Concurrent TNF-alpha and TGF-beta Impairment to Limit Radiotherapy-Induced Pulmonary Fibrosis

TNF-α 和 TGF-β 的同时损伤可限制放疗引起的肺纤维化

• 批准号: 10487478
• 负责人: Brendan Andrew Frett
• 金额: $ 26.77万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-24 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487478
• 关键词: Active Sites; Acute; Animals; Area Under Curve; Biochemical; Biological Assay; Biological Availability; C57BL/6 Mouse; Cells; Centers of Research Excellence; Chest; Chronic; Chronic Lung Injury; Chronic Phase; Clinic; Clinical; Complication; Data; Deterioration; Development; Dose; Environment; Epithelial Cells; Exposure to; Fibrosis; Funding; Human; Immune; Immune response; Immunohistochemistry; Immunotherapy; Impairment; Infiltration; Inflammation; Investigation; Ionizing radiation; Laboratories; Lead; Ligands; Long-Term Effects; Lung; MAP4K4 gene; Malignant neoplasm of lung; Measures; Mediating; Messenger RNA; Methods; Modality; Modeling; Molecular Toxicology; Monitor; Mus; Nature; Oral; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Plasma; Play; Production; Property; Proteins; Pulmonary Fibrosis; Radiation; Radiation Protection; Radiation induced damage; Radiation therapy; Regimen; Research; Respiratory Failure; Role; Severities; Signal Transduction; Structure of parenchyma of lung; Structure-Activity Relationship; TGF Beta Signaling Pathway; TNF gene; Testing; Time; Tissue Sample; Tissues; Toxic effect; Toxicology; Transcript; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; base; cancer therapy; cell injury; combat; cytokine; design; fibrogenesis; in vivo; inhibitor; insight; irradiation; lung histology; macrophage; molecular dynamics; novel; oxidative damage; pharmacokinetics and pharmacodynamics; prevent; pulmonary function; radiation countermeasure; radiation response; radiation-induced lung injury; small molecule

PROJECT 1 ABSTRACT Ionizing radiation (IR) is used extensively to treat lung cancer, but IR can damage healthy lung tissue, causing radiation-induced lung injury (RILI). When unmitigated, RILI leads to radiation-induced lung fibrosis (RILF). RILF causes deterioration of pulmonary function and respiratory failure, and upwards of 30% of patients develop RILF as a complication to radiotherapy. Investigation into treatments to block or mitigate the manifestation of RILF is of significant importance to limit chronic lung injury following radiotherapy. Despite progress in recent years, countermeasures to effectively combat or prevent RILF do not exist in the clinic, which represents a significant deficiency to treat the long-term effects of IR. This deficiency is becoming even more significant because immunotherapy, which is rapidly being incorporated into many standard chemo- and radiotherapy regimens, may also induce and exacerbate pulmonary fibrosis. In response to radiation-induced cellular injuries, a proinflammatory environment is observed in damaged tissues. In particular, elevated levels of tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β) play key roles in chronic oxidative damage and fibrogenesis following lung exposure to IR. Indeed, studies hindering TNF-α or TGF-β pathways ameliorate oxidative damage, inflammation, and pulmonary fibrosis, while the actions of both of these cytokines lead to lung fibrosis. Because of the cytokine-mediated cellular damage of TNF-α and the profibrotic effects of TGF-β, both cytokines play a role in the development of RILF. We hypothesize that simultaneously impairing TNF-α and TGF- β pathways will more effectively combat IR-induced damage to healthy lung tissue and provide better protection against RILF than impairing either cytokine separately. In our laboratory, we recently developed a small-molecule anticytokine—Tk-1—that inhibits the TGF-β receptor 1 (TGFβR1) and impairs TNF-α production by inhibiting mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) (IC50 = 0.001 µM [TGFβR1] and 0.005 µM [MAP4K4]). We hypothesize that this novel anticytokine, acting synergistically to impair IR-induced cytokine induction, will diminish proinflammatory TNF-α signaling in irradiated tissue and ameliorate TGF-β–mediated fibrosis. We will test this hypothesis in cell and animal-based models of RILF. Completion of this proposal will help generate the data necessary for R01-level funding and may uncover a novel clinical strategy to mitigate IR- induced pulmonary fibrosis.

项目1摘要 电离辐射（IR）被广泛用于治疗肺癌，但IR会损害健康的肺组织，导致 辐射引起的肺损伤（RILI）。如果不固定，RILI会导致辐射诱导的肺纤维化（RILF）。 rilf 导致肺功能和呼吸衰​​竭的恶化，并且30％以上患者发展RILF 作为放射疗法的并发症。对阻止或减轻RILF表现的治疗方法的调查为 放射治疗后限制慢性肺损伤的重要性。尽管近年来进展 在诊所中不存在有效作战或预防RILF的对策，这代表了重要的 缺乏治疗IR的长期影响。这种缺陷变得更加重要，因为 免疫疗法迅速纳入了许多标准的化学和放射治疗方案，可能 还会影响和加剧肺纤维化。响应辐射诱导的细胞损伤，a 在受损的组织中观察到促炎环境。特别是，肿瘤坏死水平升高 因子α（TNF-α）和转化生长因子β（TGF-β）在慢性氧化损伤中起关键作用 和肺暴露于IR后的纤维发生。实际上，研究阻碍TNF-α或TGF-β途径可以改善 氧化损伤，炎症和肺纤维化，而这两种细胞因子的作用导致肺 纤维化。由于TNF-α的细胞因子介导的细胞损伤和TGF-β的纤维化作用 细胞因子在RILF的发展中起作用。我们假设只是损害了TNF-α和TGF- β途径将更有效地打击IR诱导的对健康肺组织的损害，并提供更好的保护 反对RILF比单独损害任何一种细胞因子。在我们的实验室中，我们最近开发了一个小分子 抗细节 - TK-1-抑制TGF-β受体1（TGFβR1），并通过抑制损害TNF-α的产生 有丝分裂原激活的蛋白激酶激酶激酶激酶激酶激酶4（MAP4K4）（IC50 = 0.001 µM [TGFβR1]和0.005 µM [MAP4K4]）。我们假设这种新型抗细菌动物具有协同作用以损害IR诱导的细胞因子 诱导将减少辐照组织中的促炎性TNF-α信号传导，并改善TGF-β介导 纤维化。我们将在RILF的细胞和基于动物的模型中检验该假设。该提议的完成将 帮助生成R01级资金所需的数据，并可能发现一种新的临床策略来减轻IR- 诱导肺纤维化。