The goal of this study is to understand the effects of hemodynamic changes on liver structure and function with a focus on portal hypertension. Portal hypertension is a major complication of chronic liver disease. Liver cirrhosis is its most common cause, but it develops in non-cirrhotic conditions as well. In portal hypertension, portal venous flow decreases, while hepatic arterial (HA) flow increases because of a combination of a hepatic arterial buffer response and vasodilation of splanchnic arteries. How these changes influence liver structure and function is largely unknown. Our preliminary data show that rats with partial portal vein ligation (PPVL; a surgical model of portal hypertension) develop portal tract fibrosis. PPVL partially occludes the portal vein at a pre-hepatic site and leads to portal hypertension and increased HA-flow. Rats with PPVL also showed increased infiltration of macrophages and T-cells in portal tracts. Further, increased blood flow is known to cause remodeling of arterial walls, mediated by transient accumulation and activation of perivascular macrophages and T-cells. Therefore, we hypothesize that increased HA-flow in portal hypertension facilitates portal tract fibrosis by recruiting macrophages and T-cells through signals that are mediated by mechano-transduction. Liver remodeling through enhanced HA-flow could also be a second hit that amplifies liver fibrosis/cirrhosis. Further, we hypothesize that the spleen is an important source of the infiltrating immune cells. To test these hypotheses, we propose to examine the following three aims: 1) Determine the role of HA-flow in the development of portal tract fibrosis and the significance of flow-induced portal tract fibrosis in the progression of liver fibrosis/cirrhosis, 2) Determine the mechanism by which increased HA-flow causes immune cell infiltration and portal tract fibrosis, and 3) Determine the mechanism by which immune cells regulate portal tract fibrosis.

Public Health Relevance

Portal hypertension is a detrimental complication of chronic liver disease and develops in both cirrhotic and non-cirrhotic conditions. The goal of this proposed research is to understand the effects of hemodynamic changes on liver structure and function in portal hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK117597-01
Application #
9542958
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
2018-05-05
Project End
2022-04-30
Budget Start
2018-05-05
Budget End
2019-04-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code