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

Abstract

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

Plasminogen Activator Inhibitor-1 Controls Bone Marrow-Derived Cells Therapeutic Effect Through MMP9 Signaling: Role in Physiological and Pathological Wound Healing

“…Additionally, PAI-1 over-expression is observed in radiation-induced nephrosclerosis [32] and in human radiation enteritis and intestinal lesion [33,34] underlining a role for PAI-1 in radiation-induced tissue damages. Interestingly, PAI-1 knockout mice are protected against radiation-induced intestinal damage [34]. We confirmed and extended these findings by showing that PAI-1 contributes to the acute response of the endothelium to ionizing radiation, and it inhibits the angiogenic response in the wound healing process.…”

“…Moreover, ionizing radiation was shown to increase PAI-1 expression in NRK52E [30] and HEPG2 cells [31]. Additionally, PAI-1 over-expression is observed in radiation-induced nephrosclerosis [32] and in human radiation enteritis and intestinal lesion [33,34] underlining a role for PAI-1 in radiation-induced tissue damages. Interestingly, PAI-1 knockout mice are protected against radiation-induced intestinal damage [34].…”

The TG-interacting Factor TGIF1 Regulates Stress-induced Proinflammatory Phenotype of Endothelial Cells

“…Localized small intestinal radiation injury was induced by exposure of an intestinal segment to 19 Gy of radiation (7). Briefly, TGIF1…”

“…Radiation-induced up-regulation of TGF-␤1 expression levels has been shown in various organs, and, in addition to TGF-␤1 itself, several studies have shown up-regulation of intracellular effectors of TGF-␤1 signaling, in particular the canonical Smad-dependent pathway (5)(6)(7)(8).…”

Radiothérapie : quelles orientations thérapeutiques contre les séquelles digestives ?

“…Ce dernier diminue, par conséquent, le taux de plasmine et la fibrinolyse, favorisant la thrombose vasculaire. Les souris génétiquement déficientes en PAI-1 sont protégées contre les lésions digestives radioinduites [21]. Éviter l'augmentation radio-induite de la synthèse de PAI-1 ou utiliser des inhibiteurs de PAI-1 pourrait limiter les dommages intestinaux radio-induits.…”