Glutathione, antioxidant protection, immune defenses, and oxidative stress play an important role in all of these conditions. High or low levels of GSH have a significant effect on the susceptibility, tolerance and degree of injury, as well as the recovery time and outcome.

Until this century, traumatic injury was the major cause of death in human beings. In North America today, trauma has fallen to third place behind heart disease/stroke and cancer, but in some economic groups-especially poor urban male populations-trauma remains at the forefront.

A Harvard Medical School team led by M.K. Robinson showed that lab animals artificially depleted of glutathione were dramatically more prone to death and complications of blood loss (hemorrhagic shock). Their results suggest that treatment of trauma should include some way to maintain glutathione levels. This would decrease the likelihood of multi-system organ failure in the event of shock.

The role of oxidative stress and glutathione metabolism in brain and neurological tissue injuries has been the focus of much research. Head injuries often damage the crucial blood-brain barrier, and subsequent circulatory problems lead to swelling and fluid buildup in the brain. Free radicals mediate some of the complex "secondary injuries" seen in this type of trauma.

Efforts to prevent post-injury complications are a crucial part of treatment in emergency and critical care management.

Glutathione metabolism counteracts the damage caused by these oxyradicals. Increases in glutathione peroxidase activity following neurological trauma have been well documented. If injury is severe or complicated, these resources may become eventually depleted. Canadians B.H. Juurfnk and PG. Paterson of the University of Saskatchewan suggest that nutritional interventions with GSH-precursors can maximize antioxidant defenses, and that such strategies should be pursued aggressively.

E.E Ellis's team at the Department of Pharmacology and Toxicology, Medical College of Virginia, tested NAC on concussion after trauma to the brain. NAC given prior to or soon after the injury prevented some consequences of oxidative circulatory compromise. At Ohio State University, J.H. Lucas and D.G. Wheeler showed similar effects using glutathione on spinal cord injury. Using the GSH-precursors gamma-glutamyl-cysteine and OTZ elevated glutathione levels increased spinal neuron survival after ph4ysical trauma.

R. Wagner and R.R. Myers of the University of California developed an interesting therapy for nerve injury and sciatic inflammation and presented it in the journal "Pain." They were able to decrease the pathological consequences of sciatic nerve injury by using the drug NAC to raise GSH levels. Pre-treated subjects responded best. The longer the delay in administering NAC after injury, the less effective was the treatment.

Surgery is intrusive and disrupts a patient's anatomy. It leads to a host of physiological adjustments. Although from the surgeon's point ofview this is a controlled procedure with end-point objectives, from the body's point ofview, it is traumatic. Just like recovery from accidental trauma, the outcome of the operation depends on the patient's prior defenses, fitness, and immune status.

Surgery releases billions of free radicals into the body. These severely tax the patient's antioxidant defenses and poor surgical outcomes seem to go hand-in-hand with low antioxidant levels. As the cell's primary intracellular antioxidant, glutathione is drawn from stores in the liver and skeletal muscles and dispersed to reduce the damage. The result of major surgery may be whole-body glutathione depletion. Articles from the American Journal of Physiology as well as the Annals of Surgery describe a fall in glutathione levels of 40% after abdominal surgery. This may increase the patient's susceptibility to cellular oxidative injury.

Glutathione not only protects us from oxidative stress, it also bolsters immune response, controls and balances the inflammatory response and helps synthesize and repair proteins involved in the healing process. This knowledge has stimulated research into the use of GSH enhancing strategies to improve and accelerate wound repair.

Plastic surgeons from the University of Michigan, Ann Arbor showed that depleted glutathione levels lead to delayed wound healing and poor repair. Biochemists from the Max Plank Institute in Germany showed that while healing, skin wounds initially increase their production of glutathione peroxidase in order to fight free radical formation. As healing progresses GSH levels fall. Pharmacologists from the Central Drug Research Institute in India demonstrated a 60-'70% depletion of glutathione peroxidase and glutathione S-transferase levels in skin wounds after several days healing. Understanding these mechanisms at play, Van der Laan described in an article in the journal Of Surgical Research how NAC infusion could reduce tissue injury and shorten the repair period of crush injuries.

An important consideration in all surgery is disruption of blood flow to tissues (ischemia). When blood flow is re-established (reperfusion) there is a burst of free radical formation in the affected region that may affect the survival of those tissues. The Australians K.R. Knight and K. MacPhadden found that NAC, the glutathione precursor was able to decrease the amount of reperfusion injury in skin flaps. Potential applications are being investigated in cardiac surgery to avoid reperfusion injury.

BURNS

Heat or thermal burns consist of a complex series of events involving initial injury, physiological adjustments to circulatory and fluid changes, hematological and immunological responses, and an elaborate healing process. Death from heat burns is often delayed. Days after a burn, patients may die from circulatory shock, a result of loss of fluids from the burn. Weeks after a burn, patients may succumb to overwhelming infection (sepsis) because of the breakdown in their immune defenses.

Burn specialists know oxidative stress to be dramatic in severe burn patients. Consistently high lipid peroxide levels, a good measure of free radical damage, and impaired activity of glutathione and its related enzyme activities have prompted researchers to use antioxidants to protect from further damage.

A German team of pediatric surgeons conducted a two-year study on children with burns and severe inflammatory diseases. They managed to correct parameters of oxidative stress in these patients using selenium substitution (see chapter 4), which raised glutathione peroxidase. They found this a valid supportive therapy for such conditions. Other nutritionists have increased selenium delivery through TPN (Total Parenteral Nutrition or intravenous nutrition) or through tube feeding, where food is supplied directly to the stomach or intestines.

One phenomenon of the early post-burn period is a drop in hemoglobin (red blood cell count). Scientists have questioned why. A team from Varna Medical University showed that burns depleted the glutathione and antioxidant defenses of the red blood cell itself. Oxidative byproducts accumulated, leading to destruction of these cells. They suggest that adequate antioxidant therapy might prevent this complication, as long as it is begun early enough.

A Japanese team led by Y Kasanuma from the Environmental Health Sciences Division of Tohuku University of Medicine investigated the effects of mild heat injury on oxidative stress. Rather than burning tissue, they exposed animals to mild chronic heat exposure (35⁰C, 95⁰F). They showed that chronic exposure to high temperatures causes oxidative damage and that GSH-related anti-oxidative systems play an important role in defending against this damage.

A recent study published in the journal "Burns" by D. Konukoglu was aimed at the use of NAC to treat burns. Researchers were able to decrease levels of lipid peroxidation and increase GSH levels. Using antioxidant supplementation (GSH, vitamin C and NAC) to raise glutathione levels, several Boston studies published in the journal of Burn Care Rehabilitation and in Shock, showed that they could reduce mortality from 60% to zero in animals suffering third degree burns. This is strong evidence that oxidation contributes to post-burn mortality.

CONCLUSION

Surgery, burns, trauma and shock are all complex events, consisting of a series of biochemical, anatomical, physiological and immune responses. Oxidative stress and the release of free radicals are inevitable in the initial injury, the subsequent inflammatory reactions and the healing processes. Glutathione, an integral part of our body's mechanism to minimize damage and promote healing, acts both as an antioxidant and to support the immune system.

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