The interaction of C-reactive protein (CRP) with the complement system in the pathogenesis, diagnosis and therapy of the post traumatic inflammatory response

C反应蛋白(CRP)与补体系统的相互作用在创伤后炎症反应的发病机制、诊断和治疗中的作用

基本信息

项目摘要

C-reactive protein (CRP) is a highly conserved pentameric protein. It is not only a marker, but also a mediator of inflammation. As part of the innate immune system it opsonizes bacteria and can regulate activation of the complement system. In trauma, as well as in septicaemia, uncontrolled activation of the complement system can lead to exacerbation of the inflammatory immune response leading to organ damage via activation of complement C5. This uncontrolled activation of the immune response can occur during the so called second-hit, that refers to increased tissue injury in secondary events after initial traumatic tissue injury. Controlling this inflammatory response is key to preventing its detrimental consequences.We have shown previously that localized dissociation of pentameric CRP to its single monomeric subunits represents a ubiquitious mechanism by which CRP regulates the inflammatory response in areas of inflammation. Blocking this dissociation step by a novel compound leads to markedly reduced inflammation. Our data suggest that initial increase of CRP after traumatic tissue injury might be a priming process for following events leading to increased localized CRP dissociation in the event of a following secondary injury. We therefore believe that CRP is a crucial causal factor in the second- hit response. However it remians unclear how the conformational change of CRP alters the modulating properties of CRP on the complement system. Here we aim to investigate the effects of the confomational change from pentameric to monomeric CRP on its effect on complement factors regarding the modulation and aggravation of an existing inflammatory event. We will investigate the pathomechanistic sequelae from complement activation to the differential activation of leukocyte subsets with emphasis on the interaction of CRP dissociation, complement activation and activation of monocyte subsets in order to taylor specific therapeutic approaches targeting the second-hit response. We will transfer our findings to an established animal model of the second-hit response in order to confirm the causal role of CRP dissociation in the pathology of the second-hit and to prove that targeting CRP dissociation is a suitable therapeutic approach to modulate and control the exacerbated inflammatory response in second-hit. In a clinical pilot study we will investigate CRP-dissociation products and their interaction with factors of the complement system as biomarkers with predictive value in polytrauma.
C-反应蛋白(CRP)是一种高度保守的五聚体蛋白。它不仅是一种标志物,也是炎症的介质。作为先天免疫系统的一部分,它调理细菌,并可以调节补体系统的激活。在创伤以及败血症中,补体系统的不受控制的激活可导致炎性免疫应答的恶化,从而通过补体C5的激活导致器官损伤。这种免疫应答的不受控制的激活可以在所谓的二次打击期间发生,二次打击是指在初始创伤性组织损伤之后的二次事件中增加的组织损伤。控制这种炎症反应是防止其有害后果的关键,我们以前已经表明,五聚体CRP的单一单体亚基的局部解离代表了一种普遍存在的机制,CRP调节炎症区域的炎症反应。通过一种新的化合物阻断这一解离步骤导致炎症明显减少。我们的数据表明,创伤性组织损伤后CRP的初始增加可能是以下事件的引发过程,导致在继发性损伤的情况下局部CRP解离增加。因此,我们认为CRP是二次打击反应的一个关键因素.然而,CRP的构象变化如何改变其对补体系统的调节特性尚不清楚。在这里,我们的目的是研究从五聚体到单体CRP的构象变化对补体因子的影响,这些补体因子与现有炎症事件的调节和加重有关。我们将研究从补体激活到白细胞亚群的差异激活的病理机制后遗症,重点是CRP解离、补体激活和单核细胞亚群激活的相互作用,以泰勒靶向二次打击反应的特异性治疗方法。我们将把我们的发现转移到一个建立的二次打击反应的动物模型中,以证实CRP解离在二次打击病理学中的因果作用,并证明靶向CRP解离是一种合适的治疗方法来调节和控制二次打击中加剧的炎症反应。在临床初步研究中,我们将研究CRP解离产物及其与补体系统因子的相互作用,作为多发性创伤中具有预测价值的生物标志物。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients
  • DOI:
    10.3389/fimmu.2020.01789
  • 发表时间:
    2020-09-02
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
    Karasu, Ebru;Demmelmaier, Julia;Halbgebauer, Rebecca
  • 通讯作者:
    Halbgebauer, Rebecca
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Professor Dr. Steffen Ulrich Eisenhardt其他文献

Professor Dr. Steffen Ulrich Eisenhardt的其他文献

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{{ truncateString('Professor Dr. Steffen Ulrich Eisenhardt', 18)}}的其他基金

The role of the innate immune system in Inflammation - Therapeutic approaches
先天免疫系统在炎症中的作用 - 治疗方法
  • 批准号:
    448812557
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
    Heisenberg Grants
Die Rolle der angeborenen Immunantwort in Entzündungsreaktionen und entzündlichen Erkrankungen – Erforschung und Entwicklung neuer therapeutischer Ansätze
先天免疫反应在炎症反应和炎症性疾病中的作用——新治疗方法的研究和开发
  • 批准号:
    314866080
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
    Heisenberg Professorships
The non-adaptive immune system in inflammatory reactions and diseases: Developing novel therapeutic targets and strategies
炎症反应和疾病中的非适应性免疫系统:开发新的治疗靶点和策略
  • 批准号:
    269560291
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
    Heisenberg Fellowships
Untersuchung der Interaktion von C-reaktivem Protein (CRP) mit Zellmembranen bei der Entstehung der Entzündungsreaktion im Ischämie/Reperfusionsschaden
C反应蛋白(CRP)与细胞膜相互作用在缺血/再灌注损伤炎症反应发展中的研究
  • 批准号:
    220121242
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
    Research Grants
C-reactive protein (CRP) as a pathological factor in inflammation and ischemia/reperfusion injury: therapeutic implications
C反应蛋白(CRP)作为炎症和缺血/再灌注损伤的病理因素:治疗意义
  • 批准号:
    175450664
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Investigation of the regulation of the innate immune response by C-reactive protein in vascularized composite allotransplantation (VCA)
血管化复合同种异体移植(VCA)中 C 反应蛋白对先天免疫反应的调节研究
  • 批准号:
    450025008
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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    2011
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