Disturbances to healing observed under hypoxic conditions have given insights into the roles of oxygen. Wound hypoxia is more prevalent than generally appreciated, and occurs even in patients who are free of arterial occlusive disease. There is a strong scientific basis for oxygen treatment as prophylaxis against infection, to facilitate wound closure, and to prevent amputation in wounded patients. This article reviews extensive data from preclinical and human trials of supplemental inhaled oxygen, hyperbaric oxygen, and topical oxygen treatment. Oxygen supports biochemical metabolism and cellular function, and has roles in combating infection and facilitating the wound healing cascade.
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With deeper scientific understanding of oxygen physiology, and with support from randomized, prospective clinical investigations, the judicious, individualized use of oxygen therapy in wound management may now be considered mainstream.
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Each of the most common categories of chronic wounds (arterial, venous, diabetic, pressure) become established or are perpetuated because of factors that limit oxygen delivery to the wound bed.
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At the low physiologic concentration of H 2 O 2 (0.15%), topical angiogenesis is favorably influenced, distinguished from the 3% v/v strength available commercially; at this high concentration, severe oxidative damage to wounds is noted, and is thus contraindicated in modern wound management.
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Given that correction of wound hypoxia is beneficial to many aspects of healing, it does not necessarily follow that more is better, and that hyperoxygenation of normally nourished wounds confers a benefit to justify the risks.
Introduction
Common observations made many decades ago by mountain climbers who noted the inability to clear skin infections at high altitude, and Jacques Cousteau’s deep sea divers who noted that their work wounds healed fastest when they were diving, brought general appreciation of the importance of oxygen in healing. Recent years have brought an increased and more detailed scientific appreciation of the diverse roles that oxygen plays in normal physiology and disease states. As the individual steps of the wound healing cascade have become elucidated in greater detail, the involvement of oxygen at nearly every stage has become evident. More oxygen is not always better; nature seems to have adapted us to respond constructively to the relative hypoxia that characterizes the healing edge of many wounds.
There remain many gaps in understanding of the biochemical events of healing. Some of the current knowledge regarding oxygen, growth factors, and other mediators is seemingly contradictory, and classification of molecules as promoters or inhibitors of healing (eg, oxygen is good, tumor necrosis factor α [TNF-α] is bad) is simplistic. However, it seems possible to reach a unified understanding of healing that reconciles most of the thousands of basic science investigations into individual steps in the chain, and oxygen is central to this. This article summarizes oxygen physiology in wound biology, and discusses the supporting literature.
Given the central role of oxygen in healing, there is the potential to manipulate the wound environment by treatment with supplemental oxygen. Oxygen therapy in various forms has been used to ameliorate many medical conditions for centuries. However, clinical results have been varied, and frequently disappointing. There has been an indiscriminate use of oxygen treatments in the past, and there is still an aura of quackery associated with this area of medicine. However, in the face of deeper scientific understanding of oxygen physiology, and with support from randomized, prospective clinical investigations, the judicious, individualized use of oxygen therapy in wound management may now be considered mainstream. This article reviews the current rationale, regimens, and preclinical and patient data regarding various oxygen treatments that have been used to improve the outcomes of dermal wounds. See Box 1 for a summary of roles of oxygen in wound healing.
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Energy source to fuel biochemical reactions and cellular function
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Nutrient essential to the synthesis and cross-linking of collagen
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Cofactor that is manufactured into signaling molecules such as nitric oxide and hydrogen peroxide
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Substrate for generation of reactive oxygen species (ROS) that combat wound colonization and infection
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Essential component of the redox switch that turns on and off genes that encode proteins critical to the healing cascade
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Deliberate hyperoxygenation recruits endothelial progenitor cells to the wound, increases vascular endothelial growth factor (VEGF), and promotes angiogenesis
Oxygen Delivery
In normal conditions, oxygen delivery to peripheral tissues is the net result of:
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Cardiac output
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Peripheral vascular resistance
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Oxygen saturation of hemoglobin (usually 90% or greater).
