# The Thromboxane-Prostanoid Receptor in Radiation-Induced Pulmonary Fibrosis

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $689,596

## Abstract

Project Summary:
Radiation induced lung injury is a crucial dose-limiting factor in patients receiving thoracic radiotherapy, affecting
a significant proportion of patients even with use of newer radiotherapy techniques. This proposal investigates a
novel pathway regulating fibroblast activation that can be directly targeted to limit progressive radiation-induced
lung fibrosis. We found that the thromboxane-prostanoid receptor (TPr) was constitutively expressed in human
and murine fibrotic pulmonary fibroblasts and that pharmacological inhibition or conditional genetic ablation of
the TPr markedly attenuated pulmonary fibrosis in mice resulting from ionizing radiation, bleomycin-induced
oxidative stress or Hermansky-Pudlak syndrome. Although thromboxane A2 is a major ligand for TPr, we found
that TPr signaling was being driven by F2-isoprostanes (F2-IsoPs), resulting from non-enzymatic, free-radical
oxidation of arachidonic acid. We have demonstrated that ionizing radiation induces F2-IsoP generation in cell
culture and in murine pulmonary tissue in vivo, as does bleomycin. F2-IsoPs are increased in idiopathic
pulmonary fibrosis due to oxidative stress in this disease, but whether they are increased in patients who develop
radiation-induced pulmonary fibrosis (RIPF) is unknown, although preclinical and clinical studies provide key
support for the overall hypothesis that non-enzymatic free radical-induced oxidation of arachidonic acid signaling
significantly contributes to RIPF. We hypothesize that a contributing factor is via calcium-induced calpain-
mediated release of TGFβ from the latent complex in lung fibroblasts. The small molecule ifetroban is a TPr
antagonist that has undergone extensive human testing and has an excellent safety profile. Thus, research
validating TPr antagonism in inhibiting RIPF could result in rapid translation via repurposing of existing and safe
drugs. However, there are key gaps in our knowledge that need to be filled before a clinical trial would be
appropriate. First, the therapy would need to work in the context of existing standard of care, including immune
checkpoint therapy. Second, although it is likely that there is an increase in either thromboxane or F2-IsoPs in
RIPF, we need to verify that patients receiving thoracic radiation actually show an increase in one or more of
these molecules. Finally, we need a better understanding of the mechanism by which TPr regulates pulmonary
myofibroblast differentiation and activation in the context of radiation. The goal of this proposal is to fill these
gaps.

## Key facts

- **NIH application ID:** 10912036
- **Project number:** 5R01CA276352-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** MICHAEL L. FREEMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $689,596
- **Award type:** 5
- **Project period:** 2023-08-22 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912036

## Citation

> US National Institutes of Health, RePORTER application 10912036, The Thromboxane-Prostanoid Receptor in Radiation-Induced Pulmonary Fibrosis (5R01CA276352-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10912036. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*