| First Author | Milliat F | Year | 2008 |
| Journal | Am J Pathol | Volume | 172 |
| Issue | 3 | Pages | 691-701 |
| PubMed ID | 18276785 | Mgi Jnum | J:132273 |
| Mgi Id | MGI:3775587 | Doi | 10.2353/ajpath.2008.070930 |
| Citation | Milliat F, et al. (2008) Essential role of plasminogen activator inhibitor type-1 in radiation enteropathy. Am J Pathol 172(3):691-701 |
| abstractText | 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. |
