Biology, embryology, histopathology, and pathology of the tissues that constitute multicellular organisms.

kinin system

The kinin system, or kinin-kallikrein system, or kininogen-kallikrein-kinin system plays a role in inflammation, coagulation, sodium homeostasis, sensations of pain, cardioprotective effects of preconditioning, and control of blood pressure. K-k-k mediators induce vasodilation, prostaglandin biosynthesis, tissue remodeling through regulation of proteases, and pathophysiologies. The kallikrein-kinin system is complex, with several bioactive peptides that are formed in many different compartments.

high-molecular weight kininogen (HMWK)
low-molecular weight kininogen (LMWK)
● T-kininogen (in rats)
vasoactive peptides
bradykinin (BK),
kallidin (KD)
[des-Arg] kinins and B1 receptors
___actions mediated through autacoids such as eicosanoids, NO, and endothelium-derived hyperpolarizing factor
___ ● hydrolyzed by a group of kininase peptidases (diagram)
kinin receptors (GPCR)
B1 and B2
kininogenase enzymes
kininase enzymes
kininase I
angiotensin converting enzyme (ACE, or kininase II)
carboxypeptidase N
neutral endopeptidase

● produced predominantly in liver (HMWK), also locally in other tissues (LMWK)
● produced by alternative splicing of a single gene product
● release kinins upon protease hydrolysis by kininogenases
cofactors in coagulation pathway
● inhibit cysteine protease enzymes
● participate in inflammatory acute phase response

Tissue and plasma kallikreins are serine proteases that liberate vasoactive-peptide kinins (BK and KD) from the kininogens. Kallikreins are synthesized in vascular tissue and the liver. HMKW has no intrinsic catalytic activity, acts as a cofactor for coagulation and inflammation, and yields the nonapeptide bradykinin upon plasma kallikrein lysis. LMWK is produced locally in many tissues, and releases the decapeptide kallidin (KD) on lysis by tissue kallikrein. Bradykinin peptides can also be generated by aminopeptidase-mediated cleavage of kallidin peptides. Trypsin, plasmin, and some snake venoms release kinins. (diagram)

In immune and inflammatory responses, factor XIIa is activated by charged surfaces (bacterial lipopolysaccharide, oligosaccharides, connective tissue proteoglycans, or damaged basement membranes). In the presence of factor XIIa, pre-kallikrein (PK) is cleaved to plasma kallikrein which acts upon HMWK to release the vasoactive nonapeptide, bradykinin. Plasma kallikrein also converts inactive factor XII to active XIIa, participating in a positive feedback loop. The cleavage of bradykinin from HMWK is highly localized since pre-kallikrein and substrate (HMWK) circulate as a complex.

Bradykinin (BK) is has the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg, and various kininases attack different amino acid positions.(diagram) The decapeptide kallidin has the sequence Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg, which is equivalent to bradykinin with an extra amino acid (lysine) in the number one position.

Kallidin, or Lys-bradykinin, is released by the action of tissue kallikrein on LMWK. Tissue kallikrein is found in many tissues, either as the active enzyme or as a precursor requiring activation. Unlike plasma kallikrein, which acts upon HMWK as preferred substrate, tissue kallikrein can release kallidin from either HMWK or LMWK. Kallidin can subsequently be converted directly into bradykinin through the action of aminopeptidases present in both the plasma and on the surface of epithelial cells.

Kinins act via type 1 (B1) or type 2 (B2) kinin receptors. (diagram). The B2 receptor normally predominates, whereas B1 receptors are induced by tissue injury (myocardial ischaemia, inflammation). Bradykinin acts on the B receptors: B2 >> B1.

Almost all cells express GPCR-type kinin receptors, which mediate the activities of both bradykinin and kallidin. Receptor stimulation causes:
● increased vascular permeability
● relaxation of venular smooth muscle
● hypotension
● contraction of intestinal smooth muscle
● contraction of smooth muscle in airways (increasing airway resistance)
● stimulation of sensory neurons (pain)
● alteration of ion secretion by epithelial cells
● production of nitric oxide
● release of cytokines by leukocytes
● release of eicosanoids from various cell types.

Because they elicit such a broad spectrum of activity, kinins have been implicated in many pathophysiologies including pain, sepsis, asthma, symptoms associated with rhinoviral infection, rheumatoid arthritis, and a wide variety of other inflammatory diseases.

Both bradykinin and kallidin can be degraded by a variety of plasma and cell surface enzymes (kininases), the commonest of which are kininase I, kininase II (angiotensin converting enzyme, ACE), and carboxypeptidase N. In the plasma, kininase I forms [des-Arg] kinins by cleaving the C-terminal arginine from both bradykinin and kallidin. The [des- Arg] kinins act as agonists of B1 receptors (in some species) and have been implicated in the pathophysiology of chronic inflammation.

Towards understanding the kallikrein-kinin system: insights from measurement of kinin peptides. Campbell DJ. Braz J Med Biol Res. 2000 Jun;33(6):665-77. [Free Full Text Article]



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