# Pathogenic role of thrombospondin-1 in acute and chronic liver failure

> **NIH VA IK2** · OLIN TEAGUE VETERANS CENTER · 2021 · —

## Abstract

Liver failure is characterized by a loss of hepatocytes or hepatic function due to an acute liver insult or chronic
liver disease. Liver failure is often accompanied by neurological complications, called hepatic encephalopathy,
which lead to reduced quality of life and increased mortality in patients. Acute liver failure is characterized by
hepatocyte necrosis that occurs at a rate that is too rapid for the liver to regenerate resulting in a loss of liver
function. In contrast, chronic liver diseases are characterized with progressive fibrosis and cirrhosis that can
generate liver failure as hepatocyte death occurs and hepatic regeneration is impaired due to aberrant cellular
processes. During chronic liver disease, transforming growth factor β1 (TGFβ1) has been well classified as a
factor involved with apoptosis, inflammation and liver fibrosis and therefore contributes to the progression of
liver pathology. We recently demonstrated that TGFβ1 also contributes to the pathogenesis of both acute liver
failure and hepatic encephalopathy and that this signaling protein promotes increased endothelial cell
permeability following acute liver injury. Unfortunately attempts to develop therapeutics that target TGFβ
signaling have failed clinical trials. Therefore, targeting proteins involved in activating TGFβ1 and/or proteins
that interact with TGFβ1 signaling may prove to be better tolerated by patients. Taking this approach, the
overall goal of this proposal is to investigate thrombospondin-1 (TSP-1), a homotrimeric glycoprotein that
activates the propeptide form of TGFβ1, and determine its contribution to pathology associated with acute and
chronic liver failure. TSP-1 has been found to facilitate liver fibrosis through its interactions with TGFβ1,
though its actions during acute liver injury are not well classified. Our proposed specific aims will address two
central hypotheses: (1) The hepatic expression of TSP-1 is elevated during acute liver failure leading to
TGFβ1 activation which drives hepatic inflammation, apoptosis, increased mortality and the development of
hepatic encephalopathy; (2) Chronic liver failure is characterized by TGFβ1 activation via TSP-1 which
increases hepatic inflammation, fibrosis and other pathological processes associated with chronic liver
disease. In this proposal, the pathogenesis of acute liver failure will be studied using a hepatocyte cell culture
model as well as the azoxymethane-induced and acetaminophen-induced models of acute liver failure in mice.
Chronic liver failure studies will employ rats that have undergone bile duct ligation surgery, a model of
cholestasis and chronic biliary fibrosis with specific experiments targeted to assess cell-cell interactions in the
liver. At the completion of this project, we expect to have determined the role of TSP-1 signaling on the
pathological mechanisms involved with acute liver failure and chronic liver disease and will also determine the
role of this signaling pathway ...

## Key facts

- **NIH application ID:** 10046291
- **Project number:** 5IK2BX003486-05
- **Recipient organization:** OLIN TEAGUE VETERANS CENTER
- **Principal Investigator:** Matthew McMillin
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046291

## Citation

> US National Institutes of Health, RePORTER application 10046291, Pathogenic role of thrombospondin-1 in acute and chronic liver failure (5IK2BX003486-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10046291. Licensed CC0.

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