Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency.
BACKGROUND
Activation of bradykinin-mediated B2 receptor has been shown to play an important role in the onset of angioedema associated with C1 inhibitor deficiency. This finding has led to the development of novel therapeutic drugs such as the B2 receptor antagonist icatibant. However, it is unclear whether other receptors expressed on endothelial cells contribute to the release of kinins and vascular leakage in these patients. The recognition of their role may have obvious therapeutic implications.


OBJECTIVE
Our aim was to investigate the involvement of B1 and gC1q receptors in in vitro and in vivo models of vascular leakage induced by plasma samples obtained from patients with C1 inhibitor deficiency.


METHODS
The vascular leakage was evaluated in vitro on endothelial cells by a transwell model system and in vivo on rat mesentery microvessels by intravital microscopy.


RESULTS
We observed that the attack phase plasma from C1 inhibitor-deficient patients caused a delayed fluorescein-labeled albumin leakage as opposed to the rapid effect of bradykinin, whereas remission plasma elicited a modest effect compared with control plasma. The plasma permeabilizing effect was prevented by blocking the gC1q receptor-high-molecular-weight kininogen interaction, was partially inhibited by B2 receptor or B1 receptor antagonists, and was totally prevented by the mixture of the 2 antagonists. Involvement of B1 receptor was supported by the finding that albumin leakage caused by attack phase plasma was enhanced by IL-1beta and was markedly reduced by brefeldin A.


CONCLUSIONS
Our data suggest that both B1 receptor and gC1q receptor are involved in the vascular leakage induced by hereditary and acquired angioedema plasma.
Bossi
Fleur
F
Department of Life Sciences, University of Trieste, Trieste, Italy.
Fischetti
Fabio
F
Regoli
Domenico
D
Durigutto
Paolo
P
Frossi
Barbara
B
Gobeil
Fernand
F
Ghebrehiwet
Berhane
B
Peerschke
Ellinor I
EI
Cicardi
Marco
M
Tedesco
Francesco
F
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000799:Angioedema / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D065169:Bradykinin B1 Receptor Antagonists; D020126:Brefeldin A / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D050718:Complement C1 Inhibitor Protein / Q000235:genetics / Q000378:metabolism*; D056829:Hereditary Angioedema Types I and II / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D011951:Receptors, Complement / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D000911:Antibodies, Monoclonal; D065169:Bradykinin B1 Receptor Antagonists; D050718:Complement C1 Inhibitor Protein; D007155:Immunologic Factors; D053583:Interleukin-1beta; D008562:Membrane Glycoproteins; D011500:Protein Synthesis Inhibitors; C120984:R 715; D043783:Receptor, Bradykinin B1; D011951:Receptors, Complement; C032402:complement 1q receptor; D020126:Brefeldin A; C065679:icatibant; D001920:Bradykinin