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Molecular Biochemists Unlocking Fundamental Mechanisms of Hyperbaric Oxygen Therapy in Wound Healing and Reperfusion Injury

By Paul Harch, MD

Molecular biochemists at Harvard and Boston University Medical Schools are unlocking some of the fundamental mechanisms of hyperbaric oxygen therapy with a series of in vitro experiments on gene expression, mRNA, and protein synthesis. At the Advanced Topics Course in Hyperbaric Medicine in April, 1999 and the American College of Emergency Physicians Research Form in October, 1999 Drs. Jon and Wende Buras reported their findings. In the first experiment they developed a model where human umbilical vein endothelial cells were subjected to mock ischemia (four hours of hypoxia and hypoglycemia) and then reperfusion (normoxia and normoglycemia). They showed that a single exposure to hyperbaric oxygen decreased intracellular adhesion molecule (ICAM-1) protein expression and hypothesized that this effect was mediated by a reduction in ICAM-1 mRNA production. In the second experiment in the same model they measured total ICAIVI-1 mRNA during reperfusion by a variety of techniques. The cells were divided into two groups, one that received a single 2.5 ATA/90 minute hyperbaric exposure during mock ischemia and one that did not. At 2-4 hours of mock reperfusion ICAM-1 mRNA achieved maximal levels that returned to control levels at 24 hours. A single hyperbaric oxygen exposure reduced this peak level by a factor of 2.6, demonstrating that the effect of HBOT was at the DNA transcription or post-transcription point. In other words, the combination of these two experiments indicated that HBOT was blocking the ischemia/reperfusion injury caused by hypoxia and hypoglycemia by inhibiting the production of white blood cells and the protein receptor on the surface of endothelial cells responsible for adhesion of white blood cells and secondary injury during reperfusion.

The third experiment examined the effect of hyperbaric oxygen therapy on growth factor receptor expression and cellular proliferation. Dermal fibroblasts were treated with a single or multiple HBOT' s or normobaric oxygen and assays were taken at varying times after treatment. Dr. Wende Buras found that a single HBOT increased fibroblast proliferation and growth factor receptor expression within 6 hours of HBOT. Multiple treatments further increased both of these effects. This work was remarkably consistent with earlier experiments by a variety of researchers, including Siddiqui, Zhao, and Wu. In 1994, Zhao reported a synergistic effect of HBOT and platelet-derived growth factor (PDGF) in totally reversing an ischemic wound haling deficit. Siddiqui, in 1995, showed that repetitive HBOT in a rabbit ear wound chamber model generated an increased capacitance of the wound to respond to a surface oxygen challenge that became established by 14 HBOT's, indicating atrophic change in the tissue due to induction of the DNA. Finally, using the same model as Zhao, Wu, in 1995, demonstrated an HBO-mediated upregulation of PDGF receptor mRNA.

HBOT has been touted for years as an adjunctive therapy in chronic wound healing. In the past 10 years it has been increasingly viewed as a drug with one of its most powerful effects, being an inhibition of white-blood-cell-mediated reperfusion injury. Multiple clinical studies on HBOT effects have emerged in the past without a clear understanding of the underlying mechanisms. Collectively, the above studies are now elucidating what many clinicians have experienced by demonstrating the basic biochemical action of HBOT at the cellular and subcellular level. The next decade will be one of the most exciting periods in the 100-year history of clinical hyperbaric oxygen therapy as additional research defines the basic science that will spur further clinical application of HBOT.

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