CD14 AND INFLAMMATION IN HEMORRHAGIC SHOCK

越来越明显的是，失血性休克(HS)会引发炎症 这些级联反应参与器官损伤。不像 脓毒症，HS后的全身性炎症不是由于特定的部位 感染的可能性。取而代之的是，减少灌注量和 再灌流是有责任的。细菌或细菌产品(即， 怀疑是从受伤的肠道中释放出来的 HS中的炎性刺激。LP已被显示为激活响应 通过脂多糖与可溶性或膜结合的细胞相互作用 CD14在一个由内毒素结合蛋白加速的过程中。我们有 发现在休克过程中CD14表达显著上调 复苏后进一步上调。这包括戏剧性的 先前未示出的表达CD14的细胞上CD14的增加(例如， 呼吸道上皮)。我们建议解决三个关键问题，以 明确内毒素和内毒素在炎症和CD14相互作用中的作用 HS后的器官损伤。这些问题包括：1)CD14如何 休克时上调？2)内毒素与CD14的相互作用是否促进炎症 还是在HS受伤？3)肺CD14表达的增加是否导致 在HS后处于内毒素过敏状态？我们将利用我们的 在啮齿动物HS和缺血/再灌注模型方面的专业知识可利用几种 充分解决这些问题的独特资源。主要资源包括 CD14和LBP基因敲除小鼠，新型内毒素拮抗剂， 过表达CD14，以及以前无法获得的大鼠特异性试剂。在……下面 目的：探讨CD14表达上调的机制。 失血性休克，我们将确定上调的机制 使用HS动物的呼吸道上皮细胞CD14， 皮下植入气管，并培养上皮细胞。目标二： 确定CD14在炎症变化和炎症反应中的作用 失血性休克复苏后的组织损伤 特别关注CD14在炎症启动中的作用。 这将使用转基因/基因敲除动物来完成 HS和用中和抗CD14抗体或内毒素预处理的动物 对抗者。目的：探讨CD14在内毒素中的作用 失血性休克后的超敏反应，将确定 CD14表达的增加使人对内毒素的敏感性增加 在体外和体内模型中是相同的。这些实验应该会产生 休克诱导基因表达及机制的重要数据 就内毒素在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.