The kinins, bradykinin and lysylbradykinin, are important mediators of inflammatory responses. They are liberated from precursor molecules, kininogens, by the action of various proteases, collectively known as kininogenases. Three types of kininogen have been identified: high- and low-molecular weight kininogen (HMWK and LMWK respectively), and T-kininogen. These molecules are synthesized by hepatocytes and are released into the plasma, where in addition to releasing kinins, they function as (i) cofactors in the coagulation pathway; (ii) inhibitors of cysteine protease enzymes; and (iii) part of the acute phase response. The kinins are potent vasoactive basic peptides and their properties are wide ranging, including the ability to increase vascular permeability, cause vasodilation, pain, and the contraction of smooth muscle, and to stimulate arachidonic acid metabolism.
Three different pathways may lead to kinin formation during inflammation: (i) the generation of bradykinin as a result of activation of the Hageman factor and the production of plasma kallikrein; (ii) the production of lysylbradykinin by tissue kallikreins; and (iii) the action of cellular proteases in kinin formation.
The mechanism of bradykinin formation in plasma and in tissues is summarized in Figure 1.4.
Figure 1.4:
The kinin pathway forming bradykinin
In brief, HMWK and prekallikrein circulate in plasma as a 1:1 stoichoimetric complex. This complex, together with the Hageman factor, binds to negatively charged surface or collagen. Once they are exposed by tissue damage, the Hageman factor is activated, prekallikrein is converted to kallikrein, and HMWK itself is digested to release bradykinin, a nine amino acid peptide.
As bradykinin is such a potent vasoactive peptide, its
activity and its formation must be carefully controlled.
Activation of the pathway is controlled internally by the presence
of inhibitors for each of the active components. C1 inhibitor
controls the activity of the activated Hageman factor, while
-macroglobulin and C1 inhibitor act as kallikrein inhibitors.
There are a variety of enzymes in plasma that control bradykinin
activity, including carboxypeptidase N, which removes the
C-terminal arginine residue, thus inactivating the peptide.
Kallikrein also act directly on the complement pathway with direct cleavage of the chemotactically active peptide C5a from the complement component C5. Cleavage of fibrinogen by plasmin results in a number of products including fibrinopeptide B, which potentiates the action of bradykinin and has also chemotactic activity for phagocytic cells.