Biological effects of C1 inhibitor.

C1 inhibitor is a serine proteinase inhibitor (serpin) that regulates activation of both the complement and contact systems. Regulation of complement system activation takes place through inactivation of the classical pathway proteases, C1r and C1s, the lectin pathway protease, MASP2, and perhaps via inhibition of alternative pathway activation by reversible binding to C3b. Regulation of contact system activation takes place through inactivation of plasma kallikrein and coagulation factor XIIa. Deficiency of C1 inhibitor results in hereditary angioedema, which is characterized by recurrent episodes of localized angioedema of the skin, gastrointestinal mucosa or upper respiratory mucosa. A variety of clinical, in vitro and animal experiments indicate that the mediator of increased vascular permeability in hereditary angioedema is bradykinin. Animal models suggest that in addition to its utility in therapy of hereditary angioedema, C1 inhibitor may prove useful in a variety of other diseases including septic shock, reperfusion injury, hyperacute transplant rejection, traumatic and hemorrhagic shock, and the increased vascular permeability associated with thermal injury, interleukin-2 therapy and cardiopulmonary bypass. The therapeutic effect in these disease models very likely results from a combination of complement system activation, contact system activation and perhaps from other activities of C1 inhibitor. These other activities include a direct interaction with endotoxin, which may help to prevent endotoxic shock and an interaction with selectin molecules on endothelial cells, which may serve both to concentrate C1 inhibitor at sites of inflammation and to inhibit the transmigration of leukocytes across the endothelium.