The Thromboxane-Prostanoid Receptor in Radiation-Induced Pulmonary Fibrosis

辐射诱发肺纤维化中的血栓素-前列腺素受体

基本信息

批准号：
10734570
负责人：
MICHAEL L. FREEMAN
金额：
$ 72.59万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-22 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734570
关键词：
Ablation Affect Agonist Arachidonic Acids Architecture Attenuated Bleomycin Calcium Calpain Cancer Model Cell Culture Techniques Cells Chest Clinical Clinical Research Clinical Trials Collagen Complex Data Deposition Diagnostic Imaging Disease Dose Limiting Ensure Event F2-Isoprostanes Fibroblasts Fibrosis Free Radicals Gases Generations Genetic Goals Hermanski-Pudlak Syndrome Human Infiltration Inflammatory Ionizing radiation Isoprostanes Knock-out Knowledge Ligands Lung Malignant neoplasm of lung Mediating Mus Muscular Dystrophies Mutation Myofibroblast Non-Small-Cell Lung Carcinoma Orphan Drugs Oxidative Stress Oxidative Stress Induction Pathway interactions Patients Pharmaceutical Preparations Phase Phosphorylation Proliferating Prostaglandins Pulmonary Fibrosis Pulmonary Inflammation Radiation Radiation Fibrosis Radiation Oncology Radiation therapy Receptor Inhibition Receptor Signaling Regulation Research Role Safety Signal Transduction Structure of parenchyma of lung TP53 gene Techniques Testing Therapeutic Therapeutic Effect Thromboxane A2 Thromboxanes Time Tissues Toxic effect Transforming Growth Factor beta Translations Urine Work antagonist anti-PD-1 arachidonate cell type checkpoint inhibition checkpoint therapy chemoradiation coronary fibrosis epithelial injury idiopathic pulmonary fibrosis ifetroban in vivo inhibitor irradiation lung injury novel oxidation peroxidation pharmacologic preclinical study prevent programmed cell death protein 1 radiation-induced lung injury receptor research clinical testing response small molecule standard of care tumor

项目摘要

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.

项目概要：放射引起的肺损伤是接受胸部放射治疗的患者的一个重要的剂量限制因素，影响即使使用较新的放射治疗技术，仍有很大一部分患者会出现这种情况。调节成纤维细胞活化的新途径，可以直接靶向限制进行性辐射诱导的我们发现血栓素-前列腺素受体（TPr）在人类中持续表达。和小鼠纤维化肺成纤维细胞，并且药物抑制或条件性基因消融 TPR 显着减轻了由电离辐射、博莱霉素诱导的小鼠肺纤维化尽管血栓素 A2 是 TPR 的主要配体，但我们发现氧化应激或 Hermansky-Pudlak 综合征。 Tpr 信号传导由 F2-异前列腺素 (F2-IsoPs) 驱动，由非酶促自由基产生我们已经证明电离辐射会诱导细胞中 F2-IsoP 的产生。培养物和体内小鼠肺组织中，博来霉素在特发性中增加。在这种疾病中，由于氧化应激而导致肺纤维化，但在患有这种疾病的患者中，它们是否会增加放射诱发的肺纤维化 (RIPF) 尚不清楚，尽管临床前和临床研究提供了关键支持非酶自由基诱导花生四烯酸信号氧化的总体假设我们勇敢地说，钙诱导的钙蛋白酶是导致 RIPF 的重要因素。介导肺成纤维细胞潜在复合物释放 TGFβ 小分子伊非曲班是一种 TPR。拮抗剂经过了广泛的人体测试并具有出色的安全性，因此，研究。验证 TPR 拮抗作用抑制 RIPF 可以通过重新利用现有的和安全的药物来实现快速翻译然而，在进行临床试验之前，我们的知识中存在一些关键的药物空白，需要填补这些空白。首先，该疗法需要在现有护理标准（包括免疫）的背景下发挥作用。其次，尽管血栓素或 F2-IsoP 可能会增加。 RIPF，我们需要验证接受胸部放射治疗的患者实际上表现出以下一项或多项的增加：最后，我们需要更好地了解 TPR 调节肺部的机制。该提案的目标是填补放射背景下肌成纤维细胞的分化和激活。差距。