Effects of pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor-1 in radiation-induced intestinal injury.
OBJECTIVE
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
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.
Abderrahmani
Rym
R
Institute for Radiological Protection and Nuclear Safety, Laboratory of Radiopathology, Fontenay-aux-Roses, France.
François
Agnès
A
Buard
Valérie
V
Benderitter
Marc
M
Sabourin
Jean-Christophe
JC
Crandall
David L
DL
Milliat
Fabien
F
D000284:Administration, Oral; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007210:Indoleacetic Acids / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D011832:Radiation Injuries / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D000943:Antigens, Differentiation; C439971:COL3A1 protein, human; D024042:Collagen Type I; D024061:Collagen Type III; D007210:Indoleacetic Acids; D017395:Plasminogen Activator Inhibitor 1; D053773:Transforming Growth Factor beta1; C036763:monocyte-macrophage differentiation antigen; C488103:tiplaxtinin; D055513:Connective Tissue Growth Factor; D003094:Collagen