Essential role of plasminogen activator inhibitor type-1 in radiation enteropathy.
Intestinal radiation injury is a dose-limiting factor in radiation therapy for abdominal and pelvic cancers. Because transforming growth factor-beta1 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.
Milliat
Fabien
F
Laboratory of Radiopathology, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses; Unité Propre de Recherche et de l'Enseignement Supérieur, Equipe d'Accueil-2710, France. fabien.milliat@irsn.fr
Sabourin
Jean-Christophe
JC
Tarlet
Georges
G
Holler
Valerie
V
Deutsch
Eric
E
Buard
Valérie
V
Tamarat
Radia
R
Atfi
Azeddine
A
Benderitter
Marc
M
François
Agnès
A
D000230:Adenocarcinoma / Q000378:metabolism / Q000532:radiotherapy; D000818:Animals; D002478:Cells, Cultured; D004727:Endothelium / Q000378:metabolism; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D007410:Intestinal Diseases / Q000209:etiology / Q000235:genetics*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011832:Radiation Injuries / Q000235:genetics* / Q000378:metabolism; D012004:Rectal Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D012189:Retrospective Studies; D015398:Signal Transduction; D051900:Smad3 Protein / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D017395:Plasminogen Activator Inhibitor 1; D051900:Smad3 Protein; D016159:Tumor Suppressor Protein p53