title: Pravastatin limits radiation-induced vascular dysfunction in the skin.
abstract: About half of people with cancer are treated with radiation therapy; however, normal tissue toxicity still remains a dose-limiting factor for this treatment. The skin response to ionizing radiation may involve multiple inflammatory outbreaks. The endothelium is known to play a critical role in radiation-induced vascular injury. Furthermore, endothelial dysfunction reflects a decreased availability of nitric oxide. Statins have been reported to preserve endothelial function through their antioxidant and anti-inflammatory activities. In this study, wild type and endothelial nitric oxide synthase (eNOS)(-/-) mice were subjected to dorsal skin irradiation and treated with pravastatin for 28 days. We demonstrated that pravastatin has a therapeutic effect on skin lesions and abolishes radiation-induced vascular functional activation by decreasing interactions between leukocytes and endothelium. Pravastatin limits the radiation-induced increase of blood CCL2 and CXCL1 production expression of inflammatory adhesion molecules such as E-selectin and intercellular adhesion molecule-1, and inflammatory cell migration in tissues. Pravastatin limits the in vivo and in vitro radiation-induced downregulation of eNOS. Moreover, pravastatin has no effect in eNOS(-/-) mice, demonstrating that eNOS plays a key role in the beneficial effect of pravastatin in radiation-induced skin lesions. In conclusion, pravastatin may be a good therapeutic approach to prevent or reduce radiation-induced skin damage.
authors.affiliation: Institute for Radiological Protection and Nuclear Safety (IRSN), DRPH, SRBE, Laboratory of Radiopathology, Fontenay aux Roses, France. valerie.holler@irsn.fr
authors.forename: Valerie
authors.initials: V
authors.lastname: Holler
authors.forename: Valerie
authors.initials: V
authors.lastname: Buard
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Gaugler
authors.forename: Olivier
authors.initials: O
authors.lastname: Guipaud
authors.forename: Cedric
authors.initials: C
authors.lastname: Baudelin
authors.forename: Amandine
authors.initials: A
authors.lastname: Sache
authors.forename: Maria del R
authors.initials: Mdel R
authors.lastname: Perez
authors.forename: Claire
authors.initials: C
authors.lastname: Squiban
authors.forename: Radia
authors.initials: R
authors.lastname: Tamarat
authors.forename: Fabien
authors.initials: F
authors.lastname: Milliat
authors.forename: Marc
authors.initials: M
authors.lastname: Benderitter
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000503:physiopathology* / Q000528:radiation effects; D002450:Cell Communication / Q000528:radiation effects; D018932:Chemokine CCL2 / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000378:metabolism; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology* / Q000528:radiation effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000528:radiation effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology / Q000627:therapeutic use*; D011855:Radiodermatitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011878:Radiotherapy / Q000009:adverse effects*; D012867:Skin / Q000098:blood supply*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D019040:E-Selectin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017035:Pravastatin