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By: Brian A. Youn, M.D.
Geisinger Medical Center
Since our evolution as aerobic organisms we have become dependent on oxygen
as a catalyst and energy source for many cellular functions including
maintenance, metabolism, and repair.(1) Oxygen has a significant role in wound
healing, being essential to provide the additional energy source for the
repairing process.(2,3) Oxygen may, in fact, be the rate limiting step in early
wound repair. Many other components, in addition to oxygen, are interrelated to
provide the optimal environment for healing, including nutritional state, immune
function, cardiopulmonary function, oxygen carrying capacity, blood flow, blood
volume, temperature, and hormonal mediators. This article will briefly review
the multifaceted role of oxygen in wound healing.
Oxygen has two major functions in cellular metabolism, the most important of
which is the electron transfer oxidase system which is responsible for
approximately 90% of the total oxygen consumption.(1) This pathway produces high
energy phosphate bonds in the form of ATP which is the general source of
biological energy. The second category is oxygen's role in the many oxidative
reactions such as the mixed function oxidase, cytochrome P-450 system,
hydroxylases, and oxidases. These compounds are very important in the metabolism
of drugs and other metabolic intermediates. Greater than 90% of the energy
utilized in cellular metabolism is derived from oxidation of glucose to carbon
dioxide, water, and high energy phosphate products in the form of ATP. Since
there are no significant stores of ATP, oxygen utilization must be an ongoing
process to maintain cellular function. In the event that oxygen is deprived to
the tissues an alternative anaerobic pathway exists which converts glucose to
pyruvic acid and lactic acid in a much less efficient mode of energy production.
The anaerobic pathway requires almost a twenty-fold increase in glucose
utilization to provide the same amount of high energy phosphate bonds, and in
addition, the by-products of this pathway are free hydrogen ions which produce
or cause a significant metabolic acidosis. This alternative pathway is incapable
of providing sufficient ATP for cellular maintenance let alone the increased
requirements during the stress of injury and repair. In evolving an efficient
aerobic pathway, we have become critically dependent on adequate oxygen delivery
to maintain cellular metabolism.
Early in the repair of wounds, fibroblasts begin to migrate, divide, and
produce collagen which is an essential matrix for wound healing. In order to
promote fibroblast proliferation and the production of collagen, oxygen must be
present in sufficient quantities.
Oxygen is incorporated by two amino acids, proline and lysine, in collagen
chain synthesis.(4) Collagen cannot be synthesized by the fibroblast unless
adequate amounts of both proline and lysine are hydroxylated with oxygen.
Synthesis requires one atom of oxygen for every three amino acids in sequence.
Oxygen is also required in increased amounts during the repair process to
provide energy for protein synthesis.
Since the diffusion of oxygen through tissues is limited, adequate vascular
delivery via an extensive capillary network is essential. Disruption of the
capillaries from trauma produces hypoxia and release of hormonal mediators.
Macrophages release angiogenesis factor which is a potent stimuli for
endothelial cell activity.(5) The formation of new blind end capillary buds with
single red cells begins. This process is extremely delicate to mechanical
forces, oxygen level, blood volume, and nutrients. Neovascularization also
depends on the fibroblasts on the leading edge of the wound laying down collagen
as the scaffolding for repair. Comprised states such as diabetes,
atherosclerotic diseases, and irradiation impair normal angiogenesis(6) and may
lead to chronic wounds.
By definition, a wound disrupts the normal skin barrier which is the first
line of defense against invading microorganisms. In wounds, one of the first
lines of defense are migrating polymorphonuclear cells (PMNs) which locate,
identify, phagocytize, kill, and digest microorganisms. Polymorphonuclear cells
require oxygen to kill organisms by producing superoxide, hydrogen peroxide,
singlet oxygen, and other products via the respiratory burst.(7) The PMN is
protected by detoxifying free radicals with superoxide dismutase, catalase, and
glutathione. It has been shown in numerous studies that the degree of
polymorphonuclear cell function in killing of bacteria is directly dependent on
oxygen tensions.(8,9,10) There is oxygen independent killing with lysozymes,
acidic vacuoles, and lactoferrins,(11,12) however, they are less efficient and
vary significantly according to the organism.
There exists a significant gradient from the partial pressure of oxygen in
the ambient air to that available immediately to the tissues on a cellular
level. This gradient, or reduction in partial pressures, is also known as the
oxygen cascade.(1) This is a progressive decline in the partial pressures of
oxygen from the air we breath through alveolar gas, blood, major arteries,
capillaries, tissue diffusion, and finally, to what is immediately available at
the mitochondrial level. The largest gradient is from arterial to tissue and
mitochondrial. The mitochondria may function at partial pressures as low as 0.5
mmHg. Tissue injury produces two major problems involving oxygen delivery and
metabolism: (1) injury disrupts the normal delicate capillary network, thereby
reducing the effectual oxygen delivery to the injured tissues, and (2) injured
tissues have an overall increase in metabolic rate and demand for oxygen
Oxygen is important to the PMN for oxygen dependent bacterial killing.
Aerobic organisms are oxygen dependent for survival although most are
facultative and can survive in relative hypoxic environments. Oxygen is directly
lethal to strict anaerobic bacteria because of the organismÕs inability to
detoxify oxygen radicals.(13) Oxygen enhanced environments have been shown to be
bactericidal for most clostridial species(14) and inhibit alpha toxin
release.(15) Hyperbaric oxygen has been shown to be a beneficial adjunct to
therapy in Bacteroides fragilis, Fusobacterium infections,(16) and
nonclostridial anaerobic infections.(17,18)
In hyperbaric oxygen, tissue levels may approach 1200 mmHg, increased
production of superoxide, perioxide, and other oxygen radicals occurs, however,
some organisms adapt by producing increased levels of superoxide dismutase.(19)
There is no direct antibactericidal effect of enhanced oxygen on aerobic
organisms.(20) Indirect antibactericidal effects are related to improved PMN
function in killing bacteria.
Aminoglycosides such as gentamicin, tobramycin, amikacin, and netilmicin are
oxygen dependent for their antimicrobial activity. The effect of oxygen has been
studied in vivo and in vitro using Pseudomonas treated with tobramycin and
controls grown aerobically and anaerobically.(21,22) The aerobic grown
Pseudomonas controls had a 51% increase in colonies compared to the tobramycin
treated. Vancomycin is another antibiotic that does not kill microorganisms well
under low oxygen tensions. Sulfonamides antimicrobial effect is potentiated in
It has been shown in numerous clinical studies that typical wound partial
pressures of oxygen are markedly reduced and may be the rate limiting process in
wound repair. The oxygen tissue levels have been studied in rabbit ears and were
directly related to capillary distance with values of 3 mmHg of 120 um from
capillaries to values greater than 30 in dense capillary areas.(24) Chronic
wounds have been studied with implanted polygraphic oxygen electrodes and found
to be hypoxic with levels of 5 to 20 mmHg compared to control values of 30 to 50
Supplemental oxygen has been shown to enhance healing dependent on dose and
frequency,(26,27) however, excessive or continuous oxygen may impair the normal
healing process.(28,29) Some period of hypoxia in conjunction with other stimuli
(including lactate and other intermediates) is necessary to promote the healing
process. In the normal host, despite a large wound with definite hypoxia,
healing will occur as long as other factors such as nutrients, blood flow, and
immune function remain adequate to allow regeneration of capillaries and
restoration of nutrient delivery. A delicate balance exists between one of the
major stimuli to healing hypoxia and the paradoxical need for oxygen for wound
repair. In situations where oxygen delivery is impaired chronic non-healing
wounds may develop.
In summary, oxygen is essential for maintaining cellular integrity, function,
and repair when tissues are injured. Oxygen not only plays an important role in
energy metabolism, but also is very important in polymorphonuclear cell
function, neovascularization, fibroblast proliferation, and collagen deposition.
There is evidence to suggest that oxygen may indeed be a very important rate
limiting step in wound healing. Larger wounds may have significantly increased
metabolic demands, and larger areas of compromised microvascular oxygen delivery
limiting the healing process. In a normal host healing may be delayed, but may
eventually occur as progressive microcapillary neovascularization ensues and
oxygen delivery is restored. It is the problem patient with either compromised
oxygen delivery or enhanced oxygen utilization where their oxygen supply never
meets their oxygen demands and a chronic wound situation develops.
In his next article, Dr. Youn will address the role of adjunctive hyperbaric
oxygen therapy in the treatment of chronic wounds.
Brian A. Youn, M.D., is the Director of the Department of Hyperbaric Medicine
and Associate of Critical Care Medicine at Geisinger Medical Center, Danville,
Pennsylvania. He is board certified in internal medicine, board eligible in
critical care medicine, and holds the position of Clinical Instructor of
Medicine at Jefferson Medical College. Dr. Youn received his undergraduate
training from the Virginia Polytechnic Institute and his M.D. from Cifas
University, Dominican Republic. He has also completed a hyperbaric medicine
fellowship at the Maryland Institute of Emergency Medical Services Systems at
the University of Maryland.
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