# RADIOBIOLOGY OF HEPATOCYTES

> **NIH NIH R01** · DUKE UNIVERSITY · 1991 · $188,345

## Abstract

Though radiation induced fibrosis in normal tissues is a pathologic
condition that limits the radiation dose which can be safely delivered in
the treatment of tumors, the cellular and molecular events controlling this
fibrogenic reaction have not been delineated.  Of the multiple growth
factors implicated in tissue fibrogenesis during normal wound healing, the
cytokine transforming growth factor-beta (TGF-beta) is of particular
interest.  In addition to its bifunctional role in modifying cellular
proliferation (i.e. it stimulates the growth of fibroblasts but inhibits
the proliferation of epithelial cells, including hepatocytes), TGF-beta has
been shown to be chemotactic for lymphocytes and fibroblasts and
stimulatory for the cellular production of collagen and fibronectin.  These
and other data suggest that TGF-beta is involved in regulating tissue
fibrogenesis under both normal and pathological conditions.  Recently, we
have shown that TGF-beta is significantly increased in pericentral
hepatocytes, central veins and sinusoidal vessels of rat liver following
irradiation.  Additionally, our results demonstrate that elevated
concentrations of TGF-beta plays a pivotal role in the hepatic fibrosis
formation which occurs subsequent to irradiation.  Specifically, we are
proposing to determine:  1) the kinetics of TGF-beta expression in
irradiated liver as a function of radiation dose; 2) whether the increased
TGF-beta observed in irradiated liver results from platelet release during
aggregation and/or from increased cellular synthesis; 3) whether TGF-beta
observed subsequent to irradiation is present in an active or inactive
form; 4) whether the preirradiation levels of TGF-beta in the liver is
species dependent; 5) whether the extent of chronic liver fibrosis
following radiation treatment can be predicted during treatment by
measuring TGF-beta levels in tissue sections by peroxidase
immunohistochemistry or in the urine by ELISA techniques; 6) whether the
chemical milieu present in an irradiated fibrotic liver (i.e. increased
TGF-beta levels in the central lobular region, Addendum B) reduces the
capacity of hepatocytes to proliferate in response to mitogenic stimuli and
if so, whether this is mediated through changes in receptor function (i.e.
EGF, TGF-beta); and 7) the importance of reproductively viable parenchymal
hepatocytes in the etiology of chronic radiation hepatitis.  In conclusion,
during the next grant period we will utilize the rat liver as a model
system to investigate the cellular and molecular events controlling tissue
fibrogenesis and parenchymal cell homeostasis.  By more clearly defining
the role which TGF-beta plays in regulating fibrogenesis subsequent to
radiation exposure, it may be possible to ultimately reduce the fibrosis
formation which often limits the radiation dose which can be safely
delivered in the treatment of tumors, and to determine those patients
genetically predisposed to its debilitating effects.

## Key facts

- **NIH application ID:** 3179786
- **Project number:** 5R01CA040172-05
- **Recipient organization:** DUKE UNIVERSITY
- **SAM.gov UEI:** TP7EK8DZV6N5
- **Principal Investigator:** Randy L Jirtle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1991
- **Award amount:** $188,345
- **Award type:** 5
- **Project period:** 1985-07-01 → 1992-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3179786

## Citation

> US National Institutes of Health, RePORTER application 3179786, RADIOBIOLOGY OF HEPATOCYTES (5R01CA040172-05). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3179786. Licensed CC0.

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