"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
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Contact: Toni Baker
tbaker@mail.mcg.edu
706-721-4421
Medical College of Georgia
30-May-2003