Biomedical Project 5 - Chemoprevention of Asbestos-induced Lung Diseases

摘要 现在，在动物模型和人类模型中都清楚地证明了吸入石棉纤维 可导致肿瘤疾病，如恶性间皮瘤(MM)和肺癌。这是一个重要的 持续存在的问题，因为石棉仍在世界上许多国家使用，而且还有大量的 以前接触过癌症风险的人的人才库。目前没有有效的筛查或 针对这些高危人群的化学预防方法。鉴于最近的研究表明， 石棉诱发癌症的发病机制是由于慢性炎症和氧化组织损伤引起的 由持久的石棉纤维制成，具有良好的耐受性和安全性，具有消炎和抗氧化作用 因此，这些特性可能被用来预防暴露于石棉的人群中多发性硬化症的发展。 根据初步发现，我们发现亚麻籽木脂素是安全、无毒的化合物 具有强大的抗炎和抗氧化性能。因此，我们假设亚麻籽或 浓缩的亚麻籽木脂素可以作为安全、无毒的石棉化学防腐剂- 诱发间皮瘤。这笔赠款的目标是提供所需的数据，作为测试和 验证这一假设。为了实现我们的目标，我们建议：1)评估活性木脂素在 亚麻籽，二异落叶松脂醇二葡萄糖苷(SDG)，以干扰石棉诱导的ROS产生， 巨噬细胞和间皮细胞的炎性小体激活和活性氧的产生 体外培养。2)评价全谷物亚麻籽或亚麻籽-木脂素复合体预防急性胰腺炎的能力。 石棉诱导间皮细胞SV40T抗原的炎症和氧化损伤 NF2+/MUT；CDKN2a+/MUT石棉诱导的小鼠恶性间皮瘤模型，以及3)评估 全谷物亚麻籽或亚麻籽衍生木脂素SDG在饮食中预防石棉诱导的MM形成 和死亡在这些相同的小鼠模型中。如果我们的研究表明安全有效，我们的自然延伸 工作将是一项毒性和生物标记物试验，在该试验中，接触大量石棉的患者也有 暴露的生物标记物(在上文和项目6中确定)将给予亚麻籽或木脂素制剂 识别出的生物标志物的变化。如果我们在这项试验中观察到明显的变化，一项更大的化学预防试验 可以考虑在高危人群中使用。我们将与这一超级基金中的三个项目密切互动 建议包括测试项目1中修复的石棉，与动物模型研究密切合作 在项目4中，并利用项目6中的生物标记工作。我们还将与 SF提案的管理和生物统计核心以及CEET的生物标记核心。

ABSTRACT It has now been clearly established in both animal models and in humans that inhalation of asbestos fibers can lead to neoplastic diseases such as malignant mesothelioma (MM) and lung cancer. This is an important ongoing problem, since asbestos is still in used in many countries around the world and there is also a large pool of previously exposed individuals who are at risk for cancer. There is currently no effective screening or chemopreventive approach for these at-risk populations. Given that recent studies have indicated that the pathogenesis of asbestos-induced cancers is due to chronic inflammation and oxidative tissue damage caused by persistent asbestos fibers, a well-tolerated and safe agent with anti-inflammatory AND anti-oxidant properties could thus potentially be used to prevent the development of MM in asbestos exposed populations. Based on preliminary findings, we have found that flaxseed lignans are safe, non-toxic compounds that have potent anti-inflammatory and anti-oxidant properties. We therefore hypothesize that that flaxseed or enriched flaxseed lignans could function as safe, non-toxic chemopreventive agents in asbestos- induced mesothelioma. The goal of this grant is to provide data needed as the first steps to test and validate this hypothesis. To achieve our goal, we propose to: 1) Evaluate the ability of the active lignan in flaxseed, Secoisolariciresinol diglucoside (SDG), to interfere with asbestos-induced ROS generation, inflammasome activation, and reactive oxygen species generation in macrophages and mesothelial cells in vitro. 2) Evaluate the ability of wholegrain flaxseed or flaxseed-lignan complex given in diets to prevent acute asbestos-induced inflammation and oxidative damage in the mesothelial SV40 T-Antigen and the Nf2+/mut;Cdkn2a+/mut asbestos-induced malignant mesothelioma mouse models, and 3) Evaluate the ability of wholegrain flaxseed or flaxseed-derived lignan SDG given in diets to prevent asbestos-induced MM formation and death in these same mouse models. If our studies show efficacy with safety, the natural extension of our work would be a toxicity and biomarker trial in which patients with heavy asbestos exposure who also had biomarkers of exposure (identified above and in Project 6) would be given flaxseed or the lignan formulation and changes in biomarkers identified. If we observed clear changes in this trial, a larger chemoprevention trial in high risk populations could be considered. We will interact with closely with three projects in this Superfund Proposal including testing remediated asbestos from Project 1, working closely with the animal model studies in Project 4, and taking advantage of the biomarker work in Project 6. We will also interact significantly with the Administration and Biostatistics Cores of the SF proposal and the Biomarker Core of the CEET.