Simvastatin attenuates radiation-induced murine lung injury and dysregulated lung gene expression

• Published in: American journal of respiratory cell and molecular biology Vol. 44; no. 3; pp. 415 - 422
• Main Authors: Mathew, Biji, Huang, Yong, Jacobson, Jeffrey R, Berdyshev, Evegeny, Gerhold, Lynnette M, Wang, Ting, Moreno-Vinasco, Liliana, Lang, Gabriel, Zhao, Yutong, Chen, Chin Tu, LaRiviere, Patrick J, Mauceri, Helena, Sammani, Saad, Husain, Aliya N, Dudek, Steven M, Natarajan, Viswanathan, Lussier, Yves A, Weichselbaum, Ralph R, Garcia, Joe G N
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.03.2011
• Subjects: Animals; Bronchoalveolar Lavage; Gene Expression Regulation; Hyaluronan Receptors - biosynthesis; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Lung - metabolism; Lung - radiation effects; Lung Injury - drug therapy; Lung Injury - metabolism; Mice; Mice, Inbred C57BL; Protein Interaction Mapping; Radiation Injuries - drug therapy; Radiation Pneumonitis; Simvastatin - pharmacology; Transcription, Genetic
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2010-0122OC

Novel therapies are desperately needed for radiation-induced lung injury (RILI), which, despite aggressive corticosteroid therapy, remains a potentially fatal and dose-limiting complication of thoracic radiotherapy. We assessed the utility of simvastatin, an anti-inflammatory and lung barrier-protective agent, in a dose- and time-dependent murine model of RILI (18-(25 Gy). Simvastatin reduced multiple RILI indices, including vascular leak, leukocyte infiltration, and histological evidence of oxidative stress, while reversing RILI-associated dysregulated gene expression, including p53, nuclear factor-erythroid-2-related factor, and sphingolipid metabolic pathway genes. To identify key regulators of simvastatin-mediated RILI protection, we integrated whole-lung gene expression data obtained from radiated and simvastatin-treated mice with protein-protein interaction network analysis (single-network analysis of proteins). Topological analysis of the gene product interaction network identified eight top-prioritized genes (Ccna2a, Cdc2, fcer1 g, Syk, Vav3, Mmp9, Itgam, Cd44) as regulatory nodes within an activated RILI network. These studies identify the involvement of specific genes and gene networks in RILI pathobiology, and confirm that statins represent a novel strategy to limit RILI.