Bradykinin (BK) is a potent inflammatory mediator, which can release other inflammatory mediators by interacting with bradykinin B-1 and B-2 receptors. The role of kinins in regulating human PMN elastase release was studied. BK induced elastase release 5-fold over basal levels. Elastase release was inhibited by both B-1 and B-2 receptor antagonists. A specific B-1 agonist des-Arg(10)-KD increased elastase release 4-fold. Since elastase has been implicated in vascular leak, the effect of BK on endothelial cell monolayer (EM) permeability was assessed. BK increased EM leak (I-125 flux) across the EM, whereas des-Arg(10)-KD was inactive. When co-cultured with human umbilical vein endothelial cells, des-Arg(10)-KD-treated PMNs increased EM leak by 35%. The elastase inhibitor AAVPK blocked des-Arg(10)-KD-induced leak by 80% suggesting that elastase is responsible for the increase in permeability. It is concluded that BK causes increased leak by inducing PMN elastase release via activation of both B-1 and B-2 receptors. BK blockade and elastase inhibition may be beneficial in inflammatory diseases such as ARDS which is characterized by increased lung permeability and both kinin and PMN activation are thought to participate.
