Hepatic fibrosis is thought to be the result of a wound-healing process, marked by transforming growth factor beta (TGF- beta) production and the resulting upregulation of collagen I synthesis by stellate cells. However the relationship between chronic liver injury and fibrogenesis is not well understood. We have made several original observations regarding a possible mechanism linking chronic injury to fibrogenesis in the liver. First, we have directly demonstrated that hepatic stellate cells (HSC) are able to phagocytose apoptotic bodies of hepatocytes in vitro, and second this results in HSC activation and upregulation of TGF-beta1 and type I collagen production. Based on these preliminary data, we propose a CENTRAL HYPOTHESIS that phagocytosis of apoptotic bodies by HSC induces fibrogenesis in the liver.
The SPECIFIC AIMS of this proposal will be answering two key questions generated by this hypothesis: 1. Is phagocytosis of apoptotic bodies by HSC a specific and regulated process? A) Is phagocytosis by HSC a specific receptor-mediated process? B) Is phosphatidylserine eliciting a signaling cascade leading to HSC activation? 2. What are the signaling pathways leading to TGF-beta1 and type 1 collagen upregulation? A) Is engulfment of apoptotic bodies accompanied by activation of NADPH oxidase? B) Is the activation of the MAP-kinase pathway contributing to type I collagen and TGF-beta1 generation? In summary, inhibition of apoptosis, phagocytosis of apoptotic bodies by HSC, or signaling events occurring as a result of the phagocytic process, may prove to be therapeutic strategies to inhibit liver fibrogenesis and delay or even avoid liver transplantation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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University of California Davis
Internal Medicine/Medicine
Schools of Medicine
United States
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Zhan, Shan-Shan; Jiang, Joy X; Wu, Jian et al. (2006) Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo. Hepatology 43:435-43