CD14 AND INFLAMMATION IN HEMORRHAGIC SHOCK

出血性休克（HS）可引起炎症反应， 级联，这些级联参与器官损伤。不像 脓毒症，HS后的全身炎症不是由于特定的部位 感染相反，由灌注减少和 再灌注是有责任的。细菌或细菌产物（即， 从受伤的肠道释放的脂多糖，LPS）是可疑的 HS中的炎症刺激。LPS已被证明激活响应性 通过LPS与可溶性或膜结合的 CD 14在LPS结合蛋白加速的过程中。我们有 发现CD 14表达在休克期间显著上调， 复苏后进一步上调。这包括一个戏剧性的 先前未显示表达CD 14的细胞上CD 14的增加（例如， 呼吸上皮）。我们建议解决三个关键问题， 确定LPS和LPS与CD 14相互作用在炎症中的作用， HS后器官损伤。这些问题包括：1）CD 14是什么？ 在休克中表达上调2)LPS与CD 14的相互作用是否促进炎症 或HS损伤？和3）肺CD 14表达的增加是否导致 在HS后处于LPS过敏状态我们将利用我们的 啮齿动物HS和缺血/再灌注模型的专业知识， 独特的资源来充分解决这些问题。关键资源包括 CD 14和LBP敲除小鼠，新型LPS拮抗剂， 过表达CD 14，以及以前无法获得的大鼠特异性试剂。下 目的I：探讨CD 14表达上调的机制。 失血性休克，我们将确定上调的机制， 使用经受HS的动物的呼吸道上皮中的CD 14， 皮下植入气管和培养的上皮细胞。AIM II： 目的探讨CD 14在炎症反应中的作用， 失血性休克复苏后的组织损伤， 特别关注CD 14在炎症起始中的作用。 这将使用转基因/敲除动物完成， HS和用中和抗CD 14抗体或LPS预处理的动物 对手。目的：探讨CD 14在内毒素血症中的作用 失血性休克后的超敏反应，将确定 CD 14表达的增加赋予了对LPS的高度敏感性， 相同的体外和体内模型。这些实验应该会产生 关于冲击诱导基因表达机制的重要数据， 为LPS在HS介导的炎症中的作用提供明确的答案 和器官损伤

It is becoming evident that hemorrhagic shock (HS) initiates inflammatory cascades and that these cascades participate in organ damage. Unlike sepsis, the systemic inflammation after HS is not due to a specific site of infection. Instead, processes initiated by reduced perfusion and reperfusion are responsible. Bacteria or bacterial products (i.e., lipopolysaccharide, LPS) released from the injured gut are suspected inflammatory stimuli in HS. LPS has been shown to activate responsive cells through the interaction of LPS with either soluble or membrane-bound CD14 in a process that is accelerated by LPS-binding protein. We have found that CD14 expression is markedly upregulated during shock with further upregulation following resuscitation. This includes a dramatic increase in CD14 on cells not previously shown to express CD14 (e.g., respiratory epithelium). We propose to address three key questions to define the role of LPS and LPS to CD14 interaction in inflammation and organ injury following HS. These questions include: 1) How is CD14 upregulated in shock? 2) Does LPS to CD14 interaction promote inflammation or injury in HS? and 3) Does the increase in lung CD14 expression result in an LPS hypersensitive state following HS? We will take advantage of our expertise in rodent HS and ischemia/reperfusion models to utilize several unique resources to fully address these questions. Key resources include CD14 and LBP knockout mice, novel LPS antagonist, animals which overexpress CD14, and previously unavailable rat-specific reagents. Under AIM I: To determine the mechanism of the upregulation of CD14 in hemorrhagic shock, we will determine the mechanisms of upregulation of CD14 in the respiratory epithelium using animals subjected to HS, subcutaneously implanted trachea, and cultured epithelial cells. AIM II: To deter-mine the functional role of CD14 in the inflammatory changes and tissue injury following resuscitation from hemorrhagic shock, will specifically focus on the role of CD14 in the initiation of inflammation. This will be accomplished using transgenic/knockout animals subjected to HS and animals pretreated with neutralizing anti-CD14 antibodies or LPS antagonists. AIM m: To determine the role of CD14 In endotoxin hypersensitivity following hemorrhagic shock, will establish whether increases in CD14 expression confer a heightened sensitivity to LPS using the same in vitro and in vivo models. These experiments should yield important data on the mechanisms of shock-induced gene expression and provide definitive answers on the role of LPS in HS-mediated inflammation and organ damage.