The effect of tissue type-plasminogen activator deletion and associated fibrin(ogen) deposition on macrophage localization in peritoneal inflammation.
There are two plasminogen activators (PAs), urokinase type-PA (u-PA) and tissue type-PA (t-PA). While u-PA is considered to be involved in cellular migration and tissue remodeling and t-PA in fibrinolysis, this distinction is not always clear-cut. With the use of u-PA and t-PA gene deficient mice (u-PA-/- and t-PA-/- mice, respectively) we have assessed the role of each PA in acute peritonitis. The cellular infiltrate in both thioglycolate- and antigen-induced peritoneal exudates was unaffected in u-PA-/- mice; in contrast, in t-PA-/- mice, the macrophage numbers, particularly of the Mac-1(hi) population, in the peritoneal cavity by day 4 were significantly reduced compared to wild-type mice. However, examination of the peritoneal wall revealed in fact increased numbers of macrophages adhering on/in the cavity lining at all time points studied; in addition, increased fibrin(ogen) staining was observed for these mice. The reduced macrophage numbers in the peritoneal cavities of t-PA-/- mice could be increased by administration of plasmin or t-PA prior to harvesting the thioglycolate-elicited exudates. These results suggest that t-PA and not u-PA is the PA controlling fibrinolysis in murine peritonitis. In its absence macrophages adhere to the accumulated fibrin(ogen) on/in the cavity wall lining, most likely via Mac-1 binding, thus affecting migration into and/or out of the peritoneal cavity. They also highlight the need to examine both the peritoneal cavity and wall in order to monitor accurately the extent of a peritoneal inflammatory reaction. Peritoneal inflammation in t-PA-/- mice represents a useful model to study the progression of intra-abdominal adhesions during surgery and clinical peritonitis.
Cook
Andrew D
AD
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Royal Parade, Parkville, 3010, Victoria, Australia. adcook@unimelb.edu.au
Vlahos
Ross
R
Massa
Christine M
CM
Braine
Emma L
EL
Lenzo
Jason C
JC
Turner
Amanda L
AL
Way
Kerrie J
KJ
Hamilton
John A
JA
D000818:Animals; D005340:Fibrinogen / Q000378:metabolism*; D017353:Gene Deletion; D007249:Inflammation; D008264:Macrophages / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010537:Peritoneum / Q000378:metabolism*; D010538:Peritonitis / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000502:physiology*
D005340:Fibrinogen; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator