Platelet-Activating Factor and Kinin-Dependent Vascular Leakage as a Novel Functional Activity of the Soluble Terminal Complement Complex

Abstract

The infrequent occurrence of septic shock in patients with inherited deficiencies of the terminal complement components experiencing meningococcal disease led us to suspect that the terminal complement complex is involved in vascular leakage. To this end, the permeabilizing effect of the cytolytically inactive soluble terminal complement complex (SC5b-9) was tested in a Transwell system measuring the amount of fluorescein-labeled BSA (FITC-BSA) leaked through a monolayer of endothelial cells. The complex caused increased permeability to FITC-BSA after 15 min as opposed to the prompt response to bradykinin (BK). The effect of SC5b-9 was partially reduced by HOE-140 or CV-3988, two selective antagonists of BK B2 and platelet-activating factor receptors, respectively, and was completely neutralized by the mixture of the two antagonists. Also, DX-88, a specific inhibitor of kallikrein, partially inhibited the activity of SC5b-9. The permeabilizing factor(s) released after 30 min of incubation of endothelial cells with SC5b-9 caused a prompt leakage of albumin like BK. Intravital microscopy confirmed both the extravasation of circulating FITC-BSA across mesenteric microvessels 15 min after topical application of SC5b-9 and the complete neutralization by the mixture of HOE-140 and CV-3988. SC5b-9 induced opening of interendothelial junctions in mesenteric endothelium documented by transmission electron microscopy.

Local Bradykinin Formation Is Controlled by Glycosaminoglycans

“…FITC-dextran (70 kDa; Sigma-Aldrich) was injected at 10 mg/kg body weight into the retro-orbital plexus as a plasma tracer to permit visualization in fluorescence light of changes in vascular permeability. After topical application of FXIIa (25 nM) and/or D3 (10 M) in saline, macromolecular leakage was monitored for 20 min as previously described (45,46).…”

Decidual endothelial cells express surface-bound C1q as a molecular bridge between endovascular trophoblast and decidual endothelium

“…Expression of adhesion molecules and tissue factor, release of chemokines, increased permeability are some of the responses of ECs to these factors (Bossi et al, 2004;Dobrina et al, 2002;Kilgore et al, 1996;Selvan et al, 1998) and both C5a and SC5b-9 have been shown to promote transendothelial migration of PMN (Dobrina et al, 2002). However, under normal conditions the endothelium is protected from the stimulating effect of C activation products that induce a pro-inflammatory and pro-coagulant state by the regulatory proteins CD46, CD55 and CD59 expressed on their surface and the fluid phase regulator Factor H that binds to ECs (Asch et al, 1986;Hamilton et al, 1990;Jokiranta et al, 2005;McNearney et al, 1989).…”

Proteins of the Hageman Factor System in an Inflammatory Reaction in the Acute Period of Severe Brain Injury

“…В последние годы изучаются но вые роли контактных факторов, их ингибиторов в фи зиологических и патологических процессах, в частности при воспалительных реакциях различной этиологии. Установлены возможности альтернативной «неконтактной» активации СФХ, участие эндотелия, тромбоцитов и лейкоцитов в патологических реакциях этой системы, так же исследуются пути коррекции ее недостаточности или гиперфункции [3][4][5][6][7]. Для углуб ления представлений о функционировании системы фактора Хагемана в остром периоде ТЧМТ целесооб разным представляется изучение динамики и взаимо связей контактных факторов, их ингибиторов с гло бальными показателями гемокоагуляции, фибринолиза и реактантами воспаления.…”