The role of hepatic type 1 plasminogen activator inhibitor (PAI-1) during murine hemorrhagic shock.
Hemorrhagic shock (HS) followed by resuscitation (HS-R) is characterized by profound physiological changes. Even if the patient survives the initial blood loss, these poorly understood changes can lead to morbidity. One of the tissues most often affected is liver. We sought to recognize specific hepatic changes induced by this stressor to identify targets for therapeutic intervention. Gene array analyses using mouse liver mRNAs were used to identify candidate genes that contribute to hepatic damage. To verify the role of one of the genes identified using the arrays, mice were subjected to HS-R, and multiple parameters were analyzed. A profound increase in plasminogen activator inhibitor type 1 (PAI-1) mRNA was observed using hepatic mRNAs from C57Bl/6 mice after HS, both with and without resuscitation. Constitutive loss of PAI-1 resulted in notable tissue preservation and lower (P < .05) alanine aminotransferase (ALT) levels. Fibrin degradation products (FDPs) and interleukins 6 and 10 (IL-6 and IL-10) were unaffected by loss of PAI-1; however, enhanced urokinase activity, an elevation of active hepatocyte growth factor (HGF), an increase in unprocessed transforming growth factor-beta1 (TGF-beta1), and retention of ERK phosphorylation after HS-R were associated with improved hepatic function. In conclusion, PAI-1 protein is a negative effector of hepatic damage after HS-R through its influence on classic regulators of hepatic growth, as opposed to its role in fibrinolysis.
Lagoa
Claudio E
CE
Department of Surgery, University of Pittsburgh, S411-B South BST, Pittsburgh, PA 15261, USA. .
Vodovotz
Yoram
Y
Stolz
Donna B
DB
Lhuillier
Franck
F
McCloskey
Carol
C
Gallo
David
D
Yang
Runkuan
R
Ustinova
Elena
E
Fink
Mitchell P
MP
Billiar
Timothy R
TR
Mars
Wendy M
WM
D000818:Animals; D004730:Endothelium, Vascular / Q000502:physiology; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis; D022781:Hepatocytes / Q000473:pathology*; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000473:pathology* / Q000517:prevention & control; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis
D005338:Fibrin Fibrinogen Degradation Products; D015850:Interleukin-6; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C036309:fibrin fragment D; D016753:Interleukin-10; D017228:Hepatocyte Growth Factor; D014568:Urokinase-Type Plasminogen Activator