Abstract

ANNUAL REPORT FOR 2008? ? 1. This year we discovered a pathway by which IL-4 induces the synthesis of gamma-glutamylcysteinyl ligase, the rate determining step in the synthesis of the cytoprotective molecule glutathione, and protects against AILI. Our findings suggest that IL-4 signaling causes the activation of the transcription factor AP-1, which in turn induces the gene expression of gamma-glutamylcysteinyl ligase.? ? 2. This year we discovered a potential mechanism by which endogenous corticosterone released into the blood as a result of hepatocellular injury enhances the severity of AILI. Our findings suggest that corticosterone potentiates AILI at least in part by activating MAPK signaling.? ? 3. This year we provide evidence suggesting that halothane-induced liver injury is caused at least in part, by enhancing ER stress and an unfolded protein response as a consequence of its reactive metabolite, trifluoroacetyl chloride, covalently modifying chaperone proteins in the ER.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Intramural Research (Z01)
Project #
1Z01HL000962-26
Application #
7734946
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
2008
Total Cost
$1,536,028
Indirect Cost

  Institution

Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Masson, Mary Jane; Peterson, Richard A; Chung, Christine J et al. (2007) Lymphocyte loss and immunosuppression following acetaminophen-induced hepatotoxicity in mice as a potential mechanism of tolerance. Chem Res Toxicol 20:20-6
Bourdi, Mohammed; Eiras, Daniel P; Holt, Michael P et al. (2007) Role of IL-6 in an IL-10 and IL-4 double knockout mouse model uniquely susceptible to acetaminophen-induced liver injury. Chem Res Toxicol 20:208-16
Yee, Steven B; Bourdi, Mohammed; Masson, Mary Jane et al. (2007) Hepatoprotective role of endogenous interleukin-13 in a murine model of acetaminophen-induced liver disease. Chem Res Toxicol 20:734-44
Welch, Kevin D; Reilly, Timothy P; Bourdi, Mohammed et al. (2006) Genomic identification of potential risk factors during acetaminophen-induced liver disease in susceptible and resistant strains of mice. Chem Res Toxicol 19:223-33
Ju, Cynthia; Pohl, Lance R (2005) Tolerogenic role of Kupffer cells in immune-mediated adverse drug reactions. Toxicology 209:109-12
Welch, Kevin D; Wen, Bo; Goodlett, David R et al. (2005) Proteomic identification of potential susceptibility factors in drug-induced liver disease. Chem Res Toxicol 18:924-33
Lee, Hookeun; Yi, Eugene C; Wen, Bo et al. (2004) Optimization of reversed-phase microcapillary liquid chromatography for quantitative proteomics. J Chromatogr B Analyt Technol Biomed Life Sci 803:101-10
Ju, Cynthia; McCoy, J Philip; Chung, Christine J et al. (2003) Tolerogenic role of Kupffer cells in allergic reactions. Chem Res Toxicol 16:1514-9
Masubuchi, Yasuhiro; Bourdi, Mohammed; Reilly, Timothy P et al. (2003) Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease. Biochem Biophys Res Commun 304:207-12
Ju, Cynthia; Reilly, Timothy P; Bourdi, Mohammed et al. (2002) Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice. Chem Res Toxicol 15:1504-13

Showing the most recent 10 out of 12 publications