McDyre B Claire, AbdulHameed Mohamed Diwan M, Permenter Matthew G, Dennis William E, Baer Christine E, Koontz Jason M, Boyle Molly H, Wallqvist Anders, Lewis John A, Ippolito Danielle L
1 Oak Ridge Institute for Science and Education (ORISE), Frederick, Maryland, USA.
2 Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, USA.
Toxicol Pathol. 2018 Feb;46(2):202-223. doi: 10.1177/0192623317747549. Epub 2018 Jan 29.
The past decade has seen an increase in the development and clinical use of biomarkers associated with histological features of liver disease. Here, we conduct a comparative histological and global proteomics analysis to identify coregulated modules of proteins in the progression of hepatic steatosis or fibrosis. We orally administered the reference chemicals bromobenzene (BB) or 4,4'-methylenedianiline (4,4'-MDA) to male Sprague-Dawley rats for either 1 single administration or 5 consecutive daily doses. Livers were preserved for histopathology and global proteomics assessment. Analysis of liver sections confirmed a dose- and time-dependent increase in frequency and severity of histopathological features indicative of lipid accumulation after BB or fibrosis after 4,4'-MDA. BB administration resulted in a dose-dependent increase in the frequency and severity of inflammation and vacuolation. 4,4'-MDA administration resulted in a dose-dependent increase in the frequency and severity of periportal collagen accumulation and inflammation. Pathway analysis identified a time-dependent enrichment of biological processes associated with steatogenic or fibrogenic initiating events, cellular functions, and toxicological states. Differentially expressed protein modules were consistent with the observed histology, placing physiologically linked protein networks into context of the disease process. This study demonstrates the potential for protein modules to provide mechanistic links between initiating events and histopathological outcomes.
在过去十年中，与肝脏疾病组织学特征相关的生物标志物的开发和临床应用有所增加。在此，我们进行了一项比较组织学和全局蛋白质组学分析，以确定肝脂肪变性或纤维化进展过程中共同调节的蛋白质模块。我们给雄性Sprague-Dawley大鼠口服参考化学物质溴苯（BB）或4,4'-亚甲基二苯胺（4,4'-MDA），单次给药或连续5天每日给药。保存肝脏用于组织病理学和全局蛋白质组学评估。肝切片分析证实，BB给药后脂质积累或4,4'-MDA给药后纤维化的组织病理学特征的频率和严重程度呈剂量和时间依赖性增加。BB给药导致炎症和空泡化的频率和严重程度呈剂量依赖性增加。4,4'-MDA给药导致门静脉周围胶原积累和炎症的频率和严重程度呈剂量依赖性增加。通路分析确定了与脂肪生成或纤维化起始事件、细胞功能和毒理学状态相关的生物过程的时间依赖性富集。差异表达的蛋白质模块与观察到的组织学一致，将生理上相关的蛋白质网络置于疾病过程的背景中。这项研究证明了蛋白质模块在起始事件和组织病理学结果之间提供机制联系的潜力。
