The bradykinin-forming cascade and its role in hereditary angioedema

Abstract

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.

Data sources: 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.

Study selection: 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.