, FACS,et al.  Ischemic Tissue Oxygen Capacitance after Hyperbaric Oxygen Therapy: A New Physiologic Concept , 1997, Plastic and reconstructive surgery.

[16]  G. Semenza,et al.  Age-dependent Defect in Vascular Endothelial Growth Factor Expression Is Associated with Reduced Hypoxia-inducible Factor 1 Activity* , 2000, The Journal of Biological Chemistry.

[17]  Thomas A. Mustoe, MD, FACS,et al.  Hyperbaric oxygen as a signal transducer: upregulation of platelet derived growth factor-beta receptor in the presence of HBO2 and PDGF. , 1998, Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc.

[18]  V. Ferrans,et al.  Requirement for Generation of H2O2 for Platelet-Derived Growth Factor Signal Transduction , 1995, Science.

[19]  Denis Mottet,et al.  Transduction pathways involved in Hypoxia-Inducible Factor-1 phosphorylation and activation. , 2001, Free radical biology & medicine.

[20]  V. Ferrans,et al.  Regulation of reactive-oxygen-species generation in fibroblasts by Rac1. , 1996, The Biochemical journal.

[21]  T. K. Hunt,et al.  Oxidant-induced Vascular Endothelial Growth Factor Expression in Human Keratinocytes and Cutaneous Wound Healing* , 2002, The Journal of Biological Chemistry.

[22]  K. Hehenberger,et al.  Dose‐dependent hyperbaric oxygen stimulation of human fibroblast proliferation , 1997, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[23]  V. Falanga,et al.  Low oxygen tension stimulates collagen synthesis and COL1A1 transcription through the action of TGF‐β1 , 2002, Journal of cellular physiology.

[24]  T. K. Hunt,et al.  Wound hypoxia and acidosis limit neutrophil bacterial killing mechanisms. , 1997, Archives of surgery.

[25]  Thomas A. Mustoe, MD, FACS,et al.  Differential expression of platelet‐derived growth factor receptor‐β in an aging model of wound repair , 1996, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[26]  R. Kirsner,et al.  Low oxygen stimulates proliferation of fibroblasts seeded as single cells , 1993, Journal of cellular physiology.

[27]  R. O. Poyton,et al.  Oxygen sensing and molecular adaptation to hypoxia. , 1996, Physiological reviews.

[28]  R. Weiskopf,et al.  Subcutaneous perfusion and oxygen during acute severe isovolemic hemodilution in healthy volunteers. , 2000, Archives of surgery.

[29]  T. K. Hunt,et al.  Oxygen supply in healing tissue , 1972 .

[30]  N. Holbrook,et al.  Age-related decline in cellular response to oxidative stress: links to growth factor signaling pathways with common defects. , 2002, Biochemical pharmacology.

[31]  P. Moore,et al.  Effects of keratinocyte growth factor‐2 (KGF‐2) on wound healing in an ischaemia‐impaired rabbit ear model and on scar formation , 1999, The Journal of pathology.

[32]  Thomas A. Mustoe, MD, FACS,et al.  Vascular endothelial growth factor is more important than basic fibroblastic growth factor during ischemic wound healing. , 1999, Archives of surgery.

[33]  R. Galiano,et al.  Keratinocyte growth factor induces granulation tissue in ischemic dermal wounds. Importance of epithelial-mesenchymal cell interactions. , 1996, Archives of surgery.

[34]  J. Pouysségur,et al.  p42/p44 Mitogen-activated Protein Kinases Phosphorylate Hypoxia-inducible Factor 1α (HIF-1α) and Enhance the Transcriptional Activity of HIF-1* , 1999, The Journal of Biological Chemistry.

[35]  Savita Khanna,et al.  Oxygen, Oxidants, and Antioxidants in Wound Healing , 2002, Annals of the New York Academy of Sciences.

[36]  Thomas A. Mustoe, MD, FACS,et al.  Enhancement of wound healing by hyperbaric oxygen and transforming growth factor beta3 in a new chronic wound model in aged rabbits. , 2000, Archives of surgery.

