kaolinite and Angioedema

Topics: Alpha-Globulins; Angioedema; Antigen-Antibody Reactions; Blood Coagulation; Bradykinin; Carcinoid Tumor; Cell Membrane; Contact Inhibition; Enzyme Activation; Factor XII; Fibrinolysis; Humans; Hyperemia; Kallikreins; Kaolin; Kinins; Muscle, Smooth; Peptide Hydrolases; Peptides; Plasminogen; Trypsin

The first component of complement (C1) inhibitor plays a critical role in the regulation of the classical complement pathway and the contact system, and the deficiency of C1 inhibitor protein or function is associated with recurrent angioedema. In this study we evaluated the size of the C1 inhibitor antigens present in the plasmas of C1 inhibitor-deficient patients. We found that the C1 inhibitor in the plasmas existed in three forms: high molecular weight forms in complex with proteases, native 110-kD C1 inhibitor, and a modified inactive 94-kD form. The proportion of the total C1 inhibitor in the 94-kD form was 28% in nine hereditary angioedema patients, 92% in five acquired C1 inhibitor-deficiency patients, and 1.2% in five normal controls. In vitro activation of normal plasma with kaolin, but not heat-aggregated gamma-globulin generated 94-kD C1 inhibitor from 110-kD C1 inhibitor. Neither kaolin activation nor heat-aggregated gamma-globulin activation generated 94-kD C1 inhibitor in Hageman factor-deficient plasma. These results suggest that 94-kD C1 inhibitor is generated in vitro by activation of the contact system. The in vivo mechanism of 94-kD C1 inhibitor generation in C1 inhibitor-deficient patients is not known.

Topics: Angioedema; Collodion; Complement Activation; Complement C1 Inactivator Proteins; Complement Pathway, Classical; Electrophoresis, Polyacrylamide Gel; Humans; Kaolin; Molecular Weight

An enzyme-linked immunosorbent assay (ELISA) has been developed for the quantification of C1 inactivator-kallikrein (C1In-K) complexes. The formation of complexes assayed by this method parallelled the inhibition of plasma kallikrein esterase activity by C1 inactivator in purified systems. C1In-K complexes were detected when a final concentration of 5.7 nM plasma kallikrein was added to plasma, equivalent to the activation of 1% of the plasma prekallikrein. Exogenous Hageman factor fragment added to plasma induced the rapid formation of C1In-K complexes, whereas there was an appreciable delay when the plasma contact system was activated by the addition of kaolin. In both systems, the rate of formation and final amount of complex generated were directly related to the concentration of Hageman factor fragment or of kaolin added, indicating that this proteolytic pathway is tightly regulated. C1In-K complexes were not generated by kaolin in plasma congenitally deficient in Hageman factor or prekallikrein or by kallikrein in hereditary angioedema plasma deficient in C1 inactivator, thus confirming the specificity of the assay. Sucrose gradient ultracentrifugation studies showed plasma C1In-K complexes to have a molecular weight consistent with a 1:1 molar complex. In contrast, the complex displayed an anomalously high molecular weight on gel filtration chromatography. These data demonstrate that a sensitive and specific probe has been developed for documenting plasma kallikrein activation.

Topics: Angioedema; Centrifugation, Density Gradient; Chromatography, Gel; Complement C1 Inactivator Proteins; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Factor XII; Humans; Immunoenzyme Techniques; Kallikreins; Kaolin; Peptide Fragments; Prekallikrein

Activation of plasma kallikrein arginine esterase activity by kaolin resulted in peak activity at 1 min of incubation and a 50% reduction in activity at 5 min in normal plasma, and 30% reduction in the plasma of patients with hereditary angioneurotic edema who lacked the C1 inactivator. The peak esterolytic activity was inhibited by soybean trypsin inhibitor whereas the 5 min activity was resistant to this inhibitor. Acid treatment of normal and hereditary angioneurotic edema plasma destroyed the factor responsible for the fall in esterase activity at 5 min and the factor which rendered the esterase resistant to soybean trypsin inhibitor. Purified alpha(2)-macroglobulin inhibited approximately 50% of the TAMe esterase activity of purified plasma kallikrein without changing its activity toward basic amino acid esters. The interaction between the alpha(2)-macroglobulin and kallikrein resulted in alterations in the gel filtration chromatographic pattern of the TAMe esterase and biologic activity of kallikrein, indicating that kallikrein was bound to the alpha(2)-macroglobulin. The TAMe esterase activity of this complex, isolated by column chromatography, was resistant to C1 inactivator and SBTI. Studies of incubation mixtures of kallikrein, alpha(2)-macroglobulin and C1 inactivator suggested that these inhibitors compete for the enzyme, and that the alpha(2)-macroglobulin partially protects the esterase activity of kallikrein from C1 inactivator. The alpha(2)-macroglobulin isolated from kaolin-activated plasma possessed 240 times the esterolytic activity of the alpha(2)-macroglobulin purified from plasma treated with inhibitors of kallikrein and of its activation. The alpha(2)-macroglobulin blocked the uterine-containing activity and vascular permeability-inducing effects of plasma kallikrein. These studies suggest that the alpha(2)-macroglobulin is a major plasma inhibitor of kallikrein and provide a new example of an interrelationship between the coagulation, fibrinolytic, and kallikrein enzyme systems.

Topics: Alpha-Globulins; Angioedema; Aprotinin; Arginine; Blood Coagulation; Capillary Permeability; Chemical Phenomena; Chemistry; Chromatography; Chromatography, Gel; Complement System Proteins; Culture Techniques; Electrophoresis; Esterases; Factor XI Deficiency; Female; Humans; Hydrochloric Acid; Immunodiffusion; Immunoelectrophoresis; Kallikreins; Kaolin; Kinins; Macroglobulins; Uterus

Topics: Adult; Angioedema; Arginine; Enzyme Activation; Enzyme Precursors; Esterases; Estrogens; Factor XII; Female; Humans; Hypersensitivity; Kallikreins; Kaolin; Kinins; Liver Diseases; Male; Malignant Carcinoid Syndrome; Middle Aged; Pancreatitis; Shock, Septic

Topics: Acids; Alcoholism; Angioedema; Aprotinin; Arginine; Bradykinin; Carcinoid Tumor; Chemical Phenomena; Chemistry; Esterases; Esters; Factor XII; Humans; Kallikreins; Kaolin; Liver Cirrhosis; Methane