Pravastatin inhibits the Rho/CCN2/extracellular matrix cascade in human fibrosis explants and improves radiation-induced intestinal fibrosis in rats
Résumé
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. © 2007 American Association for Cancer Research.
Mots clés
ccn2 protein
collagen type 1
drinking water
fibronectin
growth factor
pravastatin
Rho factor
ROCK protein
transcription factor
unclassified drug
animal experiment
animal model
article
cancer patient
controlled study
explant
extracellular matrix
human
human tissue
intestinal fibrosis
male
mesenchyme cell
nonhuman
phenotype
priority journal
protein analysis
quality of life
radiation
radiation enteropathy
radiation exposure
rat
smooth muscle fiber
Animals
Extracellular Matrix
Fibrosis
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Immediate-Early Proteins
Intercellular Signaling Peptides and Proteins
Intestinal Diseases
Intestines
Male
Pravastatin
Radiation Injuries
Rats
Wistar
rho GTP-Binding Proteins
rho-Associated Kinases