Pravastatin Inhibits the Rho/CCN2/extracellular matrix cascade in human fibrosis explants and improves radiation-induced intestinal fibrosis in rats.

Details

Serval ID
serval:BIB_42D263856D68
Type
Article: article from journal or magazin.
Collection
Publications
Title
Pravastatin Inhibits the Rho/CCN2/extracellular matrix cascade in human fibrosis explants and improves radiation-induced intestinal fibrosis in rats.
Journal
Clinical Cancer Research
Author(s)
Haydont V., Bourgier C., Pocard M., Lusinchi A., Aigueperse J., Mathé D., Bourhis J., Vozenin-Brotons M.C.
ISSN
1078-0432 (Print)
ISSN-L
1078-0432
Publication state
Published
Issued date
2007
Peer-reviewed
Oui
Volume
13
Number
18 Pt 1
Pages
5331-5340
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Abstract
PURPOSES: Intestinal complications after radiotherapy are caused by transmural fibrosis and impair the quality of life of cancer survivors. Radiation fibrosis was considered permanent and irreversible, but recently, its dynamic nature was shown, providing new opportunities for the development of antifibrotic therapies. Among these new targets, we identified the Rho/ROCK pathway and thought to investigate whether pravastatin treatment inhibits Rho pathway activation and elicits an antifibrotic action.
EXPERIMENTAL DESIGN: Rho and ROCK activities were monitored in human explants presenting radiation fibrosis remodeling after incubation with pravastatin. Subsequent modulation of CCN2, type I collagen, and fibronectin expression were assessed ex vivo and in intestinal smooth muscle cells derived from radiation enteropathy. Then, the therapeutic relevance of the antifibrotic action of pravastatin was explored in vivo in a rat model of chronic radiation fibrosis (19 Gy X-rays) treated with 30 mg/kg/d pravastatin in the drinking water.
RESULTS: The results obtained with human explants show that pravastatin specifically inhibits Rho activity in submucosal mesenchymal cells. Pravastatin also elicits ROCK inhibition, and subsequent CCN2 production in human explants and smooth muscle cells isolated from radiation enteropathy. Inhibition of type I collagen and fibronectin does occur, showing that pravastatin modulates the secretory phenotype of mesenchymal cells. Lastly, curative pravastatin administration improves radiation enteropathy in rats. This structural improvement is associated with decreased deposition of CCN2 and subsequent decreased extracellular matrix deposition.
CONCLUSION: Targeting established fibrosis with pravastatin is an efficient and safe antifibrotic strategy in radiation-induced enteropathy, and is easily transferable into the clinic.
Keywords
Animals, Connective Tissue Growth Factor, Extracellular Matrix/metabolism, Fibrosis, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology, Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use, Immediate-Early Proteins/antagonists & inhibitors, Intercellular Signaling Peptides and Proteins, Intestinal Diseases/drug therapy, Intestinal Diseases/metabolism, Intestines/drug effects, Intestines/pathology, Male, Pravastatin/pharmacology, Pravastatin/therapeutic use, Radiation Injuries/drug therapy, Radiation Injuries/metabolism, Rats, Rats, Wistar, rho GTP-Binding Proteins/antagonists & inhibitors, rho-Associated Kinases/antagonists & inhibitors
Pubmed
Open Access
Yes
Create date
01/12/2014 17:27
Last modification date
20/08/2019 13:45
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