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OXYGEN AND ITS ROLE IN WOUND HEALING


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.
 

Energy Metabolism

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.
 

Collagen Synthesis

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.
 

Neovascularization

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.
 

Polymorphonuclear Cell Function

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.
 

Oxygen Cascade

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 utilization.
 

Oxygen and Bacteria

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.
 

Oxygen and Antibiotics

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 hyperbaric oxygen.(23)
 

Wound Oxygen Levels

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 mmHg.(25)
 

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.
 

Summary

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.
 

References
 

  1. Nunn JF. Oxygen: in applied respiratory physiology. 2nd Ed., Boston, Butterworths, 1977; Chap. 12, 375.
  2. Hunt TK, Zederfeldt B, Goldstick TK. Oxygen and healing. Am Journ. Surg. 1969; 1(18):521-525.
  3. Sheffield PJ. Tissue oxygen measurements. Davis JC (ed.), Problem Wounds, New York, Elsevier, 1988:17-53.
  4. Prockop DJ, Kivirikko KI, Tuderman L. Biosynthesis of collagen and its disorders. N. Engl. Journ. Med. 1979; 301:13-21, 77-85.
  5. Banda MI, Knighton DR, Hunt TK. Isolation of a non-mitogenic angiogenesis factor from wound fluid. Proc. Nat. Acad. Sci. USA. 1982; 79:7773.
  6. Knighton DR, Hunt TK, Schevenstuhl H, et al. Oxygen tension regulates the expression of angiogenesis factor by macrophages. Science. 1983; 221:1283-1285.
  7. Babior BM. Oxygen dependent microbial killing by phagocytes. N. Engl. Journ. Med. 1974; 298:659-668, 721-726.
  8. DeChatelet LR. Oxidative bactericidal mechanisms of polymorphonuclear leukocytes. Journ. Infect. Dis. 1975; 131:295-303.
  9. Hohn DC. Oxygen and leukocyte microbial killing. Davis JC, Hunt TL (eds.), Hyperbaric Oxygen Therapy, Bethesda, Undersea Med. Soc. 1977:101-110.
  10. Hohn DC. The effect of O2 tensions on the microbial function of leukocytes in wounds and in vitro. Surg. Forum. 1976; 27:18-20.
  11. Mason PL, Heremans JF, Schonne E. Lactoferrin and iron binding protein in neutrophilic leukocytes. Journ. Exp. Med. 1969; 130:643-658.
  12. Hunt TK, Knighton D, Goodson W. In Way L, Dunphy E (eds.), Current Surgical Diagnosis and Treatment. 7th Ed., Philadelphia, Lange Med. Pub., 1985; 99-128.
  13. McCord JM. An enzyme-based theory of obligate anaerobiosis: the physiological function of superoxide dismutase. Proc. Nat. Acad. Sci. USA. 1971; 68:1024-1027.
  14. Hill GB, Osterhour S. Experimental effects of hyperbaric oxygen on selected clostridial species. Journ. Infect. Dis. 1972; 125:17-25.
  15. VanUnnik AJM. Inhibition of toxin production in Clostridium perfringens in vitro by hyperbaric oxygen. Antonie Leewenhoet Microbial. 1969; 31:181-186.
  16. Hill GB. Hyperbaric oxygen exposure for intrahepatic abscesses produced in mice by nonspore forming anaerobic bacteria. Antimicrobial Agents Chemother. 1976; 9:312-317.
  17. Schreiner A. Hyperbaric oxygen therapy in bacteroides infections. Acta. Chir. Scand. 1974; 140:73-76.
  18. Watlyn RJ, et al. Treatment of anaerobic infection with hyperbaric oxygen. Surg. Clin. N. Amer. 1964; 44:107-112.
  19. Gregory EM, Fridovich I. Induction of superoxide dismutase by molecular oxygen. Journ. Bacteriol. 1973; 114:543-548.
  20. Brown GL. Effects of hyperbaric oxygen on S. aureus, P. aeruginosa, and C. albicans. Aviat. Space Environ. Med. 1979; 50:717-720.
  21. Adams KR. In vitro potentiation of tobramycin under hyperbaric conditions. Abstract UHMS Ann. Scientific Meeting. 1987, #69.
  22. Adams KR. Amnioglycoside potentiation with adjunctive hyperbaric oxygen therapy in experimental P. aeruginosa osteomyelitis. Abstract UHMS Ann. Scientific Meeting. 1987, #70.
  23. Keck PE, Gohlieb SF, Conley J. Interaction of increased pressures of oxygen and sulfonamides on the in vitro and in vivo growth of pathogenic bacteria. Undersea Biomed. Res. 1980; 7:95-106.
  24. Silver IA. The measurement of oxygen tension in healing tissue. In Herzog H (ed.), Progress in Respiration Research III, Basel; Skarger. 1969; 124-135.
  25. Sheffield PJ. Tissue oxygen measurements with respect to soft tissue wound healing with normobaric and hyperbaric oxygen. Hyperbaric Oxygen Review. 1985; 6(1):18-46.
  26. Knighton DR, Halliday B, Hunt TK. Oxygen as an antibiotic: a comparison of the effects of inspired oxygen concentration and antibiotic administration on in vivo bacterial clearance. Arch. Surg. 1986; 121:191-195.
  27. Winter GD. Effects of hyperbaric oxygen treatment on epidermal regeneration. In W Iwa (ed.), Proceedings of the Fourth International Congress on Hyperbaric Medicine Behavior. Williams & Wilkins. 1970; 363-368.
  28. Brosemer RW. The effect of oxygen tension on the growth and metabolism of a mammalian cell. Exp. Cell Res. 1961; 25:101-113.
  29. Niinikoski J. Effect of oxygen supply on wound healing and formation of experimental granulation tissue. Acta. Physiol. Scand. 1969; 334:1-72.


 

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