Simvastatin Attenuates Radiation-Induced Murine Lung Injury and Dysregulated Lung Gene Expression

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-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.

LY2109761 Attenuates Radiation-Induced Pulmonary Murine Fibrosis via Reversal of TGF-β and BMP-Associated Proinflammatory and Proangiogenic Signals

“…Inhibitors of PDGF, VEGF, and fibroblast growth factor (FGF) have been shown to attenuate lung fibrosis in bleomycin models (44,45), and TGF-b antibodies as well as a different small-molecule TGF-b kinase inhibitor were studied in a radiation-induced lung prevention fibrosis model in rats (46)(47)(48). Similarly, simvastatin has recently been shown to attenuate acute RILI without affecting later fibrosis or mouse survival (48).…”

Sphingosine-1–Phosphate, FTY720, and Sphingosine-1–Phosphate Receptors in the Pathobiology of Acute Lung Injury

“…The inhibition of SPT also decreased radiation-induced SphK activity in the lung, which modulated the concentrations of S1P/ dihydro-S1P in lung tissue and the circulation (52). Interestingly, simvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, attenuated RILI in the mouse model by modulating the expression of SphK and S1PL proteins and the concentrations of ceramide to S1P/dihydroS1P in lung tissue (53). These results support the notion that S1P and S1P-metabolizing enzymes offer potential therapeutic targets against RILI.…”

Nonmuscle Myosin Light Chain Kinase Activity Modulates Radiation‐Induced Lung Injury

“…Mice were anesthetized with ketamine (100 mg/ kg) and acepromazine (1.5 mg/kg) and administered radiation (20 Gy) to the thorax, as we described previously. 2 Briefly, a 5-mmthick lead block was used to shield the rest of the animal while the thorax, between the clavicles and below the sternum, was irradiated with a 250-kV x-ray beam at a dose rate of 2 Gy/minute using an orthovoltage animal irradiator. Body weight was measured for individual mice.…”

“…The mice were then killed, and indices of lung vascular leak and inflammation were assessed via bronchoalveolar lavage (BAL) fluid protein levels and cell counts, as previously described. 2 Lungs were harvested for further evaluation.…”

“…1 Although the exact molecular mechanisms of radiation-induced lung injury (RILI) are controversial and likely multifactorial, a potentially important cellular target in RILI is the lung endothelium, a functionally dynamic tissue that regulates influx of macromolecules and fluid between the vascular compartment and the lung interstitial space. 2 Disruption of endothelial cell (EC) barrier integrity is considered a key feature of pulmonary inflammation in general and RILI in particular, resulting in increased vascular permeability and alveolar flooding. Thus, stabilization or enhanced restoration of lung vascular endothelial integrity is a critical step in preventing or reducing acute or subacute RILI, as we have previously demonstrated.…”