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）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，它可以调理细菌并调节补体系统的激活。在创伤和败血症中，补体系统不受控制的激活可通过激活补体C5导致炎症免疫反应加剧，从而导致器官损伤。这种不受控制的免疫反应激活可能发生在所谓的二次打击期间，这是指在最初的创伤性组织损伤之后的继发性事件中组织损伤的增加。控制这种炎症反应是防止其有害后果的关键。我们之前已经表明，五聚体CRP的局部解离到其单一的单体亚基代表了CRP调节炎症区域炎症反应的普遍机制。用一种新的化合物阻断这一解离步骤可显著减少炎症。我们的数据表明，创伤性组织损伤后CRP的初始升高可能是后续事件的启动过程，导致继发性损伤后局部CRP解离增加。因此，我们认为CRP是二次撞击反应的关键因素。然而，目前尚不清楚CRP的构象变化如何改变CRP对补体系统的调节特性。在这里，我们的目的是研究从五聚体到单体的构象变化对补体因子在调节和加重现有炎症事件中的作用。我们将研究从补体激活到白细胞亚群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，以制定针对二次命中反应的特异性治疗方法。我们将把我们的发现转移到已建立的二次命中反应动物模型中，以确认CRP解离在二次命中病理中的因果作用，并证明靶向CRP解离是调节和控制二次命中加剧炎症反应的合适治疗方法。在一项临床初步研究中，我们将研究crp解离产物及其与补体系统因子的相互作用，作为具有预测多重创伤价值的生物标志物。

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.