Neutrophil‐induced increase in vascular permeability involves activation of the contact system

Abstract

Adhesion of polymorphonuclear leukocytes (PMN) to the endothelial cell (EC) lining leads to increased vascular permeability. Plasma prekallikrein (PK), factor XII (FXII) and H‐kininogen are principal components of the contact system assembling on the EC surface. Activated PK cleaves H‐kininogen, liberating bradykinin that triggers EC contraction and paracellular gap formation. Here, we investigated the role of the contact system in PMN‐evoked plasma extravasation. Thioglycollate‐induced pleurisy in the mouse was used to study PMN‐dependent plasma leakage. FITC‐dextran served as plasma marker. The fluorescence intensity and PMN content in the exudate was markedly increased 4 h after thioglycollate injection, whereas in neutropenic animals, the plasma leakage was abolished. Treatment with antagonists to bradykinin B1 and B2 receptors, or an inhibitor to PK/FXII largely reduced fluid extravasation by 79% and 74% respectively. Intravital microscopy of the hamster cheek pouch microcirculation revealed that treatment with the B1/B2 antagonists reduced plasma leakage without reducing PMN adhesion. These results demonstrate a critical role of contact system activation in PMN‐evoked increase in vascular permeability. Our data also indicate that PMN‐dependent permeability changes and PMN extravasation may be regulated independent of each other.