Investigation of Bronchiolitis Obliterans Caused by Artificial Butter flavoring

人造黄油调味品引起闭塞性细支气管炎的调查

• 批准号: 8734142
• 负责人: DANIEL MORGAN
• 金额: $ 51.15万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8734142
• 关键词: Affect; Air; Animal Model; Biological; Breathing; Bronchi; Bronchiolitis; Bronchiolitis Obliterans; Butter; Chemicals; Chronic; Collagen Gene; Data; Development; Diacetyl; Disease; Distal; Dose; Down-Regulation; Early Diagnosis; Employee; Epithelial; Epithelium; Exposure to; Extracellular Matrix Proteins; Female; Fibrosis; Flavoring; Food Additives; Frozen Sections; Future; Gene Expression; Genes; Goals; Graft Rejection; Inflammatory; Inhalation Exposure; Investigation; Lasers; Lesion; Lung; Lung diseases; Methods; Microarray Analysis; Minor; Molecular; Occupational; Organ; Pathogenesis; Pathologic; Pathway interactions; Peptide Hydrolases; Plants; Prevention; Protease Inhibitor; RNA; Rattus; Relative (related person); Respiratory System; Respiratory tract structure; Rodent; Site; Survival Rate; Tissue-Specific Gene Expression; Tissues; Toxic effect; Transplantation; chemokine; consumer product; cytokine; diketone; effective therapy; insight; male; microwave electromagnetic radiation; therapeutic target

Diacetyl, a reactive diketone used in artificial butter flavoring has been associated with obliterative bronchiolitis (OB) in employees at microwave popcorn packaging plants; however, the mechanisms of toxicity are unknown. We recently demonstrated that diacetyl, the major volatile component of artificial butter flavoring, caused OB-like lesions in rats after inhalation exposure. Because of concerns about diacetyl toxicity, it is being replaced in some consumer products by 2,3-pentanedione (PD), and possibly 2,3-hexanedione (HD), both structurally-related and untested chemicals. Because the toxicity of inhaled PD and HD are unknown, studies were conducted to characterize the toxicity after inhalation exposure to a range of concentrations in rodents. Male and female Wistar-Han rats were exposed to 0, 50, 100, or 200 ppm PD 6h/d, 5d/wk for up to 2 wk. HD caused only minor epithelial changes at the highest concentration; owever, PD was found to cause OB-like lesions similar to those caused by diacetyl. The epithelium lining the respiratory tract was the site of toxicity for all three chemicals. Diacetyl and PD both caused fibrotic airway lesions in rats with pathological features of OB. The histopathological and biological changes observed in rats indicate that PD is not an acceptable replacement for diacetyl. We sought to evaluate changes in gene expression in the distal bronchi of rats with PD-induced OB. Male Wistar Han rats were exposed to 200 ppm PD or air (controls) 6 h/d, 5 d/wk for 2-wks. Bronchial tissues were laser microdissected from serial sections of frozen lung. In exposed lungs, both fibrotic and non-fibrotic airways were collected. Following RNA extraction and microarray analysis, differential gene expression was evaluated. In non-fibrotic bronchi of exposed rats, 1548 genes were significantly altered relative to air-exposed controls with notable down-regulation of many inflammatory cytokines and chemokines. In contrast, in PD-exposed fibrotic bronchi, 2504 genes were significantly altered with a majority of genes being up-regulated in affected pathways. Tgf-2 and downstream genes implicated in fibrosis were significantly up-regulated in fibrotic lesions. Genes for collagens and extracellular matrix proteins were highly up-regulated. In addition, expression of genes for peptidases and for peptidase inhibitors were significantly altered suggesting tissue remodeling that may contribute to fibrosis. Our data provide new insights into the molecular mechanisms of OB, and illustrate that PD-induced OB shares pathologic features with other fibrotic lung diseases. This new information is of potential significance with regards to future therapeutic targets for treatment.

二乙酰是一种用于人造黄油调味料的反应性二酮与微波爆米花包装厂的员工中的闭塞性支气管炎（OB）有关。但是，毒性机制尚不清楚。我们最近证明，二乙酰是人造黄油调味料的主要挥发性成分，在吸入后导致大鼠的ob样病变。 由于对二乙酰毒性的担忧，因此在某些消费产品中被2,3-戊二酮（PD）替换，可能是2,3-己二烷（HD），这两种化学物质都与结构相关和未经测试的化学物质所取代。由于吸入PD和HD的毒性尚不清楚，因此进行了研究以表征吸入暴露于啮齿动物浓度范围的毒性。 雄性和雌性Wistar-Han大鼠暴露于0、50、100或200 ppm PD 6H/D，5D/wk，最多2周。 HD在最高浓度下仅引起小小的上皮变化； OWEVER，发现PD会引起与二乙酰基相似的OB样病变。 呼吸道的上皮是所有三种化学物质的毒性部位。 二乙酰基和PD都引起具有OB病理特征的大鼠的纤维化气道病变。 在大鼠中观察到的组织病理学和生物学变化表明，PD不是可接受的二乙酰基替代品。 我们试图评估具有PD诱导的OB的大鼠远端支气管中基因表达的变化。 雄性Wistar Han大鼠暴露于200 ppm pd或空气（对照组）6 h/d，5 d/d/wk的2周。 从冷冻肺的串行切片中对支气管组织进行了激光解剖。 在裸露的肺中，收集了纤维化和非纤维化气道。 在RNA提取和微阵列分析后，评估了差异基因表达。 在暴露大鼠的非纤维化支气管中，相对于空气曝光对照，有1548个基因显着改变，并且显着下调了许多炎性细胞因子和趋化因子。 相反，在暴露于PD的纤维化支气管中，2504个基因在受影响的途径中被上调，大多数基因都显着改变。 在纤维化病变中，与纤维化有关的TGF-2和下游基因显着上调。 胶原蛋白和细胞外基质蛋白的基因高度上调。另外，肽酶和肽酶抑制剂的基因表达显着改变，表明组织重塑可能有助于纤维化。 我们的数据为OB的分子机制提供了新的见解，并说明PD诱导的OB具有与其他纤维化肺部疾病的病理特征。 对于未来的治疗靶标，这一新信息具有潜在的意义。