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 supply gen 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 excess ising 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 explained aric 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 was of 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 wounds sis, 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 the on 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. Recent accurate 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 physiologic in 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 at the 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 we to 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 the beneficial 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 is conceived role in oxidative cellular respiration. Not
enough 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 factor Chicago, IL 60611-2923. Fax: (312) 695-5672;
Email: tmustoe@mnh.org.
175
WOUND REPAIR AND REGENERATION
MAYJUNE 2001 176 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.
13
gistic 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 in pected from restoring adequate nutrition to sick cells.
The nature of this interaction was worked out by Bonomo the center of many solid tumors.
14
It has become evident
in recent years that hypoxic stimulation of many genes and 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.
15
factor (PDGF) receptor protein in ischemic wounds that
were treated simultaneously with both hyperbaric oxy- On the other hand, it is now apparent that hyperoxia
also induces a distinct set of cellular responses. Because gen 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 growth ported 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 function Siddiqui 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 this trations of oxygen in ischemic wounds and that oxygen
concentration falls promptly to pretreatment levels in point in time much is conjecture, however two things
are certain. One is that oxygen supplied under hyperbaric ischemic 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 yet tissue 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, MD number of hyperbaric oxygen treatments.
4
In our view
Thomas A. Mustoe, MD these acute changes in the responsiveness of ischemic
tissue to serial hyperbaric oxygen treatments suggest a
prompt production of a transient but potent local vasodi-
REFERENCES
lator.
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3. Sheffield PJ. Tissue oxygen measurements with respect to soft
ments should be administered and for how long , at what
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10
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2
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WOUND REPAIR AND REGENERATION
VOL. 9, NO. 3 DAVIDSON ET AL. 177
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3
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