Oxygen in serum
Minimal amounts of oxygen are dissolved in the serum. Release of oxygen is governed by the hemoglobin dissociation curve. Serum P o 2 is typically about 100 mm Hg. Once released at the capillary level into normal tissue, oxygen can diffuse up to 64 μm. Given normal capillary density, this diffusion ability is sufficient to nourish and support the viability of the skin. Hunt emphasized the often-neglected but relevant point that oxygen delivery can sometimes be increased significantly by reversing the local vasoconstriction that may result from pain, cold, or other noxious stimuli.
Intact skin as barrier to oxygen
The keratin layer of intact epithelium is a barrier to oxygen diffusion; probes designed to exclude air detect only 0 to 10 mm Hg on the skin surface. Warming of the skin makes this layer more permeable and enables P o 2 to increase substantially, although it does not reach the ambient level. Stripping the statum corneum with tape enables free diffusion of oxygen into the upper layers of dermis, and the P o 2 there closely matches the oxygen tension in the environment. However, within about a day, exudation of serum and accumulation of inflammatory cells lead to formation of a soft eschar that again prevents oxygen diffusion into the skin. Therefore, the oxygen tension in subcutaneous tissue and dermis of intact skin depends on delivery through the underlying circulatory system.
Inadequate Oxygen Delivery is a Causal Factor in Many Chronic Wounds
Each of the most common categories of chronic wounds (arterial, venous, diabetic, pressure) become established or are perpetuated because of factors that limit oxygen delivery to the wound bed. Scheffield noted that chronic wounds have a P o 2 in the range of 5 to 20 mm Hg, compared with 35 to 50 mm Hg measured in normal tissue.
In the case of venous leg ulceration, the essential disturbance is abnormal venous hypertension, which is propagated back to the capillary level. The capillary-tissue pressure gradient is increased, causing water to diffuse out of the intravascular space and into the interstitium; large molecules such as fibrinogen, albumin, and α2-macroglobulin are also forced out of the vascular system, and pericapillary cuffs are formed that can be noted histologically. These cuffs and the local edema impair oxygen diffusion and render the cells furthest from the capillary hypoxic.
Lower extremity arterial and diabetic wounds, are prone to suffer macrovascular and/or microvascular occlusive disease, limiting blood flow and therefore oxygen delivery to the lesion. Pressure wounds that are not properly off-loaded become ischemic (and therefore also hypoxic) when capillary closing pressure is exceeded by the weight of the body part pressing against a support surface.
Reperfusion
In addition to ischemia/hypoxia, another mechanism of injury has been shown to play a major role in a variety of chronic wounds: reperfusion. Patients with impaired arterial inflow or venous return have repeated episodes of ischemia and reperfusion related to leg elevation or dependency. Restoring circulation induces endothelial stickiness, which draws white cells into the lesion; the already established proinflammatory environment established by ischemia intensifies as ROS flood the wound and cause further tissue destruction. Repeated episodes of ischemia and reperfusion are more detrimental to wound healing than are prolonged phases of uninterrupted ischemia.
Inflammatory cycle
It is a popular current concept that many chronic wounds are stuck in a self-perpetuating inflammatory cycle. Hypoxia may contribute to this pathophysiology in many cases. Under significant hypoxic conditions, mitochondrial adenosine-triphosphate (ATP) production ceases and ATP-dependent transmembrane transport systems such as sodium/potassium ATPase or calcium ATPase fail. Intracellular accumulation of calcium promotes release of proinflammatory cytokines such as TNF-α and interleukin (IL)-1, which attract neutrophils and macrophages. Endothelial adhesion molecules are overexpressed in hypoxia, and enable white blood cells to localize to the wound. The net effect is a self-perpetuating inflammatory vicious cycle in which tissue destruction leads to increased white cell recruitment and release of proinflammatory mediators and ROS, which leads to even more tissue destruction. Bacterial colonization, a nearly universal feature of chronic wounds, adds to the inflammatory burden by attracting and activating leukocytes. Although inflammatory cells are capable of producing ROS at low oxygen tensions, the antidotes to ROS (the most potent of which is nitric oxide) require higher oxygen tension for their synthesis.
