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 GN Garcia

Research output: Contribution to journalArticle

37 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Simvastatin
Lung Injury
Gene expression
Radiation
Gene Expression
Lung
Genes
Electric network analysis
Dosimetry
Protein Interaction Maps
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Protective Agents
Sphingolipids
Proteins
Oxidative stress
Gene Regulatory Networks
Radiotherapy
Metabolic Networks and Pathways
Infiltration
Blood Vessels

Keywords

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

ASJC Scopus subject areas

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

Cite this

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

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 44, No. 3, 01.03.2011, p. 415-422.

Research output: Contribution to journalArticle

Mathew, B, Huang, Y, Jacobson, JR, Berdyshev, E, Gerhold, LM, Wang, T, Moreno-Vinasco, L, Lang, G, Zhao, Y, Chen, CT, LaRiviere, PJ, Mauceri, H, Sammani, S, Husain, AN, Dudek, SM, Natarajan, V, Lussier, YA, Weichselbaum, RR & Garcia, JGN 2011, 'Simvastatin attenuates radiation-induced murine lung injury and dysregulated lung gene expression', American Journal of Respiratory Cell and Molecular Biology, vol. 44, no. 3, pp. 415-422. https://doi.org/10.1165/rcmb.2010-0122OC
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 GN. / Simvastatin attenuates radiation-induced murine lung injury and dysregulated lung gene expression. In: American Journal of Respiratory Cell and Molecular Biology. 2011 ; Vol. 44, No. 3. pp. 415-422.
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AU - Sammani, Saad

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