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.

项目摘要：辐射引起的肺损伤是接受胸部放射疗法的患者的关键剂量限制因素，影响即使使用较新的放射疗法技术，也很大一部分患者。该提案调查了可以直接靶向的成纤维细胞激活的新途径，以限制进行性辐射诱导的肺纤维化。我们发现，血栓烷螺旋体受体（TPR）在人类中始终表达和鼠纤维化肺成纤维细胞以及药物抑制或条件遗传消融 TPR明显减弱由电离辐射引起的小鼠，博来霉素诱导的氧化应激或Hermansky-Pudlak综合征。尽管血栓烷A2是TPR的主要配体，但我们发现该TPR信号传导是由非酶，自由基的F2-异丙烷（F2- iSOP）驱动的花生四烯酸的氧化。我们已经证明电离辐射会在细胞中诱导F2-ISOP产生培养和在体内的鼠肺组织中，博来霉素也是如此。特发性中的F2 isops增加了由于这种疾病中氧化应激引起的肺纤维化辐射诱导的肺纤维化（RIPF）尚不清楚，尽管临床前和临床研究提供了关键支持总体假设，即非酶自由基诱导的蛛网膜酸信号传导的氧化大大促进了RIPF。我们假设一个因素是通过钙诱导的钙蛋白酶从肺成纤维细胞中潜在复合物中介导的TGFβ释放。小分子ifetroban是TPR 对拮抗剂进行了广泛的人类测试，并且具有出色的安全性。那，研究通过重新利用现有和安全毒品。但是，我们的知识中存在一些关键差距，需要在临床试验之前填补合适的。首先，该疗法需要在现有护理标准的背景下工作，包括免疫检查点疗法。其次，尽管血栓烷或f2 isops可能会增加 RIPF，我们需要验证接受胸腔辐射的患者实际上显示出一个或多个的增加这些分子。最后，我们需要更好地了解TPR调节肺部的机制在辐射背景下的肌纤维细胞分化和激活。该提议的目的是填写这些空白。