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Originally published online as doi:10.2353/ajpath.2008.070930 on February 14, 2008

Published online before print February 14, 2008
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(American Journal of Pathology. 2008;172:691-701.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070930

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}§, 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,§Gustave Roussy Institute, Villejuif; and Institut National de la Santé et de la Recherche Médicale (INSERM) U482,Paris, France

Intestinal radiation injury is a dose-limiting factor in radiation therapy for abdominal and pelvic cancers. Because transforming growth factor-β1 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.






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