[37]  T. K. Hunt,et al.  Oxygen and healing. , 1969, American journal of surgery.

[38]  Thomas A. Mustoe, MD, FACS,et al.  Effect of hyperbaric oxygen and growth factors on rabbit ear ischemic ulcers. , 1994, Archives of surgery.

[39]  L. Kedes,et al.  Coordinate reciprocal trends in glycolytic and mitochondrial transcript accumulations during the in vitro differentiation of human myoblasts , 1990, Journal of cellular physiology.

[40]  Thomas A. Mustoe, MD, FACS,et al.  Differential activation of migration by hypoxia in keratinocytes isolated from donors of increasing age: implication for chronic wounds in the elderly. , 2001, The Journal of investigative dermatology.

[41]  Thomas A. Mustoe, MD, FACS,et al.  Effect of age and hypoxia on TGFβ1 receptor expression and signal transduction in human dermal fibroblasts: Impact on cell migration , 2002, Journal of cellular physiology.

[42]  T. K. Hunt,et al.  Wound healing and wound infection. What surgeons and anesthesiologists can do. , 1997, The Surgical clinics of North America.

[43]  T. K. Hunt,et al.  Oxygen tensions in human wounds. , 1972, The Journal of surgical research.

[44]  M. Robson,et al.  Wound Infection: A Failure of Wound Healing Caused by an Imbalance of Bacteria , 1997 .

[45]  D. Donato,et al.  The vaginal-psoas suspension repair of uterovaginal prolapse. , 2002, Journal of the American College of Surgeons.

[46]  R. Kirsner,et al.  Low oxygen tension increases mRNA levels of alpha 1 (I) procollagen in human dermal fibroblasts , 1993, Journal of cellular physiology.

[47]  H. Scheuenstuhl,et al.  Lactate elicits vascular endothelial growth factor from macrophages: a possible alternative to hypoxia , 2000, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[48]  G F Pierce,et al.  Collagen-embedded platelet-derived growth factor DNA plasmid promotes wound healing in a dermal ulcer model. , 2000, The Journal of surgical research.

[49]  Thomas A. Mustoe, MD, FACS,et al.  Role of hypoxia in growth factor responses: differential effects of basic fibroblast growth factor and platelet‐derived growth factor in an ischemic wound model , 1994, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[50]  T. K. Hunt,et al.  Anaerobic metabolism and wound healing: an hypothesis for the initiation and cessation of collagen synthesis in wounds. , 1978, American journal of surgery.

[51]  E. Keshet,et al.  Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis , 1992, Nature.

[52]  G. Semenza,et al.  General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[53]  V. Falanga,et al.  The levels and kinetics of oxygen tension detectable at the surface of human dermal fibroblast cultures , 2000, Journal of cellular physiology.

[54]  Thomas A. Mustoe, MD, FACS,et al.  Effects of Ischemia on Ulcer Wound Healing: A New Model in the Rabbit Ear , 1989 .

[55]  T. K. Hunt,et al.  Respiratory Gas Tensions and Collagen in Infected Wounds , 1972, Annals of surgery.

[56]  T. K. Hunt,et al.  Effect of hyperoxia on vascular endothelial growth factor levels in a wound model. , 2000, Archives of surgery.

[57]  G. Semenza,et al.  Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Thomas A. Mustoe, MD, FACS,et al.  Transforming growth factor-beta1 fails to stimulate wound healing and impairs its signal transduction in an aged ischemic ulcer model: importance of oxygen and age. , 1999, The American journal of pathology.

[59]  Z. Werb,et al.  Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. , 1998, Science.

[60]  B. Cochran,et al.  Activation of the JAK-STAT pathway by reactive oxygen species. , 1998, American journal of physiology. Cell physiology.

[61]  M. Sporn,et al.  Hypoxia upregulates the synthesis of tgf-β1 by human dermal fibroblasts , 1991 .

[62]  R. Galiano,et al.  Differential effects of oxygen on human dermal fibroblasts: acute versus chronic hypoxia , 1996, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.