ReviewCross-talk between the complement and the kinin system in vascular permeability
Highlights
► Complement and kinin systems play a role in hereditary and acquired angioedema. ► C1-inhibitor controls activation of both kinin and complement systems. ► Bradykinin contributes to angioedema attacks interacting with B2 receptors. ► Interaction of high molecular weight kininogen with gC1qR induces bradykinin release. ► B1 and gC1q receptors represent novel therapeutic targets for angioedema attacks.
Introduction
The vascular tree is covered on the inner surface by a continuous layer of endothelial cells which form a physical barrier between the circulating blood and the extravascular tissue preventing potential damage which may derive from undesired blood outflow. Besides playing a critical role in physically separating the intravascular from the extravascular sides of the vascular vessels, the endothelium exhibits other important functions to maintain vascular homeostasis. By expressing heparin sulphate, and by releasing thrombomodulin and tissue factor inhibitor, endothelial cells (ECs) expose an anti-thrombotic surface on the luminal side which controls blood flow preventing blood clot. The endothelium can also regulate the vascular tone contributing to induce changes in the blood flow in response to tissue demands. Several substance can be released by ECs which either promote vasodilation, such as nitric oxide and prostacyclin PGI2, or induce vasoconstriction, as is the case of endothelin-1 and platelet-activating factor [1].
Another important function of the endothelium is to control passage of molecules and cells to the extravascular sites where they are needed for nutritional and defence purposes. This is made possible by its structural organization as a monolayer of cells joined together by tight junctions, a structure observed in the microcirculation of almost all tissues and organs with only a few exceptions.
Perturbation of ECs caused by physicochemical stimuli induces cell activation and has functional consequences resulting in cell egression into the extravascular sites and increased vascular permeability. These changes are usually associated with inflammatory processes which are responsible for systemic manifestations, such as sepsis or generalized vasculitides, or localized reactions. However, vascular leakage which manifests as non inflammatory edema may also occur in some pathological conditions in the absence of inflammation.
The soluble systems which are mainly, though not exclusively, involved in the induction of increased vascular permeability include the complement (C) and the kinin systems, which may have a direct permeabilizing effect through the release of biologically active products or may activate other cells which in turn release vasoactive molecules. Although the two systems may act independently to induce vascular leakage, increasing evidence suggests that there is a cross-talk which involves different components of these systems. Both systems require activation to function and are involved in triggering or exacerbating pathological conditions such as hereditary and acquired AE and vasculitidis.
The focus of this review is to discuss the contribution of C and kinin systems to vascular leakage and to highlight the cross-talk between the two systems in the development of AE.
Section snippets
Contribution of the complement system to the vascular leakage
The C system is an important component of innate immunity involved in host defence against microorganisms, clearance of immune complexes and removal of apoptotic cells and acts either alone or more often in collaboration with other components of both innate and acquired immune system. To accomplish these functions, the system must be activated to release biologically active products which may directly neutralize the target or favour the participation of other components of the immune system to
The role of gC1qR and the kinin–kallikrein system in the pathophysiology of vascular permeability
The classical pathway of C and the kallikrein–kinin system are two unique proinflammatory pathways which share several features. First, both pathways use functionally homologous “active zymogens” to trigger their activation. These so-called “active zymogens” in turn are generated when the inactive precursor enzymes undergo an autoactivation process and acquire enzymatic activity – by virtue of conformational change – when bound to a suitable surface [29]. In the kinin system this is represented
Angioedema as a model of crosstalk between complement and kinin systems
The data showing that the vascular leakage induced by SC5b-9 is mediated through the release of BK clearly indicate that the C and the kinin systems are very closely linked in the stimulation of the endothelium [27]. However, it has been shown that other molecules – such as gC1qR/p33 [60] and C1 inhibitor (C1-INH) [61] – belonging to the C system are involved in the regulation and activation of the kinin system.
The multimolecular receptor complex comprising gC1qR/p33, uPAR and CK-1 present on
Acknowledgements
This work was supported by grants Università e Ricerca (PRIN 2007), Regione Friuli Venezia Giulia to F.T; R01 AI-060866 and R01 AI-084178, from the National Institutes of Health to B.G. and E.I.P.
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