The long-range goal of this project is to establish the mechanistic role(s) of aldehydic products of lipid peroxidation (4-hydroxynonenal [4-HNE] and malondialdehyde [MDA]) in chemical-induced liver fibrosis. It has become increasingly clear that these chemically reactive aldehydes display a spectrum of cellular effects ranging from enzyme inhibition to increasing transcription of specific genes involved in collagen synthesis and fibrosis. The investigator's working hypothesis predicts that AP-1 and NFkappaB are critical systems in Ito cells affected by 4-HNE and MDA the result(s) of which are manifested in an imbalance of collagen synthesis/degradation and dysregulation of hepatocyte death processes. This hypothesis will be systematically evaluated in 3 specific aims using hepatic nonparenchymal and parenchymal cells isolated form rat during the progression of CCl4-induced cirrhosis.
In Specific Aim 1, the PI will establish the fibrogenic potential of 4-HNE and MDA as regulatory elements in AP-1 transcriptional dysregulation involving alpha1-(1) procollagen, metalloproteinase-1 (MMP-1) and tissue metalloproteinase inhibitor-1 (TIMP-1) genes in cultured Ito cells. Experiments proposed for Specific Aim 2 will investigate changes NFkB signaling pathways in Ito cells during the time course of CC14-induced hepatic fibrosis and determine how regulation of this pathway in Ito cells affects cell death in hepatocytes.
In Specific Aim 3, experiments using co-cultures of hepatocytes, Kupffer cells and Ito cells will be performed to identify the cellular origin of 4-HNE or MDA and determine the ability of these aldehydes to diffuse into and effect adjacent cells. The effects of these aldehydes on Ito cells will be evaluated in terms of interactions with Kupffer cell-derived cytokines TNFalpha, and TGFbeta with the goal of identifying cellular sources and targets of cellular mediators that potentially influence pathways of cell death. These studies will greatly enhance the understanding of the mechanistic role(s) of aldehydic products of lipid peroxidation in chemical-induced liver injury and fibrosis. Identification of novel cellular targets and specific mechanisms could provide information leading to development of effective therapeutic interventions for ameliorating specific components of hepatic inflammatory and fibrotic processes.
| Roede, James R; Carbone, David L; Doorn, Jonathan A et al. (2008) In vitro and in silico characterization of peroxiredoxin 6 modified by 4-hydroxynonenal and 4-oxononenal. Chem Res Toxicol 21:2289-99 |
| Doorn, Jonathan A; Hurley, Thomas D; Petersen, Dennis R (2006) Inhibition of human mitochondrial aldehyde dehydrogenase by 4-hydroxynon-2-enal and 4-oxonon-2-enal. Chem Res Toxicol 19:102-10 |
| Petersen, Dennis R (2005) Alcohol, iron-associated oxidative stress, and cancer. Alcohol 35:243-9 |
| Carbone, David L; Doorn, Jonathan A; Kiebler, Zachary et al. (2004) Inhibition of Hsp72-mediated protein refolding by 4-hydroxy-2-nonenal. Chem Res Toxicol 17:1459-67 |
| Petersen, Dennis R; Doorn, Jonathan A (2004) Reactions of 4-hydroxynonenal with proteins and cellular targets. Free Radic Biol Med 37:937-45 |
| Carbone, David L; Doorn, Jonathan A; Petersen, Dennis R (2004) 4-Hydroxynonenal regulates 26S proteasomal degradation of alcohol dehydrogenase. Free Radic Biol Med 37:1430-9 |
| Doorn, Jonathan A; Maser, Edmund; Blum, Andreas et al. (2004) Human carbonyl reductase catalyzes reduction of 4-oxonon-2-enal. Biochemistry 43:13106-14 |
| Doorn, Jonathan A; Petersen, Dennis R (2003) Covalent adduction of nucleophilic amino acids by 4-hydroxynonenal and 4-oxononenal. Chem Biol Interact 143-144:93-100 |
| Doorn, Jonathan A; Srivastava, Satish K; Petersen, Dennis R (2003) Aldose reductase catalyzes reduction of the lipid peroxidation product 4-oxonon-2-enal. Chem Res Toxicol 16:1418-23 |
| Vasiliou, Vasilis; Qamar, Lubna; Pappa, Aglaia et al. (2003) Involvement of the electrophile responsive element and p53 in the activation of hepatic stellate cells as a response to electrophile menadione. Arch Biochem Biophys 413:164-71 |
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