Involvement of bradykinin B1 and B2 receptors in human PMN elastase release and increase in endothelial cell monolayer permeability
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Abstract:
Bradykinin (BK) is a potent inflammatory mediator, which can release other inflammatory mediators by interacting with bradykinin B1 and B2 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 B1 and B2 receptor antagonists. A specific B1 agonist des-Arg10-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 (I125 flux) across the EM, whereas des-Arg10-KD was inactive. When co-cultured with human umbilical vein endothelial cells, des-Arg10-KD-treated PMNs increased EM leak by 35%. The elastase inhibitor AAVPK blocked des-Arg10-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 B1 and B2 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.
Insights
Bradykinin (BK) triggers inflammatory mediator release via B1 and B2 receptors, increasing vascular permeability. Inhibiting BK and elastase may benefit inflammatory diseases like ARDS.
Area of Science:
- Immunology
- Vascular Biology
- Pharmacology
Background:
- Bradykinin (BK) is a key inflammatory mediator.
- BK interacts with bradykinin B1 and B2 receptors to release other inflammatory mediators.
- Kinins play a role in regulating human polymorphonuclear (PMN) elastase release.
Purpose of the Study:
- To investigate the role of kinins in regulating human PMN elastase release.
- To assess the effect of BK on endothelial cell monolayer (EM) permeability.
- To determine if elastase mediates BK-induced vascular leak.
Main Methods:
- BK-induced elastase release was measured.
- B1 and B2 receptor antagonists and agonists were used.
- Endothelial cell monolayer permeability was assessed using I125 flux.
- The effect of des-Arg10-KD-treated PMNs on endothelial cells was evaluated.
- Elastase inhibitor AAVPK was used to block des-Arg10-KD-induced leak.
Main Results:
- BK induced a 5-fold increase in elastase release, inhibited by antagonists.
- A specific B1 agonist, des-Arg10-KD, increased elastase release 4-fold.
- BK increased endothelial cell monolayer leak.
- Des-Arg10-KD alone did not affect leak, but PMNs treated with it increased leak by 35%.
- AAVPK blocked des-Arg10-KD-induced leak by 80%, indicating elastase's role.
Conclusions:
- BK increases vascular leak by inducing PMN elastase release through B1 and B2 receptor activation.
- BK blockade and elastase inhibition show potential therapeutic benefits for inflammatory diseases with increased lung permeability, such as ARDS.
- This study highlights the significant role of the kinin-kininase system in inflammatory processes and vascular integrity.