Figure 8.

Proposed schematic for the interactions of MPO with endothelial cells and the plasma kallikrein-kininogen system. When a neutrophil releases its granule constituents and oxygen radicals at sites of inflammation, MPO can leak into the lumen of the vessel. A: Endothelial cells bind and internalize MPO, in part through interactions with the cell-surface protein CK1; MPO and CK1 enter the cells in complex. B: MPO can also enter cells through other mechanisms that have yet to be fully characterized. C–F: MPO can modulate the action of the plasma kallikrein-kininogen system. c: MPO associates directly with high molecular weight kininogen (HK) and increases the amount of HK bound to the cells; this complex appears to internalize. D: When MPO and kininogen are coupled, kallikrein is unable to cleave HK. MPO uses the hydrogen peroxide generated during a neutrophil’s respiratory burst to oxidize chloride and produce hypochlorous acid (represented by the yellow asterisk). E: Hypochlorous acid can oxidize and inactivate HK by altering kallikrein’s cleavage site (F), as well as abrogate the protease activity of kallikrein. G: In the absence of MPO, endothelial surface proteins including CK1 bind circulating high molecular weight kininogen. Plasma kallikrein subsequently cleaves bradykinin (small red circle with B) from kininogen; bradykinin then binds to specific endothelial receptors to induce nitric oxide generation.