Biomedical Project 5 - Chemoprevention of Asbestos-induced Lung Diseases

摘要 在动物模型和人体中已经清楚地证实，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 这是一个持续的问题，因为石棉仍然在世界各地的许多国家使用，也有大量的 有患癌症风险的既往暴露个体的汇总。目前没有有效的筛查或 对这些高危人群采取化学预防措施。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性组织损伤引起的 持久性石棉纤维，耐受性良好，安全的抗炎和抗氧化剂 因此，这些特性可能用于预防石棉暴露人群中MM的发展。 基于初步发现，我们发现亚麻籽木脂素是安全、无毒的化合物， 具有有效的抗炎和抗氧化特性。因此，我们假设亚麻籽或 富集的亚麻籽木脂素可以作为石棉中安全、无毒的化学预防剂， 诱发间皮瘤这项赠款的目标是提供所需的数据，作为测试和 验证这个假设。为了实现我们的目标，我们建议：1）评价活性木脂素在 亚麻籽，开环异落叶松树脂酚二葡萄糖苷（SDG），以干扰石棉诱导的ROS产生， 炎性小体活化，以及巨噬细胞和间皮细胞中活性氧的产生。 体外2)评价在饮食中给予全谷亚麻籽或亚麻籽-木脂素复合物预防急性 石棉诱导的炎症和氧化损伤在间皮瘤SV 40 T-抗原和 Nf 2 +/mut; Cdkn 2a +/mut石棉诱导的恶性间皮瘤小鼠模型，以及3）评估 在饮食中给予全谷物亚麻籽或亚麻籽衍生的木脂素SDG以预防石棉诱导的MM形成 和死亡的情况。如果我们的研究显示安全有效， 这项工作将是一项毒性和生物标志物试验，在这项试验中， 暴露的生物标志物（在上文和项目6中确定）将被给予亚麻籽或木酚素制剂 和生物标志物的变化。如果我们在这个试验中观察到明显的变化，一个更大的化学预防试验 高危人群可以考虑。我们将与这个超级基金中的三个项目密切互动 建议包括测试项目1的修复石棉，与动物模型研究密切合作 在项目4中，并利用项目6中的生物标志物工作。我们还将与 SF提案的管理和生物统计学核心以及CEET的生物标志物核心。

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.