Neutrophil‐derived heparin binding protein (HBP) is an endogenous activator of the kallikrein‐kinin system

Abstract

Adhesion of polymorphonuclear leukocytes (PMN) to the endothelial cell (EC) lining leads to release of heparin binding protein (HBP) causing increased vascular permeability. We have previously reported data suggesting that the kallikrein‐kinin system (KKS) is involved in PMN‐evoked plasma extravasation. Plasma prekallikrein (PK), factor XII (FXII) and high molecular weight kininogen (HK) are principal components of the KKS. Activated PK cleaves HK, liberating bradykinin (BK) which triggers EC contraction. Endogenous activators of this system are poorly defined. Here, we investigated the role of HBP in the activation of the KKS. Stimulation of EC monolayers with HBP caused an increase in paracellular permeability that was abolished with BK B1 and B2 receptor antagonists or a peptide displacing HK from the EC surface. Western blot analysis further revealed that HBP is able to induce cleavage of HK on EC. Thioglycollate‐induced pleurisy in the mouse was used to study PMN‐evoked plasma changes in vascular permeability in vivo. Plasma extravasation was markedly increased 4 h after thioglycollate injection. Treatment with BK receptor antagonists or an antibody to HBP significantly reduced the plasma exudation. These results demonstrate a critical role of the KKS in PMN‐evoked increase in vascular permeability. The data suggest that PMN‐derived HBP may constitute an endogenous activator of this system.