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


METHODS
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.


CONCLUSIONS
Targeting established fibrosis with pravastatin is an efficient and safe antifibrotic strategy in radiation-induced enteropathy, and is easily transferable into the clinic.
Haydont
Valérie
V
UPRES EA 27-10 Radiosensibilité des Tumeurs et Tissus Sains, Institut de Radioprotection et de Sûreté Nucléaire/Institut Gustave Roussy, Villejuif, France.
Bourgier
Céline
C
Pocard
Marc
M
Lusinchi
Antoine
A
Aigueperse
Jocelyne
J
Mathé
Denis
D
Bourhis
Jean
J
Vozenin-Brotons
Marie-Catherine
MC
D000818:Animals; D055513:Connective Tissue Growth Factor; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors*; D036341:Intercellular Signaling Peptides and Proteins; D007410:Intestinal Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008297:Male; D017035:Pravastatin / Q000494:pharmacology* / Q000627:therapeutic use; D011832:Radiation Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
C526317:CCN2 protein, human; C526316:CCN2 protein, rat; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055513:Connective Tissue Growth Factor; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins; D017035:Pravastatin