Simvastatin attenuates radiation-induced murine lung injury and dysregulated lung gene expression.
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.
Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Illinois, USA.
Biji
B
Mathew
Yong
Y
Huang
Jeffrey R
JR
Jacobson
Evegeny
E
Berdyshev
Lynnette M
LM
Gerhold
Ting
T
Wang
Liliana
L
Moreno-Vinasco
Gabriel
G
Lang
Yutong
Y
Zhao
Chin Tu
CT
Chen
Patrick J
PJ
LaRiviere
Helena
H
Mauceri
Saad
S
Sammani
Aliya N
AN
Husain
Steven M
SM
Dudek
Viswanathan
V
Natarajan
Yves A
YA
Lussier
Ralph R
RR
Weichselbaum
Joe G N
JG
Garcia
D000818:Animals; D018893:Bronchoalveolar Lavage; D005786:Gene Expression Regulation; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism* / Q000528:radiation effects*; D055370:Lung Injury / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D025941:Protein Interaction Mapping; D011832:Radiation Injuries / Q000188:drug therapy*; D017564:Radiation Pneumonitis; D019821:Simvastatin / Q000494:pharmacology*; D014158:Transcription, Genetic
D018960:Hyaluronan Receptors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin