Molecular Mechanisms in Allergy and Clinical ImmunologyPathways for bradykinin formation and inflammatory disease☆,☆☆,★
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The surface
In vitro studies have typically been done with nonphysiologic substances, such as glass (negatively charged silicates activate the intrinsic coagulation cascade to clot the blood and bradykinin is formed), kaolin, and dextran sulfate. The physiologic surface, however, may be assembly of the cascade along the surface of endothelial cells, and pathologic initiators can include proteoglycans (sulfate residues on heparan sulfate or chondroitin sulfate), endotoxins (LPS), or crystals of uric acid or
Factor XII (Hageman factor)
Factor XII circulates as a single-chain zymogen (proenzyme) with no detectable enzymatic activity. Its molecular weight is 80 kd on SDS gel electrophoresis. It is synthesized in the liver and circulates at a plasma concentration of 30 to 35 μg/mL. During contact activation of normal plasma, factor XII autoactivates when bound to polyanionic surfaces, with conversion of factor XII to factor XIIa.5, 6 Once small amounts of kallikrein are formed, however, there is rapid conversion of surface-bound
Prekallikrein
Like factor XII, prekallikrein is a zymogen without detectable activity, which is converted to a functional serine protease during contact activation. SDS gel electrophoresis of purified prekallikrein yields 2 bands at 85 and 88 kd, regardless of the source.7 Activation is accomplished with either factor XIIa or factor XIIf and results in disulfide-linked 2-chain forms composed of a heavy chain of 56 kd and a light chain bearing the catalytic center. The heterogeneity shown by the zymogen is
Factor XI
Like factor XII and prekallikrein, factor XI is a zymogen that is activated to a serine protease during contact activation. Factor XI is unique among the clotting factors in that the circulating zymogen consists of 2 identical subunits linked by a disulfide bond.8, 9 The dimer has an apparent molecular weight of 160 kd on SDS gel electrophoresis. The major activator of factor XI is factor XIIa; however, thrombin also serves as an activator, particularly when factor XI is incorporated into a
High-molecular-weight kininogen
HK circulates as a single-chain glycoprotein with an apparent molecular weight of 200 kd by means of gel filtration and 115 kd by means of SDS gel electrophoresis under reducing conditions.10, 56 It circulates at a plasma concentration of 70 to 90 μg/mL and forms a noncovalent complex with prekallikrein and a similar complex with factor XI.10, 11 During contact activation, plasma kallikrein digests HK, leaving a disulfide-linked heterodimer consisting of an amino terminal heavy chain (65 kd)
Interaction of proteins and surfaces in initiation of contact activation
Surfaces that initiate activation of the plasma bradykinin-forming pathway include glass, dextran sulfate, sulfatides, endotoxin, and naturally occurring proteoglycans containing highly sulfated mucopolysaccharides such as heparan sulfate, chondroitin sulfate E, or mast-cell heparin.69, 70 The requirement for a high density of strong negative charges is suggested by the finding of a relationship between the rate of factor XII autoactivation and the sulfate content of a series of dextran sulfate
Binding to cell surfaces
Schmaier et al79 and Van Iwaarden et al80 first demonstrated that HK binds to endothelial cells and platelets in a zinc-dependent reaction. These data were soon confirmed, and both heavy and light chains of HK were shown to be responsible for binding.81 Ultimately, the site of binding was shown to be within domains 3 and 5 of HK (ie, domain 3 is the site of heavy-chain binding and domain 5 the site of light-chain binding).82, 83 The amino acid sequence of the peptides within the domains were
Activation along the cell surface
The addition of factor XII, HK, and prekallikrein to HUVECs leads to activation of all of the components (ie, conversion to factor XIIa, kallikrein, and generation of bradykinin). Thus it would appear to be similar to traditional contact activation, although much slower.86 We could demonstrate autoactivation of factor XII on binding to cloned gC1qR,104 thus providing an initiation mechanism, and sulfated proteoglycans could behave similarly. When we tested whole plasma rather than purified
Kinins and C1 inhibitor deficiency
C1 inhibitor is the sole plasma inhibitor of factor XIIa and factor XIIf,110, 111 and it is one of the major inhibitors of kallikrein,112 as well as factor XIa.113 Thus in the absence of C1 inhibitor, stimuli that activate the kinin-forming pathway will do so in a markedly augmented fashion; the amount of active enzyme and the duration of action of the enzymes are prolonged. C1 inhibitor deficiency can be familial, in which there is a mutant C1 inhibitor gene, or it can be acquired. Both the
Kinins and ace inhibition
Severe angioedema often involving the face, tongue, or both is seen as a complication of the use of ACE inhibitors. It appears that this swelling is also a consequence of elevated levels of bradykinin133; however, the accumulation of bradykinin is due to a defect in degradation rather than an excessive production. ACE, being identical to kininase II, is the major enzyme responsible for bradykinin degradation (Fig 1), and although it is present in plasma, the vascular endothelium of the lung
Kinins and allergic rhinitis
Early studies suggested activation of the plasma bradykinin-forming cascade in allergic rhinitis on the basis of the finding of tosylarginine methyl ester esterase activity in the secretions, which is indicative of production of plasma kallikrein.141 Assessment of kinins by means of HPLC demonstrated the presence of both lysyl bradykinin and bradykinin during both the immediate phase and the late phase of allergen-induced rhinitis.142, 143 The presence of lysyl bradykinin indicated release of
Bradykinin and asthma
Kinins are present in bronchoalveolar lavage fluid. Early studies demonstrated the presence of tissue kallikrein in the bronchoalveolar lavage fluid,147 but there has been no definitive assessment of the plasma bradykinin-forming cascade in bronchoalveolar lavage fluids or within lung parenchyma. Bradykinin challenge of asthmatic subjects leads to symptomatic and physiologic changes similar to those seen in the natural disease,148 and allergen challenge of asthmatic subjects leads to an
Bradykinin and anaphylaxis
The hypotension of anaphylaxis is clearly multifactorial, including the effects of multiple vasoactive mediators leading to hypovolemia and edematous tissues. Bradykinin is certainly one of those capable of causing hypotension, and one study of insect-sting anaphylaxis demonstrated 100% cleavage of HK concomitant with changes in blood coagulation and fibrinolytic parameters indicative of disseminated intravascular coagulation.155 Thus massive release of bradykinin seems likely, although kinin
Bradykinin formation
The mechanism of bradykinin formation in any IgE-mediated reaction is multifactorial, including not only tissue kallikrein secretion, as noted above, but direct activation of the plasma cascade by secreted heparin,156, 157, 158 activation along the surface of endothelial cells, or exposure to connective tissue proteoglycans. Any local dilution of plasma constituents decreases the effect of protease inhibitors and leads to an increased rate of the enzymatic reactions to augment kinin formation.
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Cited by (0)
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Reprint requests: Allen P. Kaplan, MD, Medical University of South Carolina, Department of Medicine, Division of Pulmonary/Allergy, 96 Jonathan Lucas St, PO Box 250623, Charleston, SC 29425.
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(Supported by a grant from Merck & Co, Inc, West Point, Pa)
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Series editor: Lanny J. Rosenwasser, MD