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Editorial

Oxygen in wound healing: More than a nutrient

JOHN D. DAVIDSON, MD; THOMAS A. MUSTOE, MD

Attempts to treat problem wounds with hyperbaric oxy- time to allow the consideration of any other possible

mechanism. The idea however, that one could supplygen began almost simultaneously in Japan, Europe, and

the United States during the decade of the l960s. By oxygen to hypoxic tissue only 8% of the time and make

things better was counterintuitive to some in the hyper-the late 1970s many clinical studies had been published

which suggested a beneficial role for the use of supple- baric medical community, and it was ludicrous to many

in the scientific community at large. If tissue needs oxy-mental oxygen administered under increased pressure

for the treatment of selected wounds. These early prom- gen as a respiratory metabolite, it needs it all the time.

Tissue does not have an oxygen stomach where excessising results and subsequent continued favorable re-

sponses noted by clinicians encouraged its ongoing use. can be stored and then stoked into the oxidative furnace

as needed. In the 1970s and 1980s the probable deleteri-During this era it was also quickly recognized that the

vast majority of problem wounds that responded to hyrb- ous effects of the prolonged period of hypoxia between

hyperbaric oxygen treatments was partially explainedaric oxygen therapy were associated with conditions

which compromised the blood supply and oxygenation by the assumption that an adequate supply of oxygen

persisted for several hours after each treatment. It wasof tissue. These conditions included radiation damage,

diabetes mellitus, arteriosclerosis, vasculitis, venous sta- also known that hypoxia is an early and important event

in the initiation of the healing process in acute woundssis, tobacco abuse and the increased oxygen demand of

infection.1 The pioneering studies of Hunt and Niinikoski and therefore it was assumed that a period of hypoxia

was an essential ingredient for the stimulation of theon the pivotal role of oxygen in the wound healing pro-

cess and the work of Sheffield in the measurement of healing process in chronic wounds. Recentaccurate mea-

surements of tissue oxygen during and following hyper-tissue oxygen provided the beginning of a physiologic

underpinning to support the use of hyperbaric oxygen baric oxygen treatments however, document that this

form of treatment delivers hyperoxia, not physiologicin problem wounds.1,2

During the early decades of this form of treatment concentrations of oxygen, and that adequate supplies of

oxygen remain in ischemic tissue only a few hours atthe vast majority of hyperbaric physicians thought that

hyperbaric oxygen was merely a tool to supply oxygen most.4 These facts force us to rethink the fundamental

assumptions about what we are doing. Clearly, when weto tissue that needs oxygen. Non-healing wounds were

oxygen deficient; these wounds were given oxygen and treat a patient with a non-healing hypoxic wound we are

not giving a physiologic dose of oxygen for an appro-they got better. The mechanismof thebeneficial response

was assumed to be the provision of oxygen to tissue priate amount of time if our therapy is only fuel for the

cellular oxidative furnace.in order to restore normal physiologic function. To the

physician of that era, oxygen was being used in its usually If oxygen is not functioning in its usually conceived

role, why does it work? How does it work? What role isconceived role in oxidative cellular respiration. Notenough was known about molecular mechanisms at that it playing? Some possible answers are suggested by the

work of Zhao et al. who noted a 100% reversal of the

healing deficit induced by ischemia in experimental ani-From the Division of Plastic Surgery, Northwestern Univer- mals when wounds were treated with hyperbaric oxygen

sity Medical School, Chicago, Illinois.Reprint requests: Thomas A. Mostoe, MD, Division of Plastic

Surgery, Northwestern University Medical School,19th Floor, Suite 250, 675 North St. Clair Street, PDGF Platelet-derived growth factor

VEGF Vascular endothelial growth factorChicago, IL 60611-2923. Fax: (312) 695-5672;Email: tmustoe@mnh.org.

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WOUND REPAIR AND REGENERATION

MAYJUNE 2001176 DAVIDSON ET AL.

and growth factors simultaneously.5 Clearly this syner- in keratinocytes.11,12 Endothelial cells respond to hypoxia

with a seven-fold increase in PDGF messenger RNA.13gistic response suggested a direct interaction between

oxygen and growth factors rather than the response ex- VEGF, which is the most stringently regulated of all

growth factors, is upregulated by the hypoxic milieu inpected from restoring adequate nutrition to sick cells.

