INITIATION OF INFLAMMATION IN HEMORRHAGIC SHOCK

失血性休克(HS)与组织创伤共同作用，引发一系列信号事件，最终导致炎症、终末器官损伤和功能障碍。损伤后炎症信号级联反应激活的分子基础尚不清楚。我们研究的前提是，了解创伤诱导的炎症是如何启动、放大和传播的，将导致复苏策略，从而控制创伤患者早期的过度炎症和延迟的免疫受损状态。我们的假设是，信号事件几乎在损伤后立即开始，多个重叠的通路被激活，共同作用于放大和传播全身炎症反应。我们已经积累的数据表明，在HS诱导后，MAP激酶被早期激活，以响应缺氧和循环激素。这之后是转录因子的早期上调。 生长反应基因-1(Egr-1)和诱导型一氧化氮合酶(INOS)在HS过程中和复苏前的表达。此外，我们有证据表明Egr-1和iNOS都参与了复苏后的炎症反应。我们现在提出两个目标来确定休克时活性氧物种、MAP激酶(JNK和ERK)、Egr-1和iNOS之间的调节关系以及这些通路在休克中的功能作用。 控制复苏后的炎症。目的一：确定创伤和休克后MAPK活化、Egr-1和iNOS上调的途径。在这一目标下，我们将探讨活性氧物种在MAP激酶、Egr-1和iNOS上调中的作用。此外，我们还将确定这三条通路的激活是否存在依赖顺序。目的II：探讨复苏后MAPK活性与Egr-1、iNOS上调的机制关系 感染和器官损伤。在AIM II下的实验将利用在AIM I中获得的调控信息来确定MAP激酶、Egr-1和iNOS在控制复苏后炎症反应中的作用。随着我们两个目标的完成，我们将建立这些途径与其个体之间的分子关系，以及控制复苏后炎症的协同作用。每条途径都代表了进一步开发治疗策略的潜在靶点，这些治疗策略旨在减轻 损伤后全身炎症反应的大小。

Hemorrhagic Shock (HS) combined with tissue trauma act together to initiate a cascade of signaling events that culminate in inflammation and end-organ damage and dysfunction. The molecular basis for the activation of inflammatory signaling cascades following injury are poorly understood. It has been the premise of our research that understanding how injury induced inflammation is initiated, amplified and then propagated will lead to resuscitation strategies that will control both the early hyperinflammation and the delayed immunocompromised state that develops in trauma patients. It is our hypothesis that signaling events begin almost immediately after injury, and that multiple overlapping pathways are activated that act in concert to amplify and propagate the systemic inflammatory response. We have accumulated data demonstrating that MAP kinases are activated early following the induction of HS in response to hypoxia and circulating hormones. This is followed by the upregulation of the transcriptional factor early growth response gene-1, (Egr-1), and the expression of the inducible NO synthase (iNOS) also during HS and prior to resuscitation. Furthermore, we have evidence showing that both Egr-1 and iNOS participate in the post-resuscitation inflammatory response. We now propose two aims to determine the regulatory relationships between reactive oxygen species, MAP kinases (JNK and ERK), Egr-1, and iNOS during shock and the functional roles of these pathways in controlling post-resuscitation inflammation. The aims are as follows: AIM I: To determine the pathways to MAPK activation and Egr-1 and iNOS upregulation following trauma and shock. Under this aim we will explore the role of reactive oxygen species to the upregulafion of MAP kinases, Egr-1 and iNOS. In addition, we will determine whether there is a dependent sequence in the activation of the three pathways. AIM II: To determine the mechanistic relationships between MAP kinase activation, and Egr-1 and iNOS upregulation to the post-resuscitation intlammation and organ damage. Experiments under Aim II will take advantage of the regulatory information gained in Aim I to determine the role of MAP kinases, Egr-1 and iNOS in controlling the post-resuscitation inflammatory response. With the completion of our two aims we will have established the molecular relationship between these pathways and their individual as well as synergistic roles controlling post-resuscitation inflammation. Each pathway represents a potential target for the further development of therapeutic strategies designed to attenuate the magnitude of the systemic inflammatory response following injury.