Pravastatin Limits Radiation-Induced Vascular Dysfunction in the Skin

• Published in: Journal of investigative dermatology Vol. 129; no. 5; pp. 1280 - 1291
• Main Authors: Holler, Valerie, Buard, Valerie, Gaugler, Marie-Helene, Guipaud, Olivier, Baudelin, Cedric, Sache, Amandine, Perez, Maria del R., Squiban, Claire, Tamarat, Radia, Milliat, Fabien, Benderitter, Marc
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.05.2009; Nature Publishing Group; Elsevier Limited
• Subjects: Animals; Biological and medical sciences; Blood Vessels - drug effects; Blood Vessels - physiopathology; Blood Vessels - radiation effects; Cell Communication - radiation effects; Chemokine CCL2 - metabolism; Chemokine CXCL1 - metabolism; Dermatology; Disease Models, Animal; E-Selectin - metabolism; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiopathology; Endothelium, Vascular - radiation effects; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Intercellular Adhesion Molecule-1 - metabolism; Leukocytes - radiation effects; Life Sciences; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Knockout; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Pravastatin - pharmacology; Pravastatin - therapeutic use; Radiodermatitis - metabolism; Radiodermatitis - pathology; Radiodermatitis - prevention & control; Radiotherapy - adverse effects; Skin - blood supply; Enzyme; Dermatology; Enzyme inhibitor; Statin derivative; Hypocholesterolemic agent; Pravastatin; Dysfunction; HMG-CoA reductase inhibitor; Blood vessel; Hydroxymethylglutaryl-CoA reductase; Skin; Oxidoreductases; Antilipemic agent; Blood Vessels; Disease Models; Radiodermatitis; Inbred BALB C; Male; in vitro study; Leukocytes; intercellular adhesion molecule 1; protein blood level; transgenic mouse; mouse; cell migration; skin defect; endothelial nitric oxide synthase; human cell culture; priority journal; Hydroxymethylglutaryl-CoA Reductase Inhibitors; human; protein expression; monocyte chemotactic protein 1; Nitric Oxide Synthase Type III; Cell Communication; Intercellular Adhesion Molecule-1; in vivo study; human cell; Vascular; Nitric Oxide; Radiotherapy; endothelial leukocyte adhesion molecule 1; Knockout; animal experiment; article; Endothelium; CXCL1 chemokine; Animals; controlled study; radiation; Animal; leukocyte; animal tissue; Chemokine CXCL1; E-Selectin; Mice; nonhuman; down regulation; Chemokine CCL2
• ISSN: 0022-202X; 1523-1747; 1523-1747
• DOI: 10.1038/jid.2008.360

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.