help button home button Am J Pathol ASIP 2008 Summer Academy, Molecular Methcanisms of Human Disease: Injury, Inflammation, and Tissue Repair
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
A more recent version of this article appeared on March 1, 2008

Published online before print February 14, 2008
This Article
Right arrow Full Text (Rapid PDF)
Right arrow All Versions of this Article:
ajpath.2008.070930v1
172/3/691    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Milliat, F.
Right arrow Articles by François, A.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Milliat, F.
Right arrow Articles by François, A.
Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070930

Accepted for publication December 3, 2007.

Article

Essential Role of Plasminogen Activator Inhibitor Type-1 in Radiation Enteropathy

Fabien Milliat*{dagger}@, Jean-Christophe Sabourin{ddagger}, Georges Tarlet*, Valerie Holler*, Eric Deutsch{dagger}{sect}, Valérie Buard*, Radia Tamarat*, Azeddine Atfi, Marc Benderitter*, and Agnès François*{dagger}

From the Laboratory of Radiopathology,* Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses; Unité Propre de Recherche et de l'Enseignement Supérieur, Equipe d'Accueil (UPRES EA)-2710,{dagger} Villejuif; Department of Pathology,{ddagger} Rouen University Hospital, Rouen; Department of Radiotherapy,{sect} Gustave Roussy Institute, Villejuif; and Institut National de la Santé et de la Recherche Médicale (INSERM) U482, Paris, France

@ To whom correspondence should be addressed. E-mail: fabien.milliat{at}irsn.fr.


  Abstract

Intestinal radiation injury is a dose-limiting factor in radiation therapy for abdominal and pelvic cancers. Because transforming growth factor-{beta}1 is a key mediator involved in radiation-induced damage, we hypothesized that its target gene, plasminogen activator inhibitor type 1 (PAI-1), is an essential mediator of intestinal radiation toxicity. In a model of radiation enteropathy, survival was monitored and intestinal radiation injury was assessed in both wild-type (Wt) and PAI-1 knockout mice. Immunohistochemical labeling of PAI-1 was also assessed in patients treated with preoperative radiotherapy for rectal adenocarcinoma. Finally, the molecular mechanisms involved in radiation-induced PAI-1 expression were investigated. We found that PAI-1 -/- mice exhibited increased survival and better intestinal function compared with Wt mice. Intestinal radiation injury was attenuated in irradiated PAI-1 -/- mice compared with irradiated Wt mice, and irradiation increased blood cell-endothelial cell interactions in Wt but not PAI-1 -/- mice. In vivo, radiation-induced intestinal damage in mice, as well as in patients treated with radiotherapy, was associated with the up-regulation of PAI-1 in the endothelium. In vitro, irradiation increased PAI-1 expression in endothelial cells by a p53/Smad3-dependent mechanism. Together, these data demonstrate that PAI-1 plays a critical role in radiation-induced intestinal damage, suggesting that PAI-1 is an attractive target for preventing or reducing the side effects of radiation therapy.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Copyright © 2008 by the American Society for Investigative Pathology.