Approaches toward reversal of increased vascular permeability in C1 inhibitor deficient mice

C1 inhibitor (C1INH) deficient mice have increased vascular permeability that can be demonstrated by the extravasation of Evans Blue dye. This vascular leak is reversed with protease inhibitors, such as C1INH itself, DX88 (a recombinant variant Kunitz domain plasma kallikrein inhibitor), and the bra...

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Bibliographic Details
Published in:	Immunology letters Vol. 89; no. 2; pp. 155 - 160
Main Authors:	Han Lee, Eun D., Pappalardo, Emmanuela, Scafidi, Jennifer, Davis, Alvin E.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 31-10-2003
Subjects:	Animals C1 inhibitor Capillaries - drug effects Capillaries - metabolism Capillary Permeability - drug effects Capillary Permeability - genetics Capillary Permeability - physiology Complement Complement C1 Inactivator Proteins Complement C1 Inhibitor Protein Contact system Danazol - pharmacology Estradiol - pharmacology Estrogen Antagonists - pharmacology Hereditary angioedema Mice Mutation Serpins - deficiency Serpins - genetics Serpins - metabolism C1 inhibitor Complement Hereditary angioedema Contact system
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Summary:	C1 inhibitor (C1INH) deficient mice have increased vascular permeability that can be demonstrated by the extravasation of Evans Blue dye. This vascular leak is reversed with protease inhibitors, such as C1INH itself, DX88 (a recombinant variant Kunitz domain plasma kallikrein inhibitor), and the bradykinin receptor type 2 antagonist, Hoe140. The studies described here were undertaken for the following reasons: (1) To provide a more quantitative analysis of the effects of these interventions; (2) to provide data to further test the hypothesis that increased vascular permeability results from contact system activation with kallikrein-mediated release of bradykinin; (3) to test the hypothesis that the amino terminal non-serpin domain of C1INH modulates access to complex proteases, such as kallikrein complexed with high molecular weight kininogen (HK); and (4) to determine whether attenuated androgens or estrogens exert a direct effect on C1INH synthesis. To characterize the differences in these reagents, the dose-response and the rate of reappearance of increased vascular permeability in C1INH −/− mice were determined for the following agents: human plasma-derived C1INH, a recombinant Kunitz domain plasma kallikrein inhibitor (DX88), a bradykinin receptor antagonist (Hoe140), and a recombinant C1INH with an amino terminal truncation at amino acid 98 and substitution of the P2 Ala with a Val (Cserp98,A443V). C1INH and Cserp98,A443V were equivalent in activity, which provides further support for the hypothesis that the vascular leak is mediated by bradykinin and suggests that the amino terminal domain neither enhances nor interferes with access to kallikrein within the kallikrein–HK complex. DX88 was effective at very low doses, as was Hoe140. The duration of action of Hoe140 was quite prolonged. The data indicate that, in the mouse, neither danazol nor estrogens have a significant effect on C1INH synthesis.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0165-2478 1879-0542
DOI:	10.1016/S0165-2478(03)00130-5