Journal Article•
Inhibition of activated Hageman factor and activated plasma thromboplastin antecedent by purified serum C1 inactivator.
01 Nov 1970-Journal of Laboratory and Clinical Medicine (J Lab Clin Med)-Vol. 76, Iss: 5, pp 809-815
About: This article is published in Journal of Laboratory and Clinical Medicine.The article was published on 1970-11-01 and is currently open access. It has received 210 citations till now. The article focuses on the topics: Factor XI.
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TL;DR: The kallikrein-kinin system was first recognized as a plasma and tissue proteolytic system responsible for the liberation of the vasoactive, proinflammatory mediator, bradykinin (BK).
584 citations
TL;DR: It appears that immune complex dependent activation is not under positive host regulation, but C1 activation by small immune complexes or complexes formed with nonavid antibody or with ratios of antigen to antibody far from equivalence, all of which are poor C1 activators, may well be regulated by C1-In.
Abstract: Publisher Summary This chapter focuses on the activation and regulation of the first complement component. . The chapter outlines the history of the classical pathway of the complement system. Clq and C1 are bound and activated by immune complexes or aggregates containing IgG or IgM but not by those containing IgA, IgD, or IgE . Among IgG subclasses, IgG3 is most reactive followed by IgG1, and IgG2; intact IgG4 is minimally reactive, although its Fc region binds C1. C1-In does not efficiently regulate C1 activation induced by immune complexes. It, thus, appears that immune complex dependent activation is not under positive host regulation. This is apparently largely true. However, C1 activation by small immune complexes or complexes formed with nonavid antibody or with ratios of antigen to antibody far from equivalence, all of which are poor C1 activators, may well be regulated by C1-In.
473 citations
TL;DR: Should these compounds prove effective in vivo, they could be used in conjunction with currently available assays for kallikreins, kininogens, kinins, and their various inactivated or degraded products, to provide new insights into the role of these systems in the pathogeneses of inflammatory diseases.
Abstract: Although considerable progress has been made in elucidating the molecular events occurring during kinin generation by both the plasma kinin-forming system and the tissue kallikrein system, it is only in recent years that we have come to appreciate their potential role in inflammation in a wide variety of diseases. The importance of the tissue kallikrein system depends upon secretion of the active form of the requisite enzyme in the presence of a source of kininogen. Since tissue kallikreins are widely distributed in tissues, and since lymph and interstitial fluid contains kininogen (271), a local milieu for potential kinin formation is always present. The plasma system will be activated secondary to inflammation initiated by some other process. There may be endothelial or epithelial damage exposing connective tissue. Plasma leakage caused by release of some other permeability factor (including kinin made by tissue kallikrein) would thus lead to activation of the plasma cascade in many forms of inflammation. As with all mediators, however, the contribution of kinins to an inflammatory response can only be definitively evaluated if their actions can be selectively antagonized. Competitive receptor antagonists have recently been synthesized (228) and will, we hope, soon be available for administration to humans. Should these compounds prove effective in vivo, they could be used in conjunction with currently available assays for kallikreins, kininogens, kinins, and their various inactivated or degraded products, to provide new insights into the role of these systems in the pathogeneses of inflammatory diseases.
406 citations
TL;DR: The hypothesis that angioedema is mediated by bradykinin via Bk2R is supported, as both homozygous and heterozygous C1INH-deficient mice revealed increased vascular permeability in comparison with wild-type littermates.
Abstract: Heterozygosity for C1 inhibitor (C1INH) deficiency results in hereditary angioedema. Disruption of the C1INH gene by gene trapping enabled the generation of homozygous- and heterozygous-deficient mice. Mating of heterozygous-deficient mice resulted in the expected 1:2:1 ratio of wild-type, heterozygous, and homozygous-deficient offspring. C1INH-deficient mice showed no obvious phenotypic abnormality. However, following injection with Evans blue dye, both homozygous and heterozygous C1INH-deficient mice revealed increased vascular permeability in comparison with wild-type littermates. This increased vascular permeability was reversed by treatment with intravenous human C1INH, with a Kunitz domain plasma kallikrein inhibitor (DX88), and with a bradykinin type 2 receptor (Bk2R) antagonist (Hoe140). In addition, treatment of the C1INH-deficient mice with an angiotensin-converting enzyme inhibitor (captopril) increased the vascular permeability. Mice with deficiency of both C1INH and Bk2R demonstrated diminished vascular permeability in comparison with C1INH-deficient, Bk2R-sufficient mice. These data support the hypothesis that angioedema is mediated by bradykinin via Bk2R.
354 citations
351 citations