OLIGONUCLEOTIDE TARGETING OF THE KUPFFER CELL

描述：（改编自研究者摘要）肿瘤坏死因子-a 肿瘤坏死因子（TNF-α）是细胞复制所需的细胞因子。然而，当其 其产生被上调，其触发炎症反应和细胞损伤。 枯否细胞是TNF-α的主要生产者。在内皮细胞中， 肝细胞，TNF-α：（i）激活白细胞的产生 化学引诱剂和（ii）增加细胞间粘附的表达 锚定白细胞的ICAM-1分子。锚定白细胞 （iii）刺激（中性粒细胞/单核细胞）释放潜伏的蛋白水解酶， 通过髓过氧化物酶的协同作用而被激活的酶， 过氧化氢导致细胞损伤有几种方法可以防止细胞 损伤阻断枯否细胞可减少由多种因素引起的肝损伤 肝毒素结合TNF-α、ICAM-1或锚定受体的抗体， 中性粒细胞和单核细胞（CD 11b/CD 18）在不同的细胞损伤中保护细胞 体外和体内实验条件，包括 慢性乙醇给药。虽然这些方法有助于 肝损伤的发病机制的重要见解，他们不能使用 临床上的慢性病。最近的研究表明， 寡核苷酸是治疗慢性炎症的可行的替代疗法。 条件提出的研究测试了肝损伤的一般假设， 慢性乙醇处理诱导的细胞凋亡可被反义寡核苷酸抑制， 在细胞毒性级联的三个步骤中起作用的寡核苷酸： （ii）肝细胞产生ICAM-1， 内皮细胞和（iii）髓过氧化物酶介导的细胞毒性。总体看 拟议的研究调查了新的基因型药物的有效性， 作用于肝细胞损伤的中枢机制， 酒精性肝病的可能性

DESCRIPTION: (Adapted from the Investigator's Abstract) Tumor necrosis factor-a (TNF-alpha) is a cytokine required for cell replication. However, when its production is upregulated it triggers an inflammatory response and cell injury. Kupffer cells are the main producers of TNF-alpha. In endothelial cells and hepatocytes, TNF-alpha: (i) activates the production of leukocyte chemoattractants and (ii) increases the expression of intercellular adhesion molecules (ICAM-1) which anchors leukocytes. Anchored leukocytes (neutrophils/monocytes) are stimulated to (iii) release latent proteolytic enzymes that become activated by the concerted action of myeloperoxidase and hydrogen peroxide, leading to cell damage. Several approaches can prevent cell injury. Obliteration of Kupffer cells reduces liver injury elicited by a number of hepatotoxins. Antibodies that bind TNF-a, ICAM-1, or anchoring receptors in neutrophils and monocytes (CD11b/CD18) protect against cell injury in different experimental conditions in vitro and in vivo, including liver injury induced by chronic ethanol administration. While these approaches have contributed an important insight to the pathogenesis of liver injury they cannot be used clinically in chronic conditions. Recent studies show that antisense oligonucleotides are viable therapeutic alternatives in chronic inflammatory conditions. Studies proposed test the general hypothesis that liver injury induced by chronic ethanol treatment can be suppressed by antisense oligonucleotides that act at three steps of the cytotoxic cascade: (i) TNF-alpha production by Kupffer cells (ii) ICAM-1 generation by hepatocytes and endothelial cells and (iii) myeloperoxidase-mediated cytotoxicity. Overall, the proposed research investigates the effectiveness of new genotypic drugs that act on central mechanisms of hepatocellular injury that may have therapeutic potential for alcoholic liver disease.