BIOCHEMISTRY OF TRAUMA-INDUCED INFLAMMATION

1.兔子和恒河猴的炎症模型表明， 通过静脉注射细菌脂多糖（LPS）的刺激， 途径诱导白细胞积聚在 肺血管，无迁移至血管外， 肺泡腔，无明显组织损伤。 相比之下， 支气管内LPS刺激诱导白细胞迁移， 损伤，并与TNF，IL-1，IL-8和IL-6的产生有关， 肺 这些细胞因子没有发现在肺组织后， 用LPS静脉内刺激。 我们建议确定抑制是否 这些细胞因子的改变了细胞因子的顺序出现， 肺内白细胞移出和病理生理变化。 的 IL-8的受体结合结构域已被初步鉴定， 将使用针对该结构域的抗体来评估以下重要性： IL-8在LPS诱导的白细胞迁移中的作用 肝IL-6的胞外亲水区结构域 受体，负责结合信号转导成分， GP-130，将被确定，并制备抗体。这些 抗体将用于阻断急性期肝细胞中的IL-6 蛋白，LPS结合蛋白（LBP）。 LBP可以参加 兔对LPS表现出的高反应状态的出现， 在24小时内形成。 IL-6受体的抑制可 不仅改变LBP的形成，而且改变超反应状态。 2.实验将继续对白细胞氧化剂的作用， 炎性损伤 迄今为止的研究已经确定了 暴露于白细胞氧化剂的细胞， 研究氧化剂抑制的效果。

1. Models of inflammation in rabbits and rhesus monkeys have indicated that stimulation by bacterial lipopolysaccharide (LPS) by the intravenous route induces accumulation of leukocytes on the luminal surface of pulmonary blood vessel, without emigration into the extravascular and alveolar spaces and without demonstrable tissue injury. By contrast, intrabronchial stimulation with LPS induces emigration of leukocytes and damage, and is associated with generation of TNF, IL-1, IL-8 and IL-6 in the lung. These cytokines are not found in the lung tissues after intravenous stimulation with LPS. We propose to determine if inhibition of these cytokines modifies the sequential appearance of cytokines, leukocytic emigration and pathophysiologic changes in the lung. The receptor-binding domain of IL-8 has been tentatively identified, and antibodies to this domain will be employed to assess the importance of IL-8 in LPS-induced leukocytic emigration. The domain of the extracellular hydrophilic region of the hepatic IL-6 receptor, responsible for binding the signal-transducing component, GP-130, will be identified, and antibodies prepared to it. These antibodies will be used to block IL-6 in hepatocytes of the acute phase protein, LPS-binding protein (LBP). LBP may participate in the appearance of the hyper-responsive state exhibited by rabbits to LPS that develops over a 24 hour period. Inhibition of the IL-6 receptor may modify not only LBP formation, but the hyper-responsive state. 2. Experiments will be continued on the role of leukocytic oxidants in inflammatory injury. Studies to date have defined specific changes in cells exposed to leukocytic oxidants that will help significantly in studying the effect of oxidant inhibition.