The role of plasminogen activator inhibitor type 1 in the inflammatory response to local tissue injury.
BACKGROUND
The plasma levels of the plasminogen activator-inhibitor type 1 (PAI-1) are consistently elevated in patients with sterile tissue injury, often accompanied by a systemic acute phase protein response. It remains unknown, however, whether and to what extent PAI-1 affects the host response to trauma.


RESULTS
By using the well-established murine model of turpentine-induced tissue injury we compared local and systemic inflammatory responses in PAI-1 gene-deficient (PAI-1-/-) and normal wild-type (Wt) mice. Subcutaneous turpentine injection elicited strong increases in PAI-1 protein concentration in plasma and at the site of injury, but not in liver. PAI-1 mRNA was locally increased and expressed mainly by macrophages and endothelial cells. PAI-1 deficiency greatly enhanced the early influx of neutrophils to the site of inflammation, which was associated with increased edema and necrosis at 8 h after injection. Furthermore, PAI-1-/- mice showed a reduced early interleukin (IL)-6 induction with subsequently lower acute phase protein levels and a much slower recovery of body weight loss.


CONCLUSIONS
These findings suggest that PAI-1 is not merely a marker of tissue injury but plays a functional role in the local and systemic host response to trauma.
Renckens
R
R
Laboratory of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Netherlands. r.renckens@amc.uva.nl
Roelofs
J J T H
JJ
de Waard
V
V
Florquin
S
S
Lijnen
H R
HR
Carmeliet
P
P
van der Poll
T
T
D000209:Acute-Phase Proteins / Q000378:metabolism; D000210:Acute-Phase Reaction; D000818:Animals; D001835:Body Weight; D018925:Chemokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004487:Edema; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D017403:In Situ Hybridization; D007249:Inflammation; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009336:Necrosis; D009504:Neutrophils / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014425:Turpentine / Q000494:pharmacology
D000209:Acute-Phase Proteins; D018925:Chemokines; D007375:Interleukin-1; D015850:Interleukin-6; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D014425:Turpentine