Measurement of Wound Oxygen
Accurate, repeatable measurements of wound oxygen are central to many in vivo investigations into the role of oxygen. Although numerous investigators have refined research-grade systems, measurement of oxygen at the tissue/cellular level in routine clinical practice is difficult and imprecise. There is a vast literature on oxygen measurement and a detailed review is beyond the scope of this article. Most methods are indirect and measure oxygenation of periwound skin rather than the wound bed.
Transcutaneous oximetry
Perhaps the most popular of these techniques, transcutaneous oximetry (TcP o 2 ) is subject to high variability related to fluctuations in vasomotor tone at the site of measurement, light penetration of skin, and hemoglobin level. Even perfectly performed TcP o 2 typically overestimates wound P o 2 because the skin is warmed to the point of maximal local vasodilatation, which is not representative of the ordinary state of the local vasculature. In addition, there can be significant oxygen consumption along the path from periwound intact skin to the healing tissue edge in the center of the wound. Thus, arterial blood P o 2 is ordinarily about 100 mm Hg; the P o 2 of dermal wounds ranges from 60 mm Hg at the periphery to 0 to 10 mm Hg centrally. There are many reports supporting the usefulness of TcP o 2 in determining levels of amputation healing, but many practitioners have found that the method is cumbersome and yields results that have poor repeatability. Measurements at 1 point in time and only a limited number of skin sites may not accurately portray the wound microenvironment, because wounds are not uniform and vasomotor tone may change from moment to moment.
Luminescence imaging
Luminescence lifetime imaging has recently shown significant advantages compared with earlier methods of wound oxygen estimation. A phosphorescent indicator is held in place on a plastic matrix; quenching of the phosphorescence is proportional to the amount of oxygen present. The technology provides a noninvasive, painless, reliable, sensitive estimate of wound P o 2 . Although offering potential for widespread clinical adoption, the technology is not yet available commercially in a format and at a cost that is compatible with ordinary clinic operations and economics.
Role of Oxygen in the Essential Steps of Dermal Wound Healing
Collagen synthesis
Extracellular matrix deposition is inadequate in many chronic wounds because of poor fibroblast production and inadequate remodeling of collagen, which are both oxygen dependent, and because of excessive degradation of extracorporeal membrane oxygenation (ECM) by matrix metalloproteinases (MMPs). Molecular oxygen is required for the hydroxylation of proline and lysine during collagen synthesis and for the maturation of protocollagen into stable triple-helical collagen. In the absence of sufficient oxygen, only protocollagen, which does not have the functional abilities of collagen, can be made. Collagen synthesis proceeds in direct relation to P o 2 over the range of 25 to 250 mm Hg. Prolyl hydroxylase under 20 mm Hg O 2 functions at 20% of maximal speed; the enzyme requires more than 150 mm Hg to reach 90% of maximal speed.
Angiogenesis
Many authorities have noted an apparent inconsistency in well-known observations of wound healing, whereby hypoxia is noted to increase VEGF production from fibroblasts and macrophages, but angiogenesis seems to proceed more successfully under normoxic or even hyperoxic conditions. In one set of instructive experiments, mice underwent subcutaneous injection of a gel alone, gel with VEGF, or with anti-VEGF antibodies. The animals were then maintained in various environments of 13% to 100% oxygen at 1 absolute atmosphere (ATA) to 2.8 ATA to simulate hypoxia, normoxia, and hyperoxia. The explanted gel plugs were then sectioned and graded for the degree of angiogenesis. Angiogenesis was significantly decreased in the hypoxic animals ( P = .001) and increased in those who were rendered hyperoxic ( P <.05). Addition of VEGF to the implanted gel did not prevent the deleterious effect of hypoxia. In contrast, the beneficial effect of hyperoxia was blocked by anti-VEGF antibody. These findings suggest that both adequate oxygen and the presence of VEGF are required for angiogenesis.
Sen noted that all developing vascular buds require a sheath of ECM, mainly consisting of collagen and proteoglycans, to guide tube formation and resist the pressures of blood flow. His investigations have confirmed that optimal angiogenesis requires high P o 2 ; hypoxia, by retarding synthesis of the collagen to support developing vessels, decreases angiogenesis.
Fibroblast growth
Oxygen consumption by cells has been studied by measuring changes in oxygen tension in supernatant media covering cells in tissue culture. Fibroblast cellular proliferation is directly correlated with ambient oxygen level:
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Freshly harvested cells only grow in an environment that includes 15 mm Hg O 2 , or more
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Initially, after 72 hours exposure to 1% oxygen, fibroblast proliferation increases by 71%
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During this period, fibroblast secretion of transforming growth factor (TGF)-β1 increases 9-fold, in turn causing upregulation of the procollagen gene.
This adaptation to hypoxia is only transient, and chronic oxygen deprivation severely diminishes fibroblast activity. The surface of a poorly healing wound can be mapped with oxygen tension measurements, and fibroblast growth is progressively diminished until the hypoxic center of the lesion is reached, where proliferation is minimal or nil. By contrast, under hyperoxic conditions, fibroblasts are induced to differentiate into myofibroblasts, which are critical to wound closure through contraction.
Epithelial
Numerous studies have shown that keratinocytes and fibroblasts migrate faster under hypoxic conditions. Keratinocytes express more lamellipodia proteins and collagenase, and decrease lamellin-5 (motility brake) under hypoxia. This finding is expected, considering the mechanisms of natural dry wound healing, in which new skin regenerates underneath a stable eschar. The microenvironment through which the healing edge advances is protected from ambient oxygen, and the lack of blood vessels inside the eschar engender local hypoxia. In order for the epithelial edge to migrate the keratinocytes must carve a path through the tissue/eschar interface using collagenase and other enzymes.
Energy generation and use
Fundamental biochemical events such as molecular synthesis and transport cannot occur without a source of energy, and the ubiquitous source of energy in the human body is the coenzyme ATP. ATP is synthesized in mitochondria and stores chemical energy to fuel diverse biochemical processes in the body. The process by which ATP is created is known as oxidative phosphorylation and is critically dependent on the availability of molecular oxygen. About 90% of the oxygen consumed by tissues goes to ATP synthesis. Other energy stores generated through the citric acid cycle and the breakdown of fatty acids are also highly oxygen dependent. The requirement for energy and, hence, the need for oxygen, is accentuated in healing tissue because cellular activities such as collagen synthesis, cell migration, and bacterial defense are heightened.
Influence of age
Another critical dimension to oxygen’s role in healing relates to the age of the wounded host. The demographics of chronic nonhealing wounds indicate a strong relationship between incidence and advanced age, with most cases occurring in patients more than 60 years of age. Aging fibroblasts show:
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Reduced proliferative ability
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Diminished capacity to respond to growth factor stimulation
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Increased production of destructive enzymes such as MMPs.
Advanced age induces greater sensitivity to the negative effects of hypoxia. The migratory response of fibroblasts to TGF-β1 stimulation is blunted in older patients, compared with younger ones. Mustoe and colleagues compared the effects of hypoxia on young (age 24–33 years) human dermal fibroblasts in tissue culture with fibroblasts from older (age 61–73 years) donors. Under 1% oxygen, there was greater decrease in TGF-β1 receptor expression in the aged cells (decrease of 12% in young fibroblasts vs 43% in old fibroblasts).
Responsiveness to TGF-β1 stimulation was reduced by advanced age:
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Activity of p42/p44 mitogen-activated kinase increased 50% in young cells versus decreasing 24% in the aged cells
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Unstimulated fibroblast migration increased 30% in young cells exposed to hypoxia, whereas the aged cells showed no change
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When TGF-β1 stimulation was added to the migration assay, young cells increased activity by 109% versus only 37% in the aged cells.
Mendez and colleagues studied fibroblasts harvested from the venous ulcer wound beds and used, as controls, cells taken from normal skin of the thigh.
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The 7 patients who were evaluated (mean age 51; range 36–67 years) had suffered wounds for a mean of 12.7 months (range 11–17 months)
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Chronic wound fibroblast growth rates were only one-third of those observed in the control cells ( P = .006).
β-Galactosidase (β-GAL) activity was used as a sign of cellular senescence, a state of irreversible arrest of proliferation despite maintenance of metabolism.
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Six of 7 controls had no senescence associated (SA)-β-GAL activity
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All samples from the chronic wounds had measurable activity (mean 6.3%, median 2%)
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Level of SA-β-Gal correlated inversely with cellular growth rate ( R 2 = 0.77).
The issue of cellular senescence may be more complex than mere chronologic age of the wounded patient. It may be the number of cell divisions that fibroblasts have undergone, rather than the age of the host, that defines the age of a cell. Many cell lines, including fibroblasts, are capable of only a finite number of cell divisions. Chronic wounds in young individuals may contain fibroblasts that have already reached the limit of their proliferative ability and are prematurely senescent. Thus, although the lessons learned about the roles of oxygen in wound physiology are generally applicable, the degree to which patients may react to hypoxia and hyperoxia with the predicted responses may vary according to the physiologic age of the host cells.
Nitric oxide generation
Nitric oxide synthetase metabolizes the amino acid l -arginine into nitric oxide using oxygen as a substrate. Although nitric oxide is well known for its diverse, generally beneficial, effects on inflammation, angiogenesis, and cell proliferation, a full discussion of the putative benefits of enhanced nitric oxide is beyond the scope of this article.
Role of Oxygen in Infection Control
During the initial phase of wound healing, activated leukocytes enter the wound and engulf bacteria. In the presence of adequate oxygen, an oxidative burst ensues, in which oxygen consumption increases as much as 50-fold compared with baseline conditions, and persists for hours, creating ROS that destroy the invaders. ROS include:
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Peroxide anion (HO 2 − )
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Hydroxyl ion (OH − )
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Superoxide anion (O 2 − )
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Hydrogen peroxide (H 2 O 2 ).
About 98% of oxygen consumption by leukocytes is related to this respiratory burst, which is facilitated by phagocyte (neutrophil, eosinophil, monocyte, and macrophage) cell membrane–bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase :
Glucose provides the energy to drive the reaction, generating substantial amounts of lactate in the process.
ROS, and especially superoxide, are toxic and kill bacteria, then are rapidly degraded to H 2 O 2 and other by-products. The kinetics are such that the killing process works at 50% of maximal speed in the presence of oxygen at 40 to 80 mm Hg, and as much as 400 mm Hg are required to increase the velocity to 90%. Neutrophils therefore lose most of their ability to kill bacteria at less than 40 mm Hg. Patients afflicted with chronic granulomatous disease, which is characterized by defects in the genes that encode NADPH oxidase, have increased susceptibility to infection, and also show impaired wound healing.
The results of many investigations suggest that, in a reduced P o 2 wound environment, the ability of leukocytes to generate ROS is substantially impaired, and therefore the ability to ward off colonization/infection is lowered. In vitro studies of leukocytes obtained from venous blood show that neutrophil oxygen consumption increases as ambient oxygen concentration increases, and suggest that increasing ambient oxygen to more than physiologic levels may induce even greater ROS synthesis. However, there is the theoretic potential that excess ROS may be destructive and counterproductive to wound healing. The body has a robust system for removal of ROS by superoxide dismutase, catalase, and reduced glutathione, and the wound concentration of ROS is the net result of synthesis and destruction. ROS clearance requires an adequate circulatory supply.
The potential to increase local wound oxygenation to supraphysiologic levels and cure or prevent infection was evaluated in 30 patients with chronic diabetic wounds. Patients were randomized to receive standard care (wound dressings; antibiotics guided by culture results) alone or in combination with 4 hyperbaric oxygen therapy (HBOT) treatments given during a 2-week period. In the control group, cultures grew significant colony counts of 16 different isolates at baseline, and 12 at the end of the observation period; in the patients receiving HBOT, isolates were reduced from 19 before treatment to only 3 afterward ( P <.05). HBOT seemed particularly effective in controlling Pseudomonas and Escherichia coli . Seven patients in the control group required major lower extremity amputation (5 for spreading infection) versus 2 in the HBOT-treated patients ( P <.05).
Redox Signaling
The traditional view of ROS has been that they are destructive to bacteria and host cells, necessary for wound hygiene in the early phase of healing, but otherwise counterproductive to the normal healing cascade. This view has prompted numerous clinical trials testing the role of various antioxidants in ameliorating different disease conditions, and these trials typically have shown disappointing results.
The late 1990s brought a growing appreciation that, at very low levels, ROS (particularly H 2 O 2 ) serve as signaling messengers, a role independent of bacterial killing. NADPH oxidase exists not only in neutrophils but also in nonphagocytic wound cell lines, and there is a continuous low-level production of ROS that is unrelated to leukocytes, oxidative burst, or response to wound colonization or debris. ROS bind to proteins and can alter their conformation, leading to increases or decreases in their functional abilities. H 2 O 2 functions primarily by oxidizing cysteine moieties. The molecule has a potent effect in recruiting leukocytes to the wound site, and the concentration of endogenous hydrogen peroxide increases significantly at the wound margins within the first few minutes of injury. The functions of important growth factors such as VEGF, platelet-derived growth factor (PDGF), keratinocyte growth factor (KGF), and TGF-α are inhibited in the absence of such signals. Thus, overexpression of catalase, which removes H 2 O 2 from the wound, is associated with impaired angiogenesis and delayed wound closure. Cellular functions like migration and leukocyte recruitment are also inhibited in the absence of H 2 O 2 . Micromolar levels of peroxide can be measured in normal wound fluid. Research in oncology indicates that low-level ROS foster angiogenesis, and overexpression of extracellular super oxide dismutase inhibits tumor vascularization in mice.
Note
The low physiologic concentration of H 2 O 2 must be distinguished from the 3% v/v strength that is available commercially and often used to clean and disinfect wounds; at such high concentrations, severe oxidative damage to wounds is noted, and this is contraindicated in modern wound management. However, at 0.15% H 2 O 2 , topical angiogenesis is favorably influenced.
The state of overabundance or underabundance of ROS is reflected in the redox potential of the wound microenvironment. The ratio of NADH to NAD + has been used as a redox index, and transcription of various genes important in wound repair seems to be responsive to this ratio. Every phase of the wound healing cascade (hemostasis, inflammation, proliferation, epithelialization) has been shown to have key steps that require NADPH oxidase action. Individuals with mutations in either p47 phox or Rac2, which are each associated with action of this enzyme, show impaired wound healing.
Hypoxia
Many of our conclusions about the role of oxygen in wound repair come from observations of the defects in healing that are associated with hypoxia. Absolute hypoxia is usually defined as an oxygen level less than 30 mm Hg. However, hypoxia is more typically a relative term, indicating insufficient oxygen for the tissue and physiologic situation under consideration. For example, with infection or an open wound, oxygen demand increases and levels of delivery that might be adequate for intact, uninfected dermis may be deficient. Cells challenged with hypoxia must reduce activity and rely on anaerobic metabolism, or die. Acute and mild/moderate hypoxia usually leads to cellular adaptation and survival; prolonged and more extreme hypoxia may result in cellular death.
Hypoxia is a more frequent issue in wound repair than is commonly appreciated. Wound bed oxygenation depends on:
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Pulmonary uptake
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Hemoglobin level
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Cardiac output
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Vascular patency
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Capillary density
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Factors that deplete oxygen such as parenchymal consumption and inflammatory cell activity.
Decreased wound oxygen tension occurs not only from macrocirculatory issues but also because oxygen is consumed by metabolically active and proliferative cells located along the path from capillaries to the healing edge of tissue Box 2 . As much as a 150-μm distance from the nearest capillary to the healing edge may need to be nourished by oxygen diffusion. This effect is magnified in the presence of heavy bacterial colonization or infection, further consuming oxygen and decreasing the available oxygen to the healing wound. A vicious cycle may ensue in which bacterial oxygen consumption reduces the ability of leukocytes to synthesize ROS, enabling further bacterial proliferation, and so on. The centers of even seemingly well-oxygenated wounds may be hypoxic because of high oxygen extraction along the path of diffusion from capillaries. Although circulating blood may contain a P o 2 of 100 mm Hg, the periphery of a dermal wound may be 60 mm Hg and, at the center of the wound, readings can be as low as 0 to 10 mm Hg. Many chronic wounds suffer local hypoxia; in one study, normal, nonwounded tissue showed oxygen tensions of 30 to 50 mm Hg, whereas measurements of P o 2 in nonhealing chronic wounds in the same patients were in the range of 5 to 20 mm Hg.
Clinical pearl: wound hypoxia is under-recognized and may occur in even normally perfused lesions because of high oxygen extraction along the diffusion path from the feeding capillary to the edge of healing tissue.
At present, it is not easy to reconcile all the scientific knowledge about effects of hypoxia and hyperoxia on wound tissues and to synthesize all the evidence into a coherent story. Hypoxia has been traditionally regarded as an important stimulus to fibroblast growth and angiogenesis. Hypoxia encourages angiogenesis by increasing levels of hypoxia-inducible factor 1 (HIF-1), which in turn binds to the promoter segment of the VEGF gene and activates transcription, leading to higher synthesis of VEGF, the principal angiogenetic growth factor in human physiology. Paradoxically, multiple studies have shown that hyperoxic conditions induce greater angiogenesis, perhaps by increasing local ROS.
Acute hypoxia induces temporary increases in cellular replication (3-fold increase under 5 mm Hg compared with 150 mm Hg). This has been associated with a 6.3-fold increase in the expression of TGF-β1 and enhanced procollagen synthesis. However, these increases in proliferation and metabolic activity are short lived and, when these conditions are maintained for more than a week, cellular growth and synthetic activity decrease to significantly less than baseline physiologic levels. The situation is reversible; restoration of normal oxygen levels restores typical proliferation rates, and a second bout of hypoxia induces a second temporary burst of fibroblast activity. In chronic hypoxia, the production and secretion of the most important cytokines and chemokines central to healing (including TNF-α, TGF-α, TGF-β1, KGF, EGF, PDFG, and insulin growth factor) require oxygen and are reduced or absent.
There seem to be at least 2 ways to reconcile the older concept that hypoxia is beneficial with modern understanding that healing proceeds more quickly with increased oxygen delivery.
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The true primary stimulus to VEGF secretion, angiogenesis and collagen deposition may be lactate, more than hypoxia. Even in well-perfused and properly oxygenated wounds, lactate may accumulate because leukocytes, fibroblasts, and endothelial cells lack mitochondria and rely on anaerobic glycolysis for energy production; a principal by-product of this glycolysis is lactate. Thus, lactate levels may still be increased in hyperoxia, albeit less so compared with hypoxia.
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It is possible that the P o 2 gradient between the capillary and the most distant cell may drive angiogenesis more than the absolute level of P o 2 . The immediate effect of hyperoxygenation of the blood may be to increase this gradient, and increased oxygen diffusion to areas of low P o 2 may follow.
Therapeutic Oxygen Supplementation
Because of the high incidence of wound hypoxia and the knowledge of the deleterious effects of inadequate oxygen on healing, it is natural to consider the potential of oxygen supplementation to improve wound repair Box 3 . In some instances, the most effective way to improve wound oxygenation may involve measures to enhance blood flow rather than changing the oxygen content of the blood. Such maneuvers may include hydration and relief of vasoconstriction using local warmth and analgesics. Because hemoglobin is nearly saturated in most individuals, enhancing inspired oxygen may only modestly increase peripheral delivery. Other techniques for hyperoxygenation of wounds include breathing oxygen under supranormal pressures (hyperbaric oxygen [HBO]) or bathing the wound topically with an enhanced oxygen environment (topical oxygen therapy [TOT). The remainder of this article focuses on various attempts to supplement oxygen for the benefit of healing acute and chronic wounds.
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