ABSTRACT
The plasma kinin-forming system consists of three essential proteins that interact in a complex fashion once bound to certain negatively charged inorganic surfaces, or to a macromolecular complex formed during an inflammatory response, or bound to proteins along cell surfaces. These are coagulation factor XII (Hageman factor, HF), prekallikrein, and highmolecular-weight kininogen (HK). Once factor XII is activated to factor XUa it converts prekallikrein to kallikrein and kallikrein digests HK to liberate bradykinin. Factor Xiia has a second substrate in plasma; namely, coagulation factor XI and activation of surface bound factor XI by factor Xiia initiates the intrinsic coagulation pathway. Thus the interactions of all four of these proteins are known as contact activation and the formation of bradykinin is therefore a cleavage product of the initiating step of the cascade (Fig. I) (I). There is also a tissue pathway (2) by which bradykinin is generated in which there is intracellular conversion of prokallikrein to tissue kallikrein by enzymes that are not yet well characterized. Tissue kallikrein is secreted into the local milien where it digests low-molecular-weight kininogen (LK) to generate Iysyl-bradykinin (kallidin) and an aminopeptidase converts kallidin to bradykinin. The bradykinin that is produced by either pathway is then degraded by plasma enzymes as well as enzymes that are active along the surface of endothelial cells (particularly pulmonary vascular endothelial cells) to lower-molecular-weight peptides. The major
Figure 1 The contact activation pathway leading to bradykinin formation. (From Silverberg M, Reddigari SR, Kaplan AP. The contact system and its disorders. In: Handin SI, Lux S, Stossel TP, eds. Blood, Principles and Practice. Chapter 38, Philadelphia Lippincott, 1995: 1127-1150.)
plasma enzyme is carboxypeptidase N (3). This removes the C-terminal arginine from bradykinin to yield an eight amino acid peptide (des-arg-9 bradykinin) (4). The second kininase in plasma is termed kininase II and is identical to angiotensin-converting enzyme (5). Thus is this enzyme that predominates along the pulmonary vascular endothelial cell surface. Bradykinin is thereby rapidly degraded within one or two circulation times. This enzyme removes the dipeptide phe-arg from the C-terminus of bradykinin to yield a heptapeptide and a second cleavage removes ser-pro to leave a penta peptide (6). Bradykinin acls on the B2 receptor on the surface of endothelial cells to cause vasodilatation and to increase vascular permeability. Other vasodilators such as nitric oxide are produced secondarily as a result of a B2 receptor stimulation (7). Des-arg-9 bradykinin, the product of carboxypeptidase N, is predominantly active upon BI receptors (8). These latter receptors, in contrast to B2 receptors, are not consititively produced but are induced as a result of inflammation due to the presence of cytokines such as interleukin I and tumor neurosis factor-a (TNF a) (8,9). The heptapeptide and pentapeptide products of kininase II (ACl) are inactive. A schematic diagram of the formation and degradation of bradykinin is shown in Fig. 2. Table I summarizes some of major physical chemical properties of the various proteins of the contact activation cascade.
