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Regulation of inflammatory mediator ...

Dambach, Donna Marina.

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Regulation of inflammatory mediator production during acetaminophen-induced hepatotoxicity.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Regulation of inflammatory mediator production during acetaminophen-induced hepatotoxicity./
作者:	Dambach, Donna Marina.
面頁冊數:	156 p.
附註:	Source: Dissertation Abstracts International, Volume: 63-05, Section: B, page: 2353.
Contained By:	Dissertation Abstracts International63-05B.
標題:	Health Sciences, Toxicology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3055127
ISBN:	0493693114

Regulation of inflammatory mediator production during acetaminophen-induced hepatotoxicity.
Dambach, Donna Marina.

Regulation of inflammatory mediator production during acetaminophen-induced hepatotoxicity. - 156 p.

Source: Dissertation Abstracts International, Volume: 63-05, Section: B, page: 2353.

Thesis (Ph.D.)--Rutgers The State University of New Jersey - New Brunswick and University of Medicine and Dentistry of New Jersey, 2002.

Hepatotoxicity induced by AA is associated with oxidative stress (OS). This leads to activation of transcription factors such as NF-kappaB, which regulate the production of inflammatory mediators implicated in tissue injury. The present studies were aimed at analyzing the role of OS and NF-kappaB in the generation of inflammatory cytokines in the liver during AA-induced hepatotoxicity. The role of the chemokine, monocyte chemoattractant protein-1 (MCP-1), in macrophage recruitment into the liver and hepatotoxicity were also investigated. AA administration to mice resulted in increased hepatic expression of MCP-1 and its receptor CC receptor 2 (CCR2) in the liver in centrilobular regions. This was associated with a decrease in 174/80 positive macrophages in the liver 24 hours after AA administration and increased numbers of macrosialin positive activated macrophages, which was maximal after 72 hours. In CCR2 knockout (CCR2-/-) mice, the number of macrosialin positive macrophages was significantly decreased. However, CCR2-/- mice were not protected from AA-induced injury suggesting that MCP-1 plays a role in the recruitment of macrophages into the liver that are involved in tissue repair. AA treatment of mice was also associated with increased expression of TNFalpha, IL-1beta, and KC/gro, as well as the anti-inflammatory cytokine IL-10. While administration of the antioxidant, N-acetylcysteine (NAC), protected against AA-induced tissue injury, expression of TNFalpha, IL-1beta, and KC/gro was not altered. NAC did, however, induce IL-4 and TGFbeta1 expression suggesting that the protective effects of NAC may involve upregulation of anti-inflammatory cytokine expression. To study the role of NF-kappaB in AA-induced cytokine expression, knockout mice lacking NF-kappaB p50 subunit (p50-/-) were used. Treatment of wild-type mice with AA resulted in a time-dependent increase in NF-kappaB nuclear binding activity. Although NF-kappaB, activity was not evident in p50-/- mice, AA-induced expression of TNFalpha, IL-1beta, and KC/gro was only minimally affected. The loss of NF-kappaB also had no effect on AA-induced injury. These findings suggest that NF-kappaB p50 does not play a major role in the pathogenesis of AA-induced injury. In contrast, hepatic injury was exacerbated in TNFalpha receptor-1 knockout mice (p55-/-) mice. This was associated with greater decreases in CuZn superoxide dismutase (CuZnSOD) levels. However, AA-induced expression of TNFalpha, IL-1beta, KC/gro, MCP-1, and IFNgamma was similar in p55-/- and wild type mice. In contrast, double knockout mice lacking p55 and p75 (TNFalpha receptor-2) were partially protected from AA-induced injury. This was not correlated with changes in expression of inflammatory cytokines. These data suggest that TNFalpha plays both protective and cytotoxic/inflammatory roles in AA-induced hepatotoxicity.

ISBN: 0493693114Subjects--Topical Terms:

1017752
Health Sciences, Toxicology.

Regulation of inflammatory mediator production during acetaminophen-induced hepatotoxicity.
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