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Introduction

Plasma cascade systems with emphasis on the role of C1-inhibitor

Kallikrein-kinin system
The plasma proteins involved in the kallikrein-kinin system are the proenzymes prekallikrein, factor XII (FXII or Hagemann factor), and the non-enzymatic co-factor high molecular weight kininogen (HK) (Fig. 7).

Fig. 7. The conversion of zymogen to enzyme are represented by arrows. Complexed HK is depicted as a circle. Names in italic and the fork like symbol depicts inhibition. A shaded area is drawn to portray the activating surface.

FXII autoactivates in the presence of negatively charged macromolecules like proteoglycans. Activated factor XII (FXIIa) then converts prekallikrein to kallikrein, which in turn digest HK to release bradykinin. Bradykinin binds to receptors on nearby endothelial cells which liberates vasoactive prostaglandins or nitric oxide, resulting in e.g. vasodilatation and increased capillary permeability. Bradykinin is also a potent inducer of uterine smooth muscle contractions in rodents and primates (148). Bradykinin is composed of nine amino acids and is extremely potent. Its half-life is just a few seconds, which makes a reliable direct detection in plasma samples difficult and indicates a primary local role of this peptide (149). However, when HK liberates bradykinin, a cleaved form of HK is formed which migrates differently in electrophoresis. It can thus be visualised on immunoblots.

This indirect detection of bradykinin release has been applied in this thesis (150). As bradykinin participate in inflammation a variety of clinical conditions are likely to be modulated by the kallikrein kinin system. In some of these, however, bradykinin seem to have a more important role, as e.g. in the invasive growth of tumors (151) and bacterial spread (14th International Symposium on Kinins, Denver, CO, 1995 = "KININ 95", C60), in asthma (152,153), in mediating the effects of snake poison (154) (KININ 95, C43), in the regulation of blood-pressure (155-157) and blood-glucose (158-160), in acute pancreatitis (161), in septic states (162-166), in the edema of the brain (167-170) and in the capillary leakage following cardiopulmonary bypass (171-176) (KININ 95, C20).

Angiotensin converting enzyme (ACE) has a major role in degrading bradykinin. Thus, the actions of this enzyme go far beyond liberating angiotensin II from angiotensin I. Its very wide distribution in the body and its activity in vitro in fact indicate involvement in the metabolism of several biologically active peptides, among whom bradykinin seems to be pivotal (177). The importance of the kallikrein-kinin system and bradykinin in pathophysiology is accordingly demonstrated by the expanding role of ACE-inhibitors (178). The blood pressure-lowering and cardioprotective actions of ACE-inhibitors were formerly thought to be based solely on a reduction in vascular angiotensin II formation. However, since ACE also degrades bradykinin, it is now recognised that the local accumulation of this peptide represents an important mechanism by which ACE-inhibitors reduce blood-pressure and heart-failure (179-183), increase glucose uptake (184,185), sometimes even causing hypoglycemia (186,187), have cardioprotective effects in coronary ischemia-reperfusion injuries (188) and delay the development of various nephropathies and diabetic organ failure (189-191). Although their C1-INH concentration is normal, a small but significant proportion of patients treated with ACE-inhibitors suffer from symptoms resembling acute attacks of hereditary angioedema, including life threatening upper-airway edema and edema of the gastro-intestinal tract (192-197). This complication may be much more common than has been thought (198). It is believed that excessive regional amounts of bradykinin mediates these adverse effects as well (199). All these events are in keeping with the vital role bradykinin has in the body.

Apart from liberating bradykinin from HK, kallikrein has also direct inflammatory functions by stimulating neutrophils (200). Plasma kallikrein is mainly inhibited by C1-INH and alpha-2-macroglobulin (7,201,202). Tissue kallikrein, the other form of kallikrein, has such a low concentration in the body, with the exception of glandular organs, that its role in mediating cutaneous or mucosal edema is believed to be minor. C1-INH is an inefficient inhibitor of tissue kallikrein, which makes its contribution in HAE less interesting.

In addition to being the bradykinin-donor, HK also inhibits cystein proteases, has antiadhesive and anti-platelet roles (203,204), and has recently been shown to bind to the complement C1q receptor on endothelial cells (KININ 95, L03), which is yet another example of the links between the cascade systems.

The former belief of kallikrein, HK, or FXII as participants of the so called contact system of coagulation is now abandoned (se below). Quite contrary, it has been shown that these factors promotes mild fibrinolysis (156,205-208) and several find the term "contact system of inflammation" as more appropriate (KININ 95).

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