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

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: 放射性肺损伤是胸部放疗患者的一个重要的剂量限制因素, 即使使用较新的放射治疗技术,也有相当一部分患者。该提案调查了 调节成纤维细胞活化的新途径,可直接靶向限制进行性辐射诱导的 肺纤维化我们发现血栓素-前列腺素受体(TPr)在人前列腺细胞中组成型表达, 和鼠纤维化肺成纤维细胞的药理学抑制或条件性基因消融, TPr明显减轻电离辐射、博来霉素诱导的小鼠肺纤维化, 氧化应激或赫-普二氏综合征。虽然血栓素A2是TPr的主要配体,但我们发现, TPr信号是由F2-异前列腺素(F2-IsoPs)驱动的,这是由非酶促的自由基代谢引起的。 花生四烯酸的氧化。我们已经证明,电离辐射诱导细胞中F2-IsoP的产生, 培养物和体内鼠肺组织中,博莱霉素也是如此。F2-IsoPs在特发性 肺纤维化由于氧化应激在这种疾病,但无论他们是增加患者谁发展 放射性肺纤维化(RIPF)是未知的,虽然临床前和临床研究提供了关键的 支持非酶自由基诱导花生四烯酸信号氧化的总体假设 对RIPF的贡献很大。我们假设一个促成因素是通过钙诱导的钙蛋白酶- 介导的TGF β从肺成纤维细胞中的潜在复合物中释放。小分子伊非曲班是TPr 这种拮抗剂已经过广泛的人体试验,具有良好的安全性。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 毒品然而,在临床试验之前,我们的知识存在关键空白,需要填补这些空白。 适当首先,该疗法需要在现有的护理标准的背景下起作用,包括免疫治疗。 检查点疗法第二,尽管在高血压患者中血栓素或F2-IsoPs可能增加,但在高血压患者中,血栓素或F2-IsoPs可能增加。 RIPF,我们需要验证接受胸部放射治疗的患者实际上显示出一种或多种 这些分子。最后,我们需要更好地理解TPr调节肺动脉高压的机制, 肌成纤维细胞分化和活化的辐射的背景下。该提案的目标是填补这些 差距。

项目成果

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MICHAEL L. FREEMAN其他文献

MICHAEL L. FREEMAN的其他文献

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{{ truncateString('MICHAEL L. FREEMAN', 18)}}的其他基金

Targeting DNA damage response pathways for the treatment of advanced lung cancer
靶向 DNA 损伤反应途径治疗晚期肺癌
  • 批准号:
    8776675
  • 财政年份:
    2014
  • 资助金额:
    $ 72.59万
  • 项目类别:
Nrf2 and Radiation-induced pulmonary fibrosis.
Nrf2 和辐射诱导的肺纤维化。
  • 批准号:
    8791125
  • 财政年份:
    2013
  • 资助金额:
    $ 72.59万
  • 项目类别:
Nrf2 and Radiation-induced pulmonary fibrosis.
Nrf2 和辐射诱导的肺纤维化。
  • 批准号:
    8606883
  • 财政年份:
    2013
  • 资助金额:
    $ 72.59万
  • 项目类别:
Nrf2 and Radiation-induced pulmonary fibrosis.
Nrf2 和辐射诱导的肺纤维化。
  • 批准号:
    8664750
  • 财政年份:
    2013
  • 资助金额:
    $ 72.59万
  • 项目类别:
Nrf2 and Radiation-induced pulmonary fibrosis.
Nrf2 和辐射诱导的肺纤维化。
  • 批准号:
    8442128
  • 财政年份:
    2013
  • 资助金额:
    $ 72.59万
  • 项目类别:
Development of Small Molecule Radiation Sensitizers
小分子放射增敏剂的开发
  • 批准号:
    8196782
  • 财政年份:
    2009
  • 资助金额:
    $ 72.59万
  • 项目类别:
Development of Small Molecule Radiation Sensitizers
小分子放射增敏剂的开发
  • 批准号:
    8002086
  • 财政年份:
    2009
  • 资助金额:
    $ 72.59万
  • 项目类别:
Development of Small Molecule Radiation Sensitizers
小分子放射增敏剂的开发
  • 批准号:
    7787394
  • 财政年份:
    2009
  • 资助金额:
    $ 72.59万
  • 项目类别:
Development of Small Molecule Radiation Sensitizers
小分子放射增敏剂的开发
  • 批准号:
    8518497
  • 财政年份:
    2009
  • 资助金额:
    $ 72.59万
  • 项目类别:
Development of Small Molecule Radiation Sensitizers
小分子放射增敏剂的开发
  • 批准号:
    8586851
  • 财政年份:
    2009
  • 资助金额:
    $ 72.59万
  • 项目类别:

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