Kinin formation: mechanisms and role in inflammatory disorders

Although considerable progress has been made in elucidating the molecular events occurring during kinin generation by both the plasma kinin-forming system and the tissue kallikrein system, it is only in recent years that we have come to appreciate their potential role in inflammation in a wide variety of diseases. The importance of the tissue kallikrein system depends upon secretion of the active form of the requisite enzyme in the presence of a source of kininogen. Since tissue kallikreins are widely distributed in tissues, and since lymph and interstitial fluid contains kininogen (271), a local milieu for potential kinin formation is always present. The plasma system will be activated secondary to inflammation initiated by some other process. There may be endothelial or epithelial damage exposing connective tissue. Plasma leakage caused by release of some other permeability factor (including kinin made by tissue kallikrein) would thus lead to activation of the plasma cascade in many forms of inflammation. As with all mediators, however, the contribution of kinins to an inflammatory response can only be definitively evaluated if their actions can be selectively antagonized. Competitive receptor antagonists have recently been synthesized (228) and will, we hope, soon be available for administration to humans. Should these compounds prove effective in vivo, they could be used in conjunction with currently available assays for kallikreins, kininogens, kinins, and their various inactivated or degraded products, to provide new insights into the role of these systems in the pathogeneses of inflammatory diseases.