title: 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.
mesh_terms: D002449:Cell Aggregation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005174:Factor XII / Q000494:pharmacology*; D015956:Factor XIIa; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D007781:Lactoferrin / Q000494:pharmacology; D008970:Molecular Weight; D009504:Neutrophils / Q000187:drug effects*; D010196:Pancreatic Elastase / Q000097:blood; D010446:Peptide Fragments / Q000494:pharmacology*
chemical_list: D010446:Peptide Fragments; D005174:Factor XII; D007781:Lactoferrin; D010196:Pancreatic Elastase; D015956:Factor XIIa