Purified plasma factor XIIa aggregates human neutrophils and causes degranulation

Abstract

Plasma kallikrein has been shown to aggregate human neutrophils and release human neutrophil elastase. However, neutrophils resuspended in factor XII-deficient plasma released only 30% of the elastase compared with normal plasma. Isolated human neutrophils were aggregated in a concentration-dependent fashion by 0.06 to 0.6 U/mL factor XIIa (0.022 to 0.22 mumol/L). Factor XIIa (0.1 to 1.0 U/mL) also induced neutrophil degranulation as evidenced by a concentration-dependent release of the specific granule protein, lactoferrin, and azurophilic granule protease, elastase. The release of neutrophil elastase was biphasic, reaching 40% of maximum at 15 seconds with maximal release by 90 minutes. The active site of factor XIIa was required, since the synthetic inhibitor, D-Pro-Phe-Arg-CH2Cl, which reacts with an essential histidine, and the natural plasma inhibitor, Cl-inhibitor, which interacts with the critical serine, both inhibit by more than 90% the release of elastase. The heavy chain is also required, since factor XII fragments failed to aggregate neutrophils or stimulate degranulation. Factor XIIa (0.6 U/mL) can completely correct the defect in elastase release evident in factor XII-deficient plasma. These studies demonstrate that factor XIIa, at concentrations potentially obtainable in plasma in disease states, can activate neutrophils, and thus may participate in the inflammatory response.

Specific inhibition of plasma kallikrein modulates chronic granulomatous intestinal and systemic inflammation in genetically susceptible rats

“…Together, these results strongly indicate the importance of kallikrein as a neutrophil chemotactic enzyme and agonist in vivo. Based on in vitro studies, the specific kallikrein inhibitor should decrease intestinal neutrophil recruitment (12), release of lysosomal enzymes (16), and formation of toxic oxygen radicals (14). The effect of the specific kallikrein inhibitor to suppress enterocolitis may be due in part to prevention of bradykinin release.…”

“…Kallikrein in the presence of high molecular weight kininogen stimulates neutrophil chemotaxis (12), aggregation (13), and oxygen consumption (14), and induces those cells to release elastase (15). FXIIa is also an agonist for neutrophils (16) and monocytes (17), and initiates the classical complement cascade (18). Kallikrein stimulates the cellbound fibrinolytic system by converting prourokinase to urokinase (19) and activates the alternative complement pathway (20).…”

Nafamostat Mesilate

“…In the pathologic conditions of DIC, the leukocytes, especially the neutrophils, can be activated by microcirculatory disturbances (62), cytokines (13), F.XIIa (73), kallikrein (58), and C5a (46). Activated leukocytes then release various inflammatory mediators that damage the adjacent endothelial cells.…”

Activated factor XII type A predicts long‐term mortality in patients admitted with chest pain

“…Contact activation, believed to be potentiated by negatively charged surfaces, results in the conversion of factor (F) XII to the activated form XIIa, which affects several pathophysiological processes, including hypotension, inflammation, thrombosis and fibrinolysis [7][8][9][10][11][12][13][14].…”