Liver fibrosis, the accumulation of extracellular matrix (ECM) proteins, occurs in most types of chronic liver diseases. Liver fibrosis progresses to cirrhosis with subsequent portal hypertension, hepatic failure, and hepatocellular carcinoma, Activated hepatic stellate cells (HSCs) are the major ECM producing cell in the fibrogenic liver and key fibrogenic signals have been identified, including transforming drug factor beta (TGFbeta), reactive oxygen species (ROS), and Ang II. We have demonstrated that the key signaling pathway activated by Ang II in activated HSC is the endogenous generation of ROS by NADPH oxidase and that the downstream effects module HSC proliferation, production of ECM proteins, and synthesis of inflammatory cytokines. Thus we have begun to elucidate the mechanistic relationship between inflammation, Ang II, reactive oxygen species, and hepatic fibrosis. We wish to pursue four specific aims to further characterize the role of Ang II in hepatic fibrosis and the downstream activation of NADPH oxidase. The underlying hypotheses that serve as the basis for this proposal are the following: 1.The renin-angiotensinogen system is a critical pathway in hepatic fibrosis. 2. The major mediator of the effects of Ang II including changes in gene expression is the activation of NADPH oxidase. 3. Other fibrogenic factors also induce NADPH oxidase, so that this enzyme becomes the critical mediator of the generation of reactive oxygen species and subsequent induction of fibrogenesis. 4. New insights into the mechanisms by which Ang II and NADPH oxidase mediate hepatic fibrogenesis will lead to the development of novel therapies for patients with fibrotic liver diseases.
The specific aims of the proposal are: 1. To define the components of the NADPH oxidase complex in hepatic stellic cells. 2. To assess the effect of inhibiting Ang II on hepatic fibrosis and hepatic stellate cell apoptosis. 3. To assess the effect of titrating the angiotensinogen gene in models of hepatic fibrosis. 4. To determine if other mediators of hepatic fibrosis in addition to Ang II activate NADPH oxidase.
| Tripathi, Anupriya; Debelius, Justine; Brenner, David A et al. (2018) The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 15:397-411 |
| Iwaisako, Keiko; Jiang, Chunyan; Zhang, Mingjun et al. (2014) Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci U S A 111:E3297-305 |
| Meng, Fanli; Wang, Kai; Aoyama, Tomonori et al. (2012) Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143:765-776.e3 |
| Fouts, Derrick E; Torralba, Manolito; Nelson, Karen E et al. (2012) Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J Hepatol 56:1283-92 |
| Iwaisako, Keiko; Haimerl, Michael; Paik, Yong-Han et al. (2012) Protection from liver fibrosis by a peroxisome proliferator-activated receptor ? agonist. Proc Natl Acad Sci U S A 109:E1369-76 |
| Iwaisako, Keiko; Brenner, David A; Kisseleva, Tatiana (2012) What's new in liver fibrosis? The origin of myofibroblasts in liver fibrosis. J Gastroenterol Hepatol 27 Suppl 2:65-8 |
| Nelson, David R; Teckman, Jeffrey; Di Bisceglie, Adrian M et al. (2012) Diagnosis and management of patients with ?1-antitrypsin (A1AT) deficiency. Clin Gastroenterol Hepatol 10:575-80 |
| Yan, Arthur W; Fouts, Derrick E; Brandl, Johannes et al. (2011) Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 53:96-105 |
| Scholten, David; Reichart, Donna; Paik, Yong Han et al. (2011) Migration of fibrocytes in fibrogenic liver injury. Am J Pathol 179:189-98 |
| Kisseleva, Tatiana; Brenner, David A (2011) Anti-fibrogenic strategies and the regression of fibrosis. Best Pract Res Clin Gastroenterol 25:305-17 |
Showing the most recent 10 out of 20 publications
