EXCEED THE SPACE PROVIDED. Our laboratories have been investigatingthe role of macrophages and inflammatorymediators in the hepatotoxicity of the analgesic, acetaminophen. Using pharmacologic and transgenic approaches, we have demonstrated that macrophages contribute to liver damage, and that reactive nitrogen intermediates including nitric oxide and peroxynitrite are major inflammatorymediators involved in the pathogenic process. Although much of our previous work with acetaminophen has focused on tissue injury, it is clear that macrophages also release mediators that participate in the resolution of inflammation and in tissue repair. We have discovered that there are at least two distinct populations of macrophages that respond to acetaminophen-induced injury: a rapidly responding population (F4/80+) that appears to be comprised of resident Kupffer cells, and a population of activated macrophages (CD68+) that accumulates in the tissue 24-72 hr post exposure. We hypothesize that these macrophage populations play distinct roles in tissue injury and repair. Whereas F4/80+ resident Kupffer cells release proinflammatorycytokines and cytotoxic mediators involved in tissue injury, CD68+ inflammatory macrophages release mediators important in the resolution of inflammation and initiation of tissue repair and this will be investigated in the current proposal. A second major discovery that we have made is that heat shock protein 60 (HSP 60) is a key endogenous mediator of nitric oxide production by resident Kupffer cells and of hepatic injury following acetaminophen treatment of mice. HSP 60 is rapidly upregulated in the liver after acetaminophen administration; HSP 60 effectively stimulates nitric oxide production by liver macrophages and hepatocytes. Kupffer cell nitric oxide production and hepatic necrosis are markedly reduced in mice expressing a mutated receptor for HSP 60, the toll like receptor-4 (TLR-4). Experiments are designed to test the hypothesis that HSP 60 contributes to acetaminophen toxicity by stimulating the release of proinflammatory cytokines from F4/80+ resident Kupffer cells, and bysynergizing with these mediators to generate excessive quantities of nitric oxide in the liver. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034310-20
Application #
6881992
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Okita, Richard T
Project Start
1984-12-01
Project End
2006-09-24
Budget Start
2005-05-01
Budget End
2006-09-24
Support Year
20
Fiscal Year
2005
Total Cost
$303,503
Indirect Cost
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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