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会损害健康的肺组织，导致 放射性肺损伤(RILI)。如果不加以缓解，RILI会导致放射性肺纤维化(RILF)。RILF 导致肺功能恶化和呼吸衰竭，30%以上的患者出现RILF 作为放射治疗的并发症。阻断或减轻RILF表现的治疗方法的研究 对限制放射治疗后慢性肺损伤具有重要意义。尽管近年来取得了进展， 临床上不存在有效防治RILF的对策，这是一个重要的 虚证治疗IR的远期效果。这一缺陷正变得更加明显，因为 免疫疗法正在迅速被纳入许多标准的化疗和放射治疗方案，它可能 还会诱发和加剧肺纤维化。为了应对辐射引起的细胞损伤， 在受损的组织中观察到促炎环境。特别是，肿瘤坏死率升高 肿瘤坏死因子-α和转化生长因子-β(β)在慢性氧化损伤中起关键作用 和肺暴露于IR后的纤维化。事实上，阻碍肿瘤坏死因子-α或转化生长因子-β通路的研究改善了 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 纤维化症。由于细胞因子介导的肿瘤坏死因子-α的细胞损伤和转化生长因子-β的促纤维化作用，两者 细胞因子在RILF的发生发展中起一定作用。我们假设同时损害肿瘤坏死因子-α和转化生长因子- β通路将更有效地对抗IR对健康肺组织的损伤，并提供更好的保护 抗RILF，而不是单独损伤任何一种细胞因子。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抑制转化生长因子-β受体1(转化生长因子β-1)并通过抑制抑制肿瘤坏死因子-α的产生而损害其产生 MAP4K4(IC_(50)=0.001微米[转化生长因子βR1]和0.005微米 [MAP4K4])。我们推测，这种新型的抗细胞因子，协同作用，削弱IR诱导的细胞因子 诱导，将减少受照射组织中的促炎性肿瘤坏死因子-α信号，并改善转化生长因子-β介导的 纤维化症。我们将在RILF的细胞和动物模型中检验这一假设。完成这项提案将 帮助生成R01水平资金所需的数据，并可能发现缓解IR的新临床策略。 诱导肺纤维化。

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.