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

Biji Mathew, Yong Huang, Jeffrey R. Jacobson, Evegeny Berdyshev, Lynnette M. Gerhold, Ting Wang, Liliana Moreno-Vinasco, Gabriel Lang, Yutong Zhao, Chin Tu Chen, Patrick J. LaRiviere, Helena Mauceri, Saad Sammani, Aliya N. Husain, Steven M. Dudek, Viswanathan Natarajan, Yves A. Lussier, Ralph R. Weichselbaum, Joe G N Garcia

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

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-prioritizedgenes (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.

Original languageEnglish (US)
Pages (from-to)415-422
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume44
Issue number3
DOIs
StatePublished - Mar 1 2011

Keywords

  • Gene dysregulation
  • Lung vascular permeability
  • Protein-protein interaction
  • Radiation pneumonitis
  • Simvastatin

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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  • Cite this

    Mathew, B., Huang, Y., Jacobson, J. R., Berdyshev, E., Gerhold, L. M., Wang, T., Moreno-Vinasco, L., Lang, G., Zhao, Y., Chen, C. T., LaRiviere, P. J., Mauceri, H., Sammani, S., Husain, A. N., Dudek, S. M., Natarajan, V., Lussier, Y. A., Weichselbaum, R. R., & Garcia, J. G. N. (2011). Simvastatin attenuates radiation-induced murine lung injury and dysregulated lung gene expression. American journal of respiratory cell and molecular biology, 44(3), 415-422. https://doi.org/10.1165/rcmb.2010-0122OC