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...

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Vydáno v:	Journal of thrombosis and haemostasis Ročník 3; číslo 5; s. 1018 - 1025
Hlavní autoři:	RENCKENS, R., ROELOFS, J. J. T. H., DE WAARD, V., FLORQUIN, S., LIJNEN, H. R., CARMELIET, P., VAN DER POLL, T.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Oxford, UK Blackwell Science Inc 01.05.2005
Témata:	acute phase response Acute-Phase Proteins - metabolism Acute-Phase Reaction Animals Body Weight Chemokines - metabolism Dose-Response Relationship, Drug Edema Endothelium, Vascular - metabolism Female In Situ Hybridization Inflammation Interleukin-1 - biosynthesis Interleukin-6 - biosynthesis Interleukin-6 - metabolism Macrophages - metabolism Mice Mice, Inbred C57BL Mice, Transgenic Necrosis Neutrophils - metabolism PAI‐1 Plasminogen Activator Inhibitor 1 - physiology RNA, Messenger - metabolism Time Factors Turpentine - pharmacology
ISSN:	1538-7933, 1538-7836, 1538-7836
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Abstract	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. Methods and 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. Conclusion: 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.
AbstractList	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. Methods and 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. Conclusion: 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. 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.BACKGROUNDThe 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.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.METHODS AND RESULTSBy 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.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.CONCLUSIONThese 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. 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. 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. 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.
Author	ROELOFS, J. J. T. H. FLORQUIN, S. DE WAARD, V. CARMELIET, P. VAN DER POLL, T. LIJNEN, H. R. RENCKENS, R.
Author_xml	– sequence: 1 givenname: R. surname: RENCKENS fullname: RENCKENS, R. – sequence: 2 givenname: J. J. T. H. surname: ROELOFS fullname: ROELOFS, J. J. T. H. – sequence: 3 givenname: V. surname: DE WAARD fullname: DE WAARD, V. – sequence: 4 givenname: S. surname: FLORQUIN fullname: FLORQUIN, S. – sequence: 5 givenname: H. R. surname: LIJNEN fullname: LIJNEN, H. R. – sequence: 6 givenname: P. surname: CARMELIET fullname: CARMELIET, P. – sequence: 7 givenname: T. surname: VAN DER POLL fullname: VAN DER POLL, T.
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Snippet	Background: The plasma levels of the plasminogen activator‐inhibitor type 1 (PAI‐1) are consistently elevated in patients with sterile tissue injury, often... The plasma levels of the plasminogen activator-inhibitor type 1 (PAI-1) are consistently elevated in patients with sterile tissue injury, often accompanied by...
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SubjectTerms	acute phase response Acute-Phase Proteins - metabolism Acute-Phase Reaction Animals Body Weight Chemokines - metabolism Dose-Response Relationship, Drug Edema Endothelium, Vascular - metabolism Female In Situ Hybridization Inflammation Interleukin-1 - biosynthesis Interleukin-6 - biosynthesis Interleukin-6 - metabolism Macrophages - metabolism Mice Mice, Inbred C57BL Mice, Transgenic Necrosis Neutrophils - metabolism PAI‐1 Plasminogen Activator Inhibitor 1 - physiology RNA, Messenger - metabolism Time Factors Turpentine - pharmacology
Title	The role of plasminogen activator inhibitor type 1 in the inflammatory response to local tissue injury
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