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

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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.