Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405-0068, USA.
Am J Respir Cell Mol Biol. 2010 Feb;42(2):133-9. doi: 10.1165/rcmb.2009-0206TR.
Fifteen years have passed since we published findings in the AJRCMB demonstrating that induction of early response fos/jun proto-oncogenes in rodent tracheal and mesothelial cells correlates with fibrous geometry and pathogenicity of asbestos. Our study was the first to suggest that the aberrant induction of signaling responses by crocidolite asbestos and erionite, a fibrous zeolite mineral associated with the development of malignant mesotheliomas (MMs) in areas of Turkey, led to altered gene expression. New data questioned the widely held belief at that time that the carcinogenic effects of asbestos in the development of lung cancer and MM were due to genotoxic or mutagenic effects. Later studies by our group revealed that proto-oncogene expression and several of the signaling pathways activated by asbestos were redox dependent, explaining why antioxidants and antioxidant enzymes were elevated in lung and pleura after exposure to asbestos and how they alleviated many of the phenotypic and functional effects of asbestos in vitro or after inhalation. Since these original studies, our efforts have expanded to understand the interface between asbestos-induced redox-dependent signal transduction cascades, the relationship between these pathways and cell fate, and the role of asbestos and cell interactions in development of asbestos-associated diseases. Of considerable significance is the fact that the signal transduction pathways activated by asbestos are also important in survival and chemoresistance of MMs and lung cancers. An understanding of the pathogenic features of asbestos fibers and dysregulation of signaling pathways allows strategies for the prevention and therapy of asbestos-related diseases.
十五年前，我们在 AJRCMB 上发表了研究结果，表明在鼠类气管和间皮细胞中诱导早期反应 fos/jun 原癌基因与石棉的纤维几何形状和致病性相关。我们的研究首次表明，青石棉和与土耳其地区恶性间皮瘤 (MM) 发生相关的纤维沸石矿物埃罗石诱发的信号转导反应异常，导致基因表达改变。新数据质疑当时广泛持有的观点，即石棉在肺癌和 MM 发展中的致癌作用是由于遗传毒性或诱变作用。我们小组后来的研究表明，原癌基因表达和石棉激活的几种信号通路依赖于氧化还原，这解释了为什么暴露于石棉后肺和胸膜中的抗氧化剂和抗氧化酶水平升高，以及它们如何缓解体外或吸入石棉后许多表型和功能效应。自这些最初的研究以来，我们的努力已经扩展到了解石棉诱导的依赖氧化还原的信号转导级联之间的界面、这些途径与细胞命运之间的关系，以及石棉和细胞相互作用在石棉相关疾病发展中的作用。非常重要的是，石棉激活的信号转导途径在 MM 和肺癌的存活和化疗耐药性中也很重要。对石棉纤维的发病特征和信号通路的失调的理解，可以为预防和治疗石棉相关疾病提供策略。
