ToxSci Advance Access published online on May 9, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn091
PLASMINOGEN ACTIVATOR INHIBITOR-1 LIMITS LIVER INJURY AND FACILITATES REGENERATION AFTER ACETAMINOPHEN OVERDOSE
* Liver Research Institute, University of Arizona, Tucson, AZ 85724
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (mbajt{at}kumc.edu; hyan{at}kumc.edu; hjaeschke{at}kumc.edu)
Department of Pathology, Brackenridge Hospital, Austin, TX 78701 (AFarhood{at}seton.org)
For Correspondence: Hartmut Jaeschke, Ph.D., Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160. Tel. (913) 588 7969, Fax. (913) 588 7501. Email: hjaeschke{at}kumc.edu
Received February 21, 2008; revision received May 4, 2008; accepted May 4, 2008
 |
Abstract |
|---|
Deficiency in plasminogen activator inhibitor-1 (PAI-1) gene expression is known to promote growth factor activation and regeneration in a number of hepatotoxicity models. To evaluate if PAI-1 has similar effects in acetaminophen (APAP) hepatotoxicity, wildtype and PAI-1 gene knockout mice (PAI-KO) were treated with 200 mg/kg APAP and liver injury and its repair were assessed. In wildtype animals, plasma alanine aminotransferase (ALT) activities increased during the first 12h and then returned to baseline within 48h. The area of necrosis increased in parallel to the ALT values, peaked between 12 and 24h and was completely resolved by 96h. The regenerative response of cells outside the necrotic area, as indicated by proliferating cell nuclear antigen (PCNA) protein and cyclin D1 gene expression, was observed within 24h, peaked at 48h and then declined but remained elevated until 96h. Liver injury in response to APAP was similar in PAI-KO as in wildtype animals during the first 12h. However, plasma ALT values and the area of necrosis further increased during the following 12h with development of massive intrahepatic hemorrhage. Approximately 50% of the PAI-KO animals did not survive. Although liver injury of the surviving animals was repaired, the regeneration process was delayed until 48h. A potential reason for this delay may have been due to the more severe injury and/or the increased expression of the cell cycle inhibitor p27. Our data indicate that PAI activation limits liver injury and mortality during APAP hepatotoxicity by preventing excessive hemorrhage and thereby facilitating tissue repair.