Research Review
Kallikrein-Kinin System: A Surgical Perspective in Post-Aprotinin Era

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Kallikrein-kinin system (KKS) plays an important role in inflammation, ischemia-reperfusion (IR) injury, and development of neoplasia. There is evidence to suggest that KKS plays an important role in organ protection during preconditioning. Aprotinin is a nonspecific serine protease inhibitor, which has been extensively used in cardiac surgery for the control of post operative bleeding. The anti-inflammatory effects of aproprotin are due to its inhibitory effect on the kallikrein-kinin system (KKS). We herein review KKS and its role as applied to the practice of surgery.

Introduction

Aprotinin was first discovered by Kraut et al. in 1930 in bovine lymph nodes, and subsequently by Kunitz and Northrop in 1936 in bovine pancreas 1, 2. Royston and co-workers in 1987 accidentally discovered that aprotinin could be used to reduce bleeding in patients undergoing cardiac surgery when used in high doses [3]. Aprotinin is a nonspecific serine protease inhibitor and is derived from bovine lung. Being a serine protease inhibitor, aprotinin inhibited plasmin as well as both plasma and tissue kallikreins. The lysine residue at position 15 in the aprotinin molecule binds to the active serine residue in proteases and forms an inactive complex. The anti-inflammatory effects of aproprotin are due to its inhibitory effect on the kallikrein-kinin system (KKS).

Until recently, aprotinin has been widely used in high-risk cardiac surgery patients to reduce bleeding and decrease systemic inflammatory response. Exposure of blood to extracorporeal circulation causes activation of the intrinsic pathway of coagulation, fibrinolysis, KKS, and complement system. Activation of these cascades produces systemic inflammatory response. Kinins have a close relationship to the coagulation cascade; they activate factor XII and stimulate fibrinolysis via plasminogen activators 4, 5. Plasmin mediated fibrinolysis is suppressed by aprotinin as assessed by lower levels of fibrin degradation and d-dimer products in patients treated with aprotinin during cardiac surgery 5, 6.

However, due to the controversy surrounding an apparent increase in the number of thrombotic complications 7, 8, 9, aprotinin has been removed from the market. A thorough knowledge of KKS and its protective role against ischemia reperfusion (IR) injury would be beneficial in avoiding future pitfalls and utilization of full benefits of the native protective pathways.

Section snippets

Kallikrein-Kinin System

KKS plays an important role in inflammation, ischemia-reperfusion (IR) injury, and development of neoplasia. Furthermore, it is now becoming apparent that KKS may play a central role in organ protection against IR injury. KKS is ubiquitously involved in renin-angiotensin system, coagulation cascade, and complement activation pathways. Kinins are formed by plasma and tissue kallikreins. Kallikreins convert kininogens to produce vasoactive kinin peptides, bradykinin (BK) and lys-bradykinin

KKS and Renin-Angiotensin-Aldosteron System

Renin is an enzyme secreted by juxtaglomerular (JG) cells located in the afferent arteriole of glomerulus. Angiotensinogen is synthesized in liver and circulates in plasma. Renin acts on angiotensinogen to form angiotensin I. Angiotensin converting enzyme (same as Kininases II) converts angiotensin I to angiotensin II. Angiotensin II produces powerful vasoconstriction. This can cause significant rise in systolic and diastolic blood pressure. Angiotensin converting enzyme inhibitors (ACEI)

KKS and Inflammation

Tissue injury, ischemia, or infections initiate chemotactic migration of neutrophils that produce the beneficial and harmful effects of inflammation. There is a rapid generation of kinin following tissue injury. Kinins produce vasodilatation, increase capillary permeability, cause chemotaxis, and produce the associated pain response 24, 25. Both the kinin receptors seem to be involved in the inflammatory response.

A high level of B1 receptor endogenous agonists has an important role in causing

KKS and Cardiovascular System

KKS is directly involved in a number of physiologic and pathophysiologic processes involving cardiovascular system that include hypertension, left ventricular hypertrophy, cardiac failure, and myocardial ischemia 37, 38, 39, 40, 41, 42, 43, 44, 45. Hypertension, myocardial ischemia, and myocardial hypertrophy are associated with a low activity of KKS pathway and up regulation of B1 and B2 receptors. Local and systemic administration of BK can increase coronary blood flow and improve myocardial

KKS in Neoplasia

The development of neoplasms involves multiplication and abnormal growth of cells, infiltration of malignant cells into the normal surrounding tissues, and development of metastasis. Tissue kallikrein and plasma kallikrein are distributed in a wide variety of cells throughout the body as a part of KKS. We have previously investigated the link between neoplasia and KKS 69, 70, 71. Kinins acting via B1 and B2 receptors cause the proliferation and migration of cells 10, 72. Expression and

Common Pathways in Neoplasia and Protection Against Ischemia-Reperfusion Injury

PI3K pathway is involved in the development and growth of malignant cells and facilitates cancer cells to be resistant to apoptosis. Inhibition of epidermal growth factor receptors caused apoptosis of malignant mesothelioma cells in mesothelioma cells lines [77]. This effect was related to the down-regulation of PI3K signalling pathway. Protection of cardiomyocytes exposed to lethal ischemia following IPC is also via PI3K pathway [78]. Cellular protection from BK is dependent on the opening of

Summary

The KKS pathway has an important role in normal physiology and is involved in a number of important pathologic processes. It is possible that the observed increase in myocardial infarction and stroke with aprotinin use was at least in part due to inhibition of KKS and, thus, lead to a loss of the protective effects of kinins against IR injury. Selective modulation of KKS may be useful in protecting against IR injury in various clinical scenarios and in treating certain malignancies.

Acknowledgment

This study was supported by the National Health and Medical Research Council of Australia (NHMRC), project grant 557507.

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