The kallikreinkinin system in human disease and experimental models

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There is increasing evidence for the role of the kallikrein-kinin system in human disease. The kallikrein-kinin system appears to exert a significant effect in various surface-mediated defense reactions including hereditary angioedema (HAE), systemic inflammatory response syndrome (SIRS), previously known as sepsis, cardiopulmonary bypass, rheumatoid arthritis and inflammatory bowel disease. HAE is a congenital condition associated with a deficiency or defect in Cl-INH. Acute attacks of HAE have been well documented to be associated with activation of the kallikrein-kinin system. BK liberation is believed to be a major mediator of the edema seen in this condition. Activation of the kallikrein-kinin system has been postulated to be one of the mediators of SIRS. Historically, studies of patients with SIRS, showed that factor XII, PK and Cl-INH were decreased. However, whether activation of the contact system was an early event or a result of complications associated with SIRS was not demonstrated until recently in studies with human normal volunteers given a low dose of E. coli endotoxin. Functional prekaliikrein levels were significantly lower in the endotoxin group compared with controls as early as 2 h after infusion and remained lower throughout the rest of the experimental protocol (24 h). In an established experimental baboon model of SIRS, irreversible hypotension correlated with activation of the kallikrein-kinin system. Furthermore, treatment with a monoclonal antibodv directed against human factor XII which is able in vitro to inhibit its autoactivation, prevented the irreversible lethal hypotension induced by E. coli in this experimental animal model of SIRS.

Clinical cardiopulmonary bypass (CPB) is performed on over 350 000 Americans each year. During CPB, there is an extensive contact between blood anticoagulated with heparin and the synthetic surface of the extracorporeal circuit. In simulated CPB there is a significant increase in kallikrein-Cl-lNH complex formation. Further studies have demon strated that aprotinin, an inhibitor of both plasmin and plasma kallikrein, reduced blood loss after cardiac operations and decreased the elevated postoperative bleeding time. In a simulated extracorporeal bypass model, in which no plasmin is found, aprotinin decreased both kallikrein-Cl-INH and CI-CI INH complexes, resulting in a marked inhibition of the release of neutrophil elastase.

The role of the kallikrein system in inflammatory arthritis has been investigated in a model of acute and chronic relapsing arthritis induced by intraperitoneal injection of proteoglycan-polysaccharide from group A streptococci (PG-APS) into Lewis rats. In this model, PK and HK functional levels were significantly decreased. There was a striking inverse correlation between functional HK concentration and joint enlargement. Further experiments showed in this experimental animal model that rats injected with PG-APS receiving orally a potent plasma kallikrein inhibitor (P8720 or Bz-Pro-Phe-boro-Arg-OH, K{ = 0.15 nM) had a significant decrease (61%) in joint swelling with a disappearance of most of the dense neutrophil infiltration and mononuclear cells observed in animals not receiving P8720. The beneficial aspect of P8720 in this experimental animal model could be explained in part by prevention of BK generation from HK by the action of plasma kallikrein.

BK effects its changes in the intramuscular compartment by binding to at least two receptors, the B1 and the B2 receptors. Both of these receptors are G-coupled and this binding of BK stimulates cellular signal transduction. Further studies employing this experimental animal model of acute and chronic relapsing arthritis have shown a beneficial effect when a B2 receptor antagonist was administered to the rats. Interestingly, a deleterious effect was noticed when either therapy with B1 receptor antagonist or a combined B1-B2 receptor antagonist was used. In a similar model of Crohn's disease, P8720 inhibited both acute and chronic gross and histological features including edema, granuloma formation as well as the systemic manifestation of splenomegaly, leukocytosis, anemia and the acute phase reaction.

See also: Asthma; Atopic allergy; Clotting system; Histamine; Prostaglandins.

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Treating Rheumatoid Arthritis With Herbs Spices Roots

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