The pathogenesis of hereditary angioedema.

Hereditary angioedema (HAE), which is characterized by episodic localized angioedema of the skin or mucosa, results from heterozygous deficiency of the plasma protease inhibitor, C1 inhibitor (C1INH). The most obvious biologic role of C1INH, therefore, is prevention of excessive vascular permeability. A variety of data indicate that this role is primarily a product of regulation of the contact system proteases, factor XIIa and plasma kallikrein. The C1INH deficient mouse, although it does not have episodes of cutaneous angioedema, does have increased vascular permeability which is reversed by treatment with C1INH, with the plasma kallikrein inhibitor, DX88, and with the bradykinin 2 receptor (Bk2R) antagonist, Hoe140. In addition, mice deficient in both C1INH and the Bk2R do not have increased vascular permeability. These analyses strengthen the argument that angioedema is mediated by bradykinin. This mouse also provides a system to test new potential therapeutic approaches. In addition to its role in the regulation of vascular permeability, C1INH also is an important modulator of inflammatory responses via regulation of activation of both the contact and the complement systems, and very likely via activities unrelated to protease inhibition.