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

项目1摘要 电离辐射（IR）被广泛用于治疗肺癌，但IR可损伤健康的肺组织，导致肺组织损伤。 放射性肺损伤（RILI）。当未缓解时，RILI导致辐射诱导的肺纤维化（RILF）。RILF 导致肺功能恶化和呼吸衰竭，超过30%的患者发生RILF 放疗的并发症研究阻断或减轻RILF表现的治疗方法是 对限制放射治疗后的慢性肺损伤具有重要意义。尽管近年来取得了进展， 有效对抗或预防RILF的对策在临床上不存在，这代表了一个重要的问题。 缺乏治疗IR的长期影响。这种缺乏变得更加重要，因为 免疫疗法正迅速被纳入许多标准的化疗和放疗方案中， 也会诱发和加重肺纤维化。为了应对辐射诱导的细胞损伤， 在受损组织中观察到促炎环境。尤其是肿瘤坏死程度的升高 TNF-α和TGF-β在慢性氧化损伤中起关键作用 事实上，阻碍TNF-α或TGF-β通路的研究改善了肺组织的炎症反应， 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。 纤维化由于TNF-α和TGF-β的促纤维化作用， 细胞因子在RILF的发展中起作用。我们假设同时损伤TNF-α和TGF-β， β通路将更有效地对抗IR诱导的健康肺组织损伤，并提供更好的保护 而不是单独损害任一细胞因子。在我们的实验室里，我们最近开发了一种小分子 抗细胞因子-Tk-1-抑制TGF-β受体1（TGFβR1）并通过抑制TNF-α的产生来损害TNF-α的产生 丝裂原活化蛋白激酶4（MAP 4K 4）（IC 50 = 0.001 µM [TGFβR1]和0.005 µM [MAP4K4]）。我们推测，这种新的抗细胞因子，协同作用，削弱IR诱导的细胞因子， 诱导，将减少照射组织中的促炎性TNF-α信号传导，并改善TGF-β介导的 纤维化我们将在RILF的细胞和动物模型中测试这一假设。完成本提案将 帮助生成R 01级资金所需的数据，并可能发现一种新的临床策略，以减轻IR- 诱发肺纤维化。

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.