The bradykinin-forming cascade and its role in hereditary angioedema.
OBJECTIVE
To review the mechanisms by which bradykinin is generated in hereditary angioedema (HAE) (C1 inhibitor deficiency), including the role of human plasma proteins and endothelial cells.


METHODS
Published articles in reviewed journals that address (1) the fundamentals of bradykinin formation, (2) interactions between kinin-forming proteins and endothelial cells, (3) clinical evidence that bradykinin causes swelling in HAE, and (4) therapeutic options focused on inhibition of the plasma kallikrein-kinin cascade.


METHODS
Historical articles that have made fundamental observations. Recent articles that address evolving concepts of disease pathogenesis and treatment.


RESULTS
C1 inhibitor deficiency causes dysregulation of the plasma bradykinin-forming cascade with overproduction of bradykinin due to uninhibited effects of activated factor XII and plasma kallikrein. Swelling in HAE and production of bradykinin are localized (and may then disseminate); activation along the endothelial cell surface involves cell membrane ligands of factor XII and high-molecular-weight kininogen, release of endothelial cell heat shock protein 90, activation of the high-molecular-weight kininogen-prekallikrein complex, and endothelial cell activation at the B2 receptor. Attacks of swelling may be terminated by treatment with a kallikrein inhibitor or B2 receptor blockade. Replenishing C1 inhibitor can abort attacks of swelling and provide prophylaxis with intravenous administration.


CONCLUSIONS
Bradykinin is the mediator of swelling in types I and II HAE and is overproduced because of a deficiency in C1 inhibitor. Inhibition of bradykinin formation by novel agentscan provide targeted therapeutic approaches that address the pathophysiologic abnormalities.
Kaplan
Allen P
AP
Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA. kaplana@musc.edu
Joseph
Kusumam
K
D000728:Androgens / Q000627:therapeutic use; D054179:Angioedemas, Hereditary / Q000188:drug therapy / Q000378:metabolism*; D001920:Bradykinin / Q000378:metabolism*; D003174:Complement C1 Inactivator Proteins / Q000627:therapeutic use; D051056:Complement Inactivating Agents / Q000627:therapeutic use; D042783:Endothelial Cells / Q000378:metabolism; D005174:Factor XII / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019679:Kininogen, High-Molecular-Weight / Q000378:metabolism; D020842:Plasma Kallikrein / Q000378:metabolism; D011288:Prekallikrein / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000378:metabolism
D000728:Androgens; D003174:Complement C1 Inactivator Proteins; D051056:Complement Inactivating Agents; D018841:HSP90 Heat-Shock Proteins; D019679:Kininogen, High-Molecular-Weight; D043782:Receptor, Bradykinin B2; D005174:Factor XII; D011288:Prekallikrein; D007610:Kallikreins; D020842:Plasma Kallikrein; D001920:Bradykinin