title: Polymorphonuclear leukocyte phagocytic function increases in plasminogen knockout mice.
abstract: BACKGROUND
  Mice lacking plasminogen (PG-/-) require alternative pathways of fibrinolysis for survival. This may depend on polymorphonuclear leukocytes (PMN) that can clear soluble and insoluble fibrin(ogen) through PG-independent processes. Our objective was to demonstrate that PMNs from PG-/- mice exhibit increased Mac-1 dependent phagocytic activity, which may explain their increased fibrin(ogen)lytic activity compared with wild type (PG+/+) mice.
  
  
  METHODS
  Phagocytic activity of PMNs from PG-/- and PG+/+ mice was compared following exposure to Staphylococcus aureus (S. aureus) particles and the expression of Mac-1 was assessed in parallel by flow cytometric analysis. Resistance to phorbol-12-myristate-13-acetate (PMA)-induced cell death was compared between PMNs from the different genotypes.
  
  
  RESULTS
  Stimulation of PG-/- PMNs by opsonized S. aureus diluted in PG-/- plasma significantly increased phagocytosis (15-fold) compared with stimulation of PG+/+ PMNs in PG+/+ plasma. Incubation of PG-/- PMNs with PG+/+ plasma (control) or PG-/- plasma supplemented with human PG inhibited this increased phagocytic activity. Mac-1 cell surface density increased 6.2+/-1.0-fold in PG-/- PMNs versus 2.9+/-0.6-fold in PG+/+ PMNs (P < 0.01) indicating that Mac-1 may be associated with increased phagocytic activity. Supporting this, treatment of PG-/- PMNs with an anti-Mac-1 antibody in PG-/- plasma inhibited phagocytic activity. In addition, physiologic PG blocked Mac-1 accessibility at the surface of PMNs. Addition of PMA resulted in 33% death of PMNs from PG-/- mice versus 68% in PG+/+ controls (P < 0.001).
  
  
  CONCLUSIONS
  PMNs from PG-/- mice exhibit a Mac-1 dependent increase in phagocytic activity that is suppressed with human PG, an anti-Mac-1 antibody or the plasma from PG+/+ mice. The propensity for PMNs from PG-/- mice to be activated in response to PMA together with their relative resistance to PMA-toxicity may contribute to increased PMN half-life and enhanced fibrin(ogen) clearance in the setting of PG deficiency.
authors.affiliation: Vascular Biology Group, ANZAC Research Institute, Concord, NSW 2139, Australia.
authors.forename: P K
authors.initials: PK
authors.lastname: Witting
authors.forename: B
authors.initials: B
authors.lastname: Zeng
authors.forename: M
authors.initials: M
authors.lastname: Wong
authors.forename: A C
authors.initials: AC
authors.lastname: McMahon
authors.forename: B S
authors.initials: BS
authors.lastname: Rayner
authors.forename: A J
authors.initials: AJ
authors.lastname: Sapir
authors.forename: H C
authors.initials: HC
authors.lastname: Lowe
authors.forename: S B
authors.initials: SB
authors.lastname: Freedman
authors.forename: D B
authors.initials: DB
authors.lastname: Brieger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005342:Fibrinolysis / Q000502:physiology; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D010958:Plasminogen / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D013211:Staphylococcus aureus / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D017931:DNA Primers; D016177:Macrophage-1 Antigen; D010958:Plasminogen; D013755:Tetradecanoylphorbol Acetate