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首页> 外文学位 >Countermeasures against vesicant-induced epithelial de-adhesion in the cornea.
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Countermeasures against vesicant-induced epithelial de-adhesion in the cornea.

机译：角膜囊泡诱导的上皮脱粘的对策。

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摘要

Sulfur mustard is a chemical weapon and vesicant (blister-inducer) that causes severe effects to the cornea. These injuries are characteristically delayed in healing and may be recurrent over time. The experiments in this dissertation were designed to test the efficacy of countermeasures targeting metalloproteinases, thought to be over-activated in the cornea following vesicant exposure. An ex vivo culture model was developed using dissected corneas from young adult rabbit eyes. Each cornea was exposed drop wise to 20 nmol 2-chloroethyl ethyl sulfide (CEES, half mustard) or 100 nmol nitrogen mustard (NM). These are less potent and less toxic analogs of sulfur mustard, and induce mild or moderate injury, respectively.;Twenty-four hours after NM exposure there are observable separations between the epithelium and the stroma, termed microbullae. I hypothesize that the microbullae are caused by activation of the enzyme ADAM17 (a disintegrin and a metalloprotease 17), causing cleavage of the transmembranous anchoring protein, collagen XVII. Four ADAM17 inhibitors were compared to evaluate the effect of attenuating activity of this enzyme. The countermeasures effectively improved the appearance of the epithelial-stromal junction as seen by the preservation of epithelial-stromal attachments and improved histology as well as and decreasing ADAM17 activity.;After vesicant exposures there was also upregulation of MMP-9, the protease responsible for the necessary matrix degradation after wounding that leads to healing. The MMP-9 levels after vesicant exposure are enhanced abnormally. The MMP inhibitors, doxycycline and minocycline, were employed as effective countermeasures to inhibit the prolonged upregulation of MMP-9. To determine whether activation of ADAM17 and MMP-9 are due to ERK signaling, the inhibitor PD98059 was assessed. When used immediately after exposure, the compound was able to inhibit the ability of ERK to phosphorylate the cytoplasmic domain of ADAM17, thereby inhibiting collagen XVII cleavage. MMP-9 upregulation after 24 hrs was also inhibited as a downstream affecter of the ERK pathway when PD98059 was used. These experiments identify which countermeasures are the best candidates to test in vivo in rabbits exposed to sulfur mustard, and explore a mechanism of how mustards affect the extracellular matrix of the epithelial-stromal junction.
机译：芥菜酱是一种化学武器和发泡剂（起泡剂），会对角膜产生严重影响。这些伤害通常会延迟愈合，并可能随着时间的流逝而复发。本文设计的实验旨在测试针对金属蛋白酶的对策的有效性，认为金属蛋白酶在暴露于溶剂后会在角膜中过度活化。建立了一种离体培养模型，该模型使用了来自成年幼兔眼的解剖角膜。将每个角膜逐滴暴露于20nmol 2-氯乙基乙基硫化物（CEES，半芥末）或100nmol氮芥末（NM）。它们是硫芥末的效力较低且毒性较低的类似物，分别引起轻度或中度伤害。； NM暴露后二十四小时，上皮和基质之间可观察到分离，称为微球。我推测微球是由ADAM17酶（解整合素和金属蛋白酶17）的激活引起的，导致跨膜锚定蛋白XVII的裂解。比较了四种ADAM17抑制剂，以评估该酶的减毒活性。通过保留上皮间质附着，改善组织学以及降低ADAM17活性，可以有效地改善上皮间质连接的外观。暴露于泡剂后，引起蛋白酶MMP-9的表达上调。受伤后必要的基质降解会导致愈合。暴露于水泡剂后，MMP-9水平异常升高。 MMP抑制剂强力霉素和米诺环素被用作抑制MMP-9长期上调的有效对策。为了确定ADAM17和MMP-9的激活是否归因于ERK信号传导，评估了抑制剂PD98059。当暴露后立即使用时，该化合物能够抑制ERK磷酸化ADAM17胞质结构域的能力，从而抑制胶原XVII的裂解。当使用PD98059时，作为ERK途径的下游影响者，在24小时后MMP-9的上调也被抑制。这些实验确定了哪些对策是测试暴露于硫芥末的家兔体内体内的最佳候选方法，并探讨了芥末如何影响上皮-基质连接的细胞外基质的机制。

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  • 作者

    Rodrigues, Andrea DeSantis.;

  • 作者单位

    Rutgers The State University of New Jersey - New Brunswick and University of Medicine and Dentistry of New Jersey.;

  • 授予单位 Rutgers The State University of New Jersey - New Brunswick and University of Medicine and Dentistry of New Jersey.;
  • 学科 Health Sciences Toxicology.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 162 p.
  • 总页数 162
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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