Collateral Damage  pg. 2

The production of free radicals by neutrophils and macrophages is called oxidative or oxidant stress, and it is a critical part of infection control.

Oxidative stress goes hand in hand with inflammation. The first response is the neutrophil or macrophage engulfing a bacterium. Then, as a consequence, is the oxidative burst that leads to the generation of hydrogen peroxide, superoxide and other free radicals that acutely damage the invading organism.

Free radicals are important in killing bacteria, but, in doing so, they can damage surrounding tissue. Oxidative damage has been linked to the development of Alzheimer’s disease, certain forms of cancer, and other inflammatory diseases, which suggests that antioxidants might be useful in preventing or treating such disorders.

Free radicals don’t last very long in tissues, making it difficult to measure their impact directly. However, their damage can be assessed indirectly. At Vanderbilt, the late Jason Morrow, M.D., and his colleague, L. Jackson Roberts, M.D., identified and characterized a unique class of oxidatively-damaged fats, called isoprostanes. Circulating levels of isoprostanes provide an accurate and non-invasive index of oxidative stress in humans.

Morrow and colleagues at Oregon State University also found that the extreme exercise involved in an ultra-marathon (a 32-mile run) caused increased production of isoprostanes and inflammatory cytokines. Runners who took high doses of antioxidant vitamins had significantly lower levels of isoprostanes in their blood compared to runners who took a placebo, but the vitamins had no effect on measures of inflammation.

“We de-linked the protein (cytokine) component of inflammation from the oxidative stress component,” Morrow said in 2004. “This says that inflammation is a multi-factor pathway and not all of those pathways are regulated in the same way—if we block one pathway (such as oxidative stress) we may still have another pathway that can be damaging.”

One of the other potentially destructive arms of inflammation involves lipid-derived molecules called eicosanoids. These molecules, which include the prostaglandins and leukotrienes, are produced by nearly every cell in the body. They act as local hormones, regulating many biological functions including smooth muscle contraction.

Prostaglandins are also released by damaged cells and by macrophages, and they contribute to the cardinal signs of inflammation. They stimulate pain receptors in the damaged tissue, promote vasodilation (heat and redness), and increase capillary permeability, leading to the accumulation of fluid in tissue (swelling).

Prostaglandins are made from arachidonic acid by the cyclooxygenase (COX) enzymes, which come in two forms. In the early 1990s, researchers determined that prostaglandin production by one of the enzymes, called COX-1, protects the stomach lining, whereas activation of a related enzyme, COX-2, in other tissues can lead to inflammation, pain and tumor growth.

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