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Nitric oxide, a pervasive gas involved in countless body functions, has an important role in fever regulation as well, says a Medical College of Georgia researcher.
Previous studies have suggested conflicting information, including that the diffusible gas induces fever, suppresses fever and plays no role in fever, says Dr. Wieslaw E. Kozak, physiologist and biochemist.
Dr. Kozak's work, published in the June issue of the Journal of Applied Physiology, shows that nitric oxide does indeed have a role in fever regulation, a complicated and surprising one. The article is part of a highlighted topics series on Genetic Models in Applied Physiology featured in the journal's April, May and June issues.
His work to better define the steps of inflammation and resulting fever has implications for finding better ways to treat a host of maladies, from major infections to chronic inflammation that can result in a range of diseases from Alzheimer's to cardiovascular disease to arthritis.
Nitric oxide is produced by at least three enzymes in different tissues throughout the body. Endothelial nitric oxide synthase is found in the endothelial cells of the blood vessels where it plays a big role in blood pressure control. Neuronal nitric oxide synthase is expressed in neuronal cells in the spinal cord, brain, kidney and peripheral nervous system where it works as a cellular messenger. A third enzyme, inducible nitric oxide synthase, is induced by inflammatory agents of the immune system and can be found throughout the body. It may turn out that 'inducible' is a misnomer, because some believe this enzyme always is expressed at some level but that it's over-expressed in inflammation, Dr. Kozak says.
Knockout mice missing one of each of these three enzymes already were available for study, so Dr. Kozak induced fever in the genetically engineered mice, expecting to see a similar course in all three because although the enzymes are different, their product, nitric oxide, is not. To ensure the genetically-altered mice weren't somehow compensating for the missing enzyme, he also studied mice in which the enzymes were inhibited pharmacologically.
"The response was quite different," says Dr. Kozak of the three different knockout mice when exposed to infectious agents. Each enzyme played a distinctive, but likely interactive, role. During fever associated with a systemic bacterial infection, neuronal nitric oxide synthase was involved in initiating fever; once the fever was initiated, inducible nitric oxide synthase was involved in maintaining fever. In contrast, endothelial nitric oxide synthase was involved in fever resulting only from localized, non-bacterial inflammation. "Each enzyme has a role," Dr. Kozak says of his findings, which provide a few more pieces of the puzzle of fever regulation.
"When we get fever during infection, we have this fever for a certain period of time, for one day, two days, three days, sometimes. So nitric oxide is involved in that. When inducible nitric oxide is not depressed after a while, we continue to have fever because induction of this enzyme correlates with maintaining fever. For the fever to go down, it has to go down," says Dr. Kozak, who has followed the path of fever/inflammation for more than 20 years.
This system where the players seem to have distinct but interrelated roles may result from yet another commonality: they all need heme, the oxygen-carrying part of hemoglobin, to become active, Dr. Kozak says. Since there is only so much heme in the body it may be necessary for the activity of one of these – and other fever/inflammation- related agents – to go down before another becomes active.
And there is yet another twist – which Dr. Kozak points out further indicates how little is known about the mechanisms of fever – because the roles of these different enzymes that make nitric oxide also changed depending on the infectious agent they were exposed to.
For his studies, Dr. Kozak used lipopolysaccharide or endotoxin, a standard laboratory fever inducer derived from gram-negative bacteria that can cause inflammation throughout the body or septic shock. He also used turpentine oil, another commonly used lab agent which induces bacteria-free tissue necrosis that results in only localized inflammation.
As an example of the impact of the different infectious agents, the mice missing inducible nitric oxide synthase, which maintains fever, experienced a reduced fever in response to the systemic infection resulting from exposure to endotoxin. But the fact that they were missing the enzyme had no effect on their response to fever induced during localized inflammation.
Journal
Journal of Applied Physiology