OLIGONUCLEOTIDE TARGETING OF THE KUPFFER CELL

描述：(改编自《调查者摘要》)肿瘤坏死因子-a (肿瘤坏死因子-α)是细胞复制所必需的细胞因子。然而，当它的 生产被上调，它会触发炎症反应和细胞损伤。 库普弗细胞是产生肿瘤坏死因子-α的主要细胞。在血管内皮细胞和 肝细胞，肿瘤坏死因子-α：(I)激活白细胞的产生 趋化物质和(Ii)增加细胞间黏附的表达 锚定白细胞的分子(ICAM-1)。锚定的白细胞 (3)刺激中性粒细胞/单核细胞释放潜在的蛋白水解物 髓过氧化物酶和髓过氧化物酶的协同作用而激活的酶 过氧化氢，导致细胞损伤。几种方法可以防止细胞 受伤。清除Kupffer细胞可减少由多种因素引起的肝损伤 肝毒素。结合肿瘤坏死因子-a、细胞间黏附分子-1或锚定受体的抗体 中性粒细胞和单核细胞(CD11b/CD18)在不同条件下对细胞损伤的保护作用 体外和体内实验条件，包括三氯甲烷致肝损伤 长期服用乙醇。虽然这些方法为我们提供了 对肝损伤发病机制的重要认识它们不能被使用 临床上处于慢性状态。最近的研究表明，反义 寡核苷酸是治疗慢性炎症性疾病的可行选择 条件。研究建议检验肝脏损伤这一普遍假设 慢性乙醇处理可被反义抑制 在细胞毒级联反应的三个步骤中起作用的寡核苷酸：(I) 枯否细胞产生肿瘤坏死因子-α(II)肝细胞产生细胞间黏附分子-1 内皮细胞和(Iii)髓过氧化物酶介导的细胞毒性。总体而言， 拟议的研究调查了新的基因类型药物的有效性 作用于肝细胞损伤的中枢机制，可能具有治疗作用 有可能患上酒精性肝病。

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.