# MODIFICATION OF RADIATION-INDUCED VASCULAR PERMEABILITY

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 1988 · $139,176

## Abstract

This proposal will study mechanisms responsible for the
development of post radiation pulmonary fibrosis (PRPF).  PRPF
shares many common features with idiopathic pulmonary fibrosis,
which has received extensive attention from investigators in
pulmonary physiology and medicine.  We will use this research, in
addition to studies in radiobiology, as a basis for our study of
pathways leading to PRPF.  We hypothesize that changes in
vascular permeability in the rat lung during the first month after
radiation exposure are directly related to the development of
fibrosis 6 to 12 months later.  Changes in vasculr permeability
may act as a cause of PRPF, due to leakage of material from the
vasculature into the interstitium, or as an early measure of more
general lung injury.  We will test these hypotheses with six drugs
to block different pathways to increased vascular permeability,
and then monitoring subsequent development of PRPF.

We have developed a unique, sensitive, and quantitative dual
isotope technique to measure the lung vascular permeability
surface area product (PS) to albumin.  We have shown that lung PS
increases immediately after whole thorax radiation, returns to
normal, and then increases again approximately 20 days later.  We
will examine the effectiveness of six pharmacological agents in
suppressing early changes in PS, and late changes in breathing
rate in whole thorax irradiated rats and blood flow in hemithorax
irradiated rats.  The development of PRPF will be verified with
histology.  Each drug has been selected because of its ability to
block a different step in the hypothesized pathway to increased
vascular permeability and subsequent pulmonary fibrosis.  We
hypothesized that the early effects of these agents will define the
importance of the corresponding blocked pathway and will predict
the efficacy of the drug in reducing or preventing PRPF.

We will then extend this approach by combining the most
effective drugs to block the underlying process at several points.
This should interrupt the cycle of cell activation and tissue injury
that probably leads to end stage PRPF.  Finally, the successful
combination treatments will be modified and evaluated with
multifraction radiotherapy to determine whether the sequence of
events leading to fibrosis is different when lung injury occurs over
an extended period of time.

Post radiation pulmonary fibrosis is a serious complication in
approximately 10% of patients with breast cancer or lung cancer
who receive radiotherapy.  These studies will aid our
understanding of the development of radiation injury in the lung
and should provide clinically relevant information on prevention
of fibrosis.

## Key facts

- **NIH application ID:** 3173821
- **Project number:** 5R01CA036272-05
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **SAM.gov UEI:** HD1WMN6945W6
- **Principal Investigator:** Michael M. Graham
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1988
- **Award amount:** $139,176
- **Award type:** 5
- **Project period:** 1983-12-01 → 1990-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3173821

## Citation

> US National Institutes of Health, RePORTER application 3173821, MODIFICATION OF RADIATION-INDUCED VASCULAR PERMEABILITY (5R01CA036272-05). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3173821. Licensed CC0.

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