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| Research article summary (published 29 Jun 2009): |
Effects of pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor-1 in radiation-induced intestinal injury.
Full Abstract
PURPOSE: To investigate effects of plasminogen activator inhibitor 1 (PAI-1) genetic deficiency and pharmacological PAI-1 inhibition with PAI-039 in a mouse model of radiation-induced enteropathy. METHODS AND MATERIALS: Wild-type (Wt) and PAI-1(-/-) knockout mice received a single dose of 19 Gy to an exteriorized localized intestinal segment. Sham and irradiated Wt mice were treated orally with 1 mg/g of PAI-039. Histological modifications were quantified using a radiation injury score. Moreover, intestinal gene expression was monitored by real-time PCR. RESULTS: At 3 days after irradiation, PAI-039 abolished the radiation-induced increase in the plasma active form of PAI-1 and limited the radiation-induced gene expression of transforming growth factor beta1 (TGF-beta1), CTGF, PAI-1, and COL1A2. Moreover, PAI-039 conferred temporary protection against early lethality. PAI-039 treatment limited the radiation-induced increase of CTGF and PAI-1 at 2 weeks after irradiation but had no effect at 6 weeks. Radiation injuries were less severe in PAI-1(-/-) mice than in Wt mice, and despite the beneficial effect, 3 days after irradiation, PAI-039 had no effects on microscopic radiation injuries compared to untreated Wt mice. CONCLUSIONS: A genetic deficiency of PAI-1 is associated with amelioration of late radiation enteropathy. Pharmacological inhibition of PAI-1 by PAI-039 positively impacts the early, acute phase increase in plasma PAI-1 and the associated radiation-induced gene expression of inflammatory/extracellular matrix proteins. Since PAI-039 has been shown to inhibit the active form of PAI-1, as opposed to the complete loss of PAI-1 in the knockout animals, these data suggest that a PAI-1 inhibitor could be beneficial in treating radiation-induced tissue injury in acute settings where PAI-1 is elevated.
Author information
Author/s: Abderrahmani, Rym (R); François, Agnès (A); Buard, Valérie (V); Benderitter, Marc (M); Sabourin, Jean-Christophe (JC); Crandall, David L (DL); Milliat, Fabien (F);
Affiliation: Institute for Radiological Protection and Nuclear Safety, Laboratory of Radiopathology, Fontenay-aux-Roses, France.
Journal and publication information
Publication Type: Journal Article
Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys), published in United States. (Language: eng)
Reference: 2009-Jul; vol 74 (issue 3) : pp 942-8
Dates: Created 2009/06/01; Completed 2009/06/18;
PMID: 19480973, status: MEDLINE (last retrieval date: 6/18/2009, IMS Date: )
Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.
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