Regardless of the etiology, fibrosis is the final common pathway for chronic liver injury and failure. Fibrosis with subsequent complications of cirrhosis results in the death of patients with end stage liver disease if liver transplantation is not performed. As a result of the liver's unique regenerative capacity, progression to severe complications is a slow process often spanning decades. Slowing the progression of fibrosis will therefore have significant long-term benefit and mandates a greater understanding of the molecular and cellular basis of hepatic fibrosis. Stromal cell derived factor-11 (SDF-11/CXCL12), is a chemokine that promotes retention of hematopoietic stem cells in the bone marrow, cancer metastasis, angiogenesis and migration of lymphocytes to sites of injury through interactions with its receptor, CXCR4. Hepatic stellate cell (HSC) activation is central feature of fibrosis in all forms of chronic liver injury and we have established that HSCs express functional CXCR4 receptor and its engagement by SDF-11 induces cellular activation, collagen I expression, and proliferation, providing a direct link between SDF-11 and liver disease pathogenesis. The hepatic expression of SDF-11 is predominantly localized to biliary epithelial cells (BECs). During liver injury, BECs undergo marked proliferation associated with elevated hepatic and plasma protein levels of SDF-11. Importantly, plasma levels of SDF-11 correlate with increased liver fibrosis in patients with chronic HCV, indicating an important relationship to fibrosis. Interestingly, nearly all lymphocyte infiltration into the injured liver is localized to the SDF-11-expressing periportal region, indicating an additional role for SDF-11 in lymphocyte migration to the liver. Therefore I propose that BEC-derived SDF-11 promotes fibrosis by activation of hepatic stellate cells and mediates hepatic inflammation via recruitment of inflammatory cells.
The aims of this proposal are: 1) To determine the importance of the SDF-11/CXCR4 axis in promoting hepatic fibrosis and inflammation in mechanistically distinct mouse models of liver injury (BDL and CCl4) by blocking the SDF-11/CXCR4 (SDF-11 neutralizing antibody or CXCR4 small molecule inhibitor). Fibrosis will be assessed using Sirius Red staining for collagen/morphometric analysis, hydroxyproline quantitation, and qRT-PCR for fibrogenic markers and inflammation will be assessed by histologic grading and characteristics of inflammatory infiltrate will be analyzed using FACS for cell-specific markers. 2) To evaluate the factors leading to increased SDF-11 expression by BECs by measuring mRNA and protein levels of SDF-11 in culture stimulated BECs and to determine whether BEC produced SDF-11 is sufficient to promote HSC biology in in vitro co-culture models.

Public Health Relevance

Fibrosis with subsequent complications of cirrhosis results in the death of patients with end stage liver disease if liver transplantation is not performed. Given the shortage of donor organs there is an urgent need to develop effective anti-fibrotic treatments. The results from this proposal will help us understand the molecular basis of the fibrotic liver and reveal the feasibility modulating of the SDF-11/CXCR4 axis as an anti-fibrotic strategy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DK090986-03
Application #
8422998
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (O1))
Program Officer
Podskalny, Judith M,
Project Start
2011-01-17
Project End
2015-01-16
Budget Start
2013-01-17
Budget End
2014-01-16
Support Year
3
Fiscal Year
2013
Total Cost
$47,232
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Saiman, Yedidya; Jiao, JingJing; Fiel, M Isabel et al. (2015) Inhibition of the CXCL12/CXCR4 chemokine axis with AMD3100, a CXCR4 small molecule inhibitor, worsens murine hepatic injury. Hepatol Res 45:794-803
Saiman, Yedidya; Agarwal, Ritu; Hickman, DaShawn A et al. (2013) CXCL12 induces hepatic stellate cell contraction through a calcium-independent pathway. Am J Physiol Gastrointest Liver Physiol 305:G375-82