Objective. Systemic inflammation (including sepsis) is the main cause of hospital death in the US. Systemic inflammation is accompanied by either fever (in mild cases) or hypothermia (in severe cases), and the direction of the body temperature (Tb) response may determine the difference between life and death. Yet, no other inflammatory phenomenon is so mysterious and understudied as the switch between fever and hypothermia. We will study mechanisms of this phenomenon by using a rat model of systemic inflammation. Hypothesis. We propose that three mechanisms are involved: 1) the severity of inflammation determines which subtype (1 or 2) of the enzyme cyclooxygenase (COX) is activated;2) each type of COX produces the same lipid, but then sends this lipid to two different sets of terminal synthases (enzymes that produce a wide spectrum of molecules called prostanoids);3) some of these prostanoids (those that are produced with participation of COX-2) act on cells in the brain that activate several heat-production and heat-conservation mechanisms in the body (thus causing Tb to rise), whereas prostanoids produced with participation of COX- 1 act on a different group of cells in the brain to turn off the main heat-production organ in the rat body, brown fat (thus causing Tb to fall). Approach. A separate set of experiments will be aimed at studying each of the mechanisms proposed. First, we will study the two COX enzymes by measuring their expression and activity in inflammation and by using selective inhibitors to block each of the enzymes separately. Second, we will use a wide variety of methods and techniques to study different synthases and prostanoids. We will determine which prostanoids cause fever and which cause hypothermia, and we will find whether synthases that produce these prostanoids are overexpressed during inflammation, and whether they are functionally coupled to COX-2 or COX-1. Third, we will study brain mechanisms of the thermoregulatory action of selected prostanoids. We will determine which brain areas are activated in inflammation-associated hypothermia (but not in fever), and whether these areas have receptors for the hypothermia-inducing prostanoids. We will then place small chemical lesions in these brain areas and study how such lesions affect the main heat-production and heat- loss mechanisms in systemic inflammation, as well as Tb responses to the prostanoids of interest. Significance. This will be the first attempt to understand how systemic inflammation causes fever in some cases but hypothermia in other cases. We will identify some of the mechanisms involved. We may also gain insight into the therapeutic use of selective COX inhibitors in systemic inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041233-06
Application #
7614280
Study Section
Special Emphasis Panel (ZRG1-IFCN-D (02))
Program Officer
Mitler, Merrill
Project Start
2000-05-01
Project End
2012-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
6
Fiscal Year
2009
Total Cost
$352,127
Indirect Cost
Name
St. Joseph's Hospital and Medical Center
Department
Type
DUNS #
131606022
City
Phoenix
State
AZ
Country
United States
Zip Code
85013
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