Thenature of this interaction was workedout by Bonomo the center of many solid tumors.14 It has become evident

in recent years that hypoxic stimulation of many genesand his co-workers who reported a statistically signifi-

cant rise in the production of platelet derived growth depends upon the activation of hypoxia inducible fac-

tor.15factor (PDGF) receptor protein in ischemic wounds thatwere treated simultaneously with both hyperbaric oxy- On the other hand, it is now apparent that hyperoxia

also induces a distinct set of cellular responses. Becausegen and PDGF.6 This finding lends strong support to the

concept that hyperbaric oxygen functions as an intracel- hyperbaric oxygen has been shown to modify the expres-

sion of VEGF and PDGF receptors, could it be that hyper-lular signal transducer and thus is a modulator of gene

function. In addition, Hunt and his colleagues have re- oxia may act via an oxygen sensing transduction pathway

to impact on other important regulators of cell growthported complementary evidence for this concept by dem-

onstrating an increased production of vascular and metabolism?

All of the data mentioned above support the hypothe-endothelial growth factor (VEGF) by macrophages after

exposure to hyperoxia.79 sis that transient hyperoxia functions as an intracellular

signal transduction agent or modulator of gene functionSiddiqui et al. documented that hyperbaric oxygen

treatment produces hyperoxic (not physiologic) concen- via more than one signaling pathway in addition to sup-

plying the critical element for cellular respiration. At thistrations of oxygen in ischemic wounds and that oxygenconcentration falls promptly to pretreatment levels in point in time much is conjecture, however two things

are certain. One is that oxygen supplied under hyperbaricischemic tissue.4 They also demonstrated a progressive

increase in the peak oxygen concentration in ischemic conditions is more than nutrition for oxygen starved

cells. The other is that there is much exciting work yettissue when it was challenged with 100% oxygen at one

atmosphere as well as a more rapid washout of oxygen to be done to learn how hyperbaric oxygen lays its heal-

ing touch on ischemic chronic wounds.from tissue after serial hyperbaric oxygen treatments.

The magnitude of these changes was proportional to the

John D. Davidson, MDnumber of hyperbaric oxygen treatments.4 In our view

Thomas A. Mustoe, MDthese acute changes in the responsiveness of ischemic

tissue to serial hyperbaric oxygen treatments suggest a

prompt production of a transient but potent local vasodi-

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New York: Elsevier, 1988.produce optimal therapeutic benefit in patients with

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3. Sheffield PJ. Tissue oxygen measurements with respect to softments should be administered and for how long , at whattissue wound healing with normobaric and hyperbaric oxygen.

pressure, and how frequently? None of these questionsHBO Review 1985;6:1846.

have been studied in a systemic way. The current clinical 4. Siddiqui A, Davidson JD, Mustoe TA. Ischemic tissue oxygen ca-pacitance after hyperbaric oxygen therapy: a new physiologicapproach has grown out of a welter of empiric observa-concept. Plast Reconstr Surg 1997;99:14855.tions, many of which are not germane to chronic hypoxic

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ulcers. Arch Surg 1994;129:10439.studies has been obtained from wounds that bear little6. Bonomo S, Davidson JD, Yu Y, Xia Y, LinX, Mustoe TA. Hyperbaricbiochemical resemblance to the wounds that have been

oxygen as a signal transducer: upregulation of platelet derivedpresent in our patients for months or years.10

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poxia. Chemoreceptors in the carotid body and in the angiogenesis. Undersea Hyperb Med 1997;24 (S):134.9. Feng JJ, GibsonJJ, Constant JS. Hyperoxia stimulatesmacrophageaortic arch respond to a fall in sensed oxygen tension.

vascular endothelial growth factor (VEGF) production. WoundHypoxia also induces cellular proliferation and an in-Rep Reg 1998;6:122.

crease in the production of transforming growth factor- 10. Bonomo SR, Davidson JD, Tyrone JW, Lin X, Mustoe TA. Enhance-ment of wound healing by hyperbaric oxygen and transforming in fibroblasts, as well as enhanced cellular migration

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genesis. Nature 1992;359:8438.12. OToole EA, Marinkovich MP, Peavey CL, Amieva MR, Furthmayr

H, Mustoe TA, Woodley, DT. Hypoxia increases human keratino- 15. Bunn HF, Poyton RO. Oxygen sensing and molecular adaptation

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