Molecular pathways of complement-mediated effects in the pathophysiology of shock

补体级联可能通过三种不同的途径被激活：经典途径、替代途径和最近发现的凝集素途径。虽然经典途径依赖于免疫球蛋白，但后两种途径在缺乏获得性免疫的情况下会产生反应，并在先天免疫反应中提供关键的第一线防御。我们最近的观察表明，凝集素和替代途径形成了一个功能单位，凝集素途径在其中启动，替代途径放大补体的激活，以最大化对微生物入侵的先天性免疫反应。凝集素途径的激活是由体液碳水化合物识别分子(即MBL和3种不同的无花果蛋白)与细菌(包括内毒素)和酵母上典型的多聚体碳水化合物结构结合而启动的，并通过丝氨酸蛋白酶MASP-2激活补体级联反应。这一建议是基于一项初步研究的结果，该研究有力地支持了我们的工作假设，即凝集素途径通过产生强大的过敏性毒素和促炎性补体激活产物而在休克的病理生理学中起作用。我们的目标是研究事件链，并监测凝集素途径激活复合体与细菌感染或内毒素之间的直接相互作用如何影响肿瘤坏死因子的释放。为此，我们将在四种不同的休克实验模型中评估三种补体激活途径中每一种关键成分选择性缺乏的基因靶向小鼠品系：i。内毒素休克II。)细菌引起的感染性休克，III.)过敏性休克，静脉注射。)过敏性休克。

The complement cascade may be activated via three different routes: the classical pathway, the alternative pathway and the most recently discovered lectin pathway. While the classical pathway is dependent on immunoglobulins, the latter two are responsive in absence of acquired immunity and provide a critical first line defence within the innate immune response. Our recent observations suggest that the lectin and the alternative pathway form a functional unit in which the lectin pathway initiates and the alternative pathway amplifies activation of complement to maximise the innate immune response to microbial invasion. Activation of the lectin pathway is initiated by the binding of humoral carbohydrate recognition molecules (i.e. MBL and 3 different ficolins) to multimeric carbohydrate structures typically present on bacteria (including LPS) and yeasts and activates the complement cascade via the serine protease MASP-2. This proposal is based on results of a pilot study that strongly supports our working hypothesis that the lectin pathway contributes to the pathophysiology of shock by generating potent anaphylatoxins and proinflammatory complement activation products. We aim to study the chain of events and monitor how the direct interaction between the lectin pathway activation complex and bacterial infection or LPS affect the release of TNF. For this purpose we will assess gene-targeted mouse strains selectively deficient in key components for each of the three complement activation routes in 4 different experimental models of shock: i.) endotoxin shock, ii.) bacteria-induced septic shock, iii.) anaphylactic shock, and iv.) anaphylactoid shock.