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Mechanisms of microcystin-LR toxicity.

机译:微囊藻毒素-LR毒性的机制。

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摘要

Microcystin-LR (MCLR) is a cyanobacterial hepatotoxin that inhibits serine/threonine protein phosphatases types 1 and 2A in hepatocytes in vivo and in vitro, and disrupts actin microfilament (MF), microtubule (MT) and intermediate filament (IF) networks. The sequential ultrastructural and biochemical changes induced by MCLR were studied in the isolated perfused rat liver model. Livers were perfused with doses ranging from 0.1 to 5.0 {dollar}mu{dollar}g/ml for 5 to 40 min in order to characterize the earliest observable morphologic changes presumably induced by disorganization of the hepatocyte cytoskeleton, and to follow the progression of lesions over time. The earliest toxin-induced changes were observed at 0.1 {dollar}mu{dollar}g/ml after 15-20 min exposure, or at 0.3 {dollar}mu{dollar}g/ml after 5-10 min. Earliest lesions included loss of hepatocyte microvilli, widening of sinusoidal fenestrae with disruption of sinusoidal endothelium, dilation of bile canaliculi, widening of intercellular spaces, and the initial stages of hepatocyte separation. Lesions progressed in severity and extent with increasing dose and exposure time. The observed changes are likely to be attributable in large measure to altered hepatocyte cytoskeletal structure and function.; The effects of MCLR on the organization of MFs, IFs, and MTs in hepatocytes, renal epithelial cells and fibroblasts were compared using silver-enhanced gold labeling, and the sequence of toxin-induced changes was determined. Changes in fibroblasts and some hepatocytes were characterized initially by disorganization of IFs, followed rapidly by disorganization of MTs, with the progressive collapse of both networks around cell nuclei. The onset of changes in MF structure occurred later than with the other cytoskeletal elements in all cell types and at all doses. In many hepatocytes, however, and especially at later time points, changes were noted in MTs and MFs prior to effects on IFs. Changes in MTs had not been reported in cells exposed to MCLR prior to this study. The similarity of effects among different cell types suggests a common mechanism of action, once the toxin is able to gain entry into hepatocytes or non-hepatocytes. However, differences among hepatocytes in the sequence of cytoskeletal changes, and between hepatocytes and non-hepatocytes suggests that the toxin acts to destabilize the hepatocyte cytoskeleton at more than point.
机译:微囊藻毒素-LR(MCLR)是一种蓝细菌肝毒素,可在体内和体外抑制肝细胞中1和2A型丝氨酸/苏氨酸蛋白磷酸酶,并破坏肌动蛋白微丝(MF),微管(MT)和中间丝(IF)网络。在分离的灌流大鼠肝脏模型中研究了由MCLR诱导的连续超微结构和生化变化。肝灌注剂量为0.1到5.0 {μmol} g / ml,持续5到40分钟,以表征最早可观察到的由肝细胞骨架紊乱引起的可观察到的形态学变化,并跟踪病变的进展随着时间的推移。暴露15-20分钟后观察到最早的毒素诱导的变化,为0.1 {μg} / g,而5-10分钟后为0.3μg/ ml。最早的病变包括肝细胞微绒毛的丧失,正弦窗孔的扩大和正弦血管内皮的破坏,胆小管的扩张,细胞间隙的扩大以及肝细胞分离的初始阶段。随着剂量和暴露时间的增加,病变的严重程度和程度逐渐加重。所观察到的变化可能在很大程度上归因于肝细胞细胞骨架结构和功能的改变。使用银增强金标记比较了MCLR对肝细胞,肾上皮细胞和成纤维细胞中MF,IF和MT的组织的影响,并确定了毒素诱导的变化的顺序。成纤维细胞和某些肝细胞的变化最初以IFs紊乱为特征,然后迅速以MTs紊乱为特征,细胞核周围的两个网络都逐渐崩溃。在所有细胞类型和所有剂量下,MF结构变化的发生都比其他细胞骨架元件的发生晚。但是,在许多肝细胞中,尤其是在较晚的时间点,MT和MF的变化在影响IF之前就已注意到。在此研究之前,尚未报道过暴露于MCLR的细胞MT的变化。一旦毒素能够进入肝细胞或非肝细胞,不同细胞类型之间的作用相似性表明了一种共同的作用机制。然而,肝细胞之间的细胞骨架变化序列之间的差异以及肝细胞与非肝细胞之间的差异表明,该毒素的作用不仅使肝细胞的细胞骨架不稳定。

著录项

  • 作者

    Wickstrom, Mark Lee.;

  • 作者单位

    University of Illinois at Urbana-Champaign.;

  • 授予单位 University of Illinois at Urbana-Champaign.;
  • 学科 Biology Veterinary Science.; Health Sciences Toxicology.; Agriculture Animal Pathology.; Health Sciences Pathology.
  • 学位 Ph.D.
  • 年度 1996
  • 页码 183 p.
  • 总页数 183
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 动物学;毒物学(毒理学);动物医学(兽医学);病理学;
  • 关键词

  • 入库时间 2022-08-17 11:49:14

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