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.

• Authors: Allen P Kaplan, Kusumam Joseph
• Journal: Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology (Ann Allergy Asthma Immunol) Vol. 104 Issue 3 Pg. 193-204 (Mar 2010) ISSN: 1081-1206 [Print] United States
• PMID: 20377108 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Androgens
• Complement C1 Inactivator Proteins
• Complement Inactivating Agents
• HSP90 Heat-Shock Proteins
• Kininogen, High-Molecular-Weight
• Receptor, Bradykinin B2
• Factor XII
• Prekallikrein
• Kallikreins
• Plasma Kallikrein
• Bradykinin

Topics

• Androgens (therapeutic use)
• Angioedemas, Hereditary (drug therapy, metabolism)
• Bradykinin (metabolism)
• Complement C1 Inactivator Proteins (therapeutic use)
• Complement Inactivating Agents (therapeutic use)
• Endothelial Cells (metabolism)
• Factor XII (metabolism)
• HSP90 Heat-Shock Proteins (metabolism)
• Humans
• Kallikreins (antagonists & inhibitors, metabolism)
• Kininogen, High-Molecular-Weight (metabolism)
• Plasma Kallikrein (metabolism)
• Prekallikrein (metabolism)
• Receptor, Bradykinin B2 (metabolism)