Oxygen; the new growth factor?

Oxygen; the new growth factor?

In recent years our understanding of the intercellular communication of healing has increased considerably. Cells within a wound receive a myriad of signals from their environment – the sum of which govern the activity of a cell. The term “cytokine” is applied to those substances which function as cellular signals. Growth factors are a subclass of cytokines that specifically stimulate the proliferation of cells. This stimulation may occur through several different mechanisms. For example, some growth factors have chemo-tactic activities that attract fibroblasts and inflammatory cells, some act as mitogens, stimulating cell division, and some effect the production and degradation of the extra-cellular matrix. All of these phenomena are the end result of a cytokine (growth factor) signaling the cell nucleus to produce proteins, which account for the observed activities. A clear understanding of growth factor physiology carries the promise of clinical advances in wound management. Currently one cytokine, Platelet Derived Growth Factor, is in clinical use for the management of problem wounds. As our knowledge of these substances expands, other growth factors will be added to our clinical armamentarium for the management of non-healing wounds.

Non-healing wounds can also be managed by optimizing the metabolic requirements of healing, e.g. protein, trace elements, and oxygen. The most frequent common denominator in non-healing wounds is inadequate tissue oxygenation, which impairs healing and host defenses. Correction of such hypoxia by means of revascularization or hyperbaric oxygen therapy results in healing for most patients. Conventional wisdom suggests that oxygen is just a metabolite and therefore healing, in these circumstances, is simply a reflection of having sufficient oxygen to meet the energy demands of wound repair. However, some exciting evidence is now emerging to suggest that oxygen serves a dual role as both a metabolite and a growth factor. The conceptualization of oxygen as a growth factor has considerable relevance to the field of hyperbaric oxygen therapy.

The idea of oxygen acting as a cell signal has already been established in the setting of hypoxia. As an example, gene expression for erythropoietin production is largely proportional to the pO2 level in the kidney. It has been proposed that cells in a non-healing wound may respond to hyperbaric therapy because the supra-physiologic elevation of tissue oxygen serves as a trigger signaling that enough oxygen is in the environment to proceed with normal healing.1 Subsequent daily exposure to the threshold oxygen level reinforces this signal and results in gene expression of the protein building blocks required for healing. Teleologically, it makes sense for cells to conserve resources until the environmental signals are strong enough and consistent enough to activate the cell nucleus and begin the healing process.

This past year two separate groups of investigators have published findings that support this concept of oxygen as a growth factor. Following a single one-hour exposure to hyperbaric oxygen, Hehenberger, et al. (1997) demonstrated a dose dependent stimulation of normal in vitro fibroblasts with a peak increase in cell proliferation at 2.5 ATA O2. The dose-dependent effect of a single 1-hour exposure to oxygen suggests a pharmacologic effect of oxygen on cells, as opposed to an increased metabolic availability of oxygen. These findings suggest, therefore, that a single brief exposure to hyperbaric oxygen on a daily basis provides a strong initiating signal for the intracellular events that culminate in cell proliferation, while sustained hyperoxia has the opposite effect.

In a study of in vitro fibroblast proliferation using tritium-labeled thymidine, Tompach, et al., found that a single dose of HBO (2.4 ATA for 120 minutes) produced a sustained stimulation of fibroblasts for 72 hours.3 If a second exposure to HBO was given on the same day there was no additional increase in cell proliferation. Similarly, cultured endothelial cells remained stimulated for 72 hours following a single 15-minute exposure to HBO. Again, these findings suggest that we must reconsider oxygen as being more than just a metabolite.

This new paradigm of oxygen as a growth factor is consistent with the clinical observation that a BID dosing of HBO appears to offer no clear benefit over a QD dosing schedule for the treatment of chronic wounds. As our understanding of oxygen physiology increases, we will be in a better position to determine the optimal dosing of oxygen in both its metabolic and stimulatory roles.

References:

1. Siddiqui A, Davidson JD, Mustoe TA. Ischemic tissue oxygen capacitance after hyperbaric oxygen therapy: A new physiologic concept. Plastic Reconstructive Surgery 1997; 99:148-69.

2. Hehenberger K, Brismar K, Folke L, Gunnar K. Dose-dependent hyperbaric oxygen stimulation of human fibroblast proliferation. Wound Rep Reg 1997; 5:147-50.

3. Tompach PC, Lew D, Stoll JL. Cell response to hyperbaric oxygen treatment. Int J Oral Maxillofac Surgery 1997; 26: 82-86.

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