Effect of Administration of Lovastatin on the Development of Late Pulmonary Effects after Whole-Lung Irradiation in a Murine Model

Abstract

Our group's work on late radiation effects has been governed by the hypothesis that the effects observed in normal tissues are a consequence of multicellular interactions through a network of mediators. Further, we believe that inflammation is a necessary component of this process. We therefore investigated whether the recruitment of mononuclear cells, observed during the pneumonitic period in the irradiated normal lung, is dependent on the expression of chemokines, notably Mcp1. Since statins have been shown to reduce chemokine expression and inflammatory cell recruitment, we specifically examined whether statins could be used to reduce monocyte recruitment. Mice received 15 Gy whole-lung irradiation; treated groups were administered lovastatin three times weekly starting either immediately or 8 weeks postirradiation. At subsequent intervals, animals were killed humanely, and cellular, mRNA and protein analyses were undertaken. Statin-treated animals demonstrated a statistically significant reduction in both macrophage and lymphocyte populations in the lung compared to radiation alone as well as improved rates of survival and decreased collagen content. In addition, ELISA measurements showed that radiation-induced increases in Mcp1 protein were reduced by statin treatment. Additional experiments are needed to assess whether statins offer a potential treatment for the amelioration of late effects in breast and lung cancer patients undergoing radiation therapy.

Pravastatin Inhibits the Rho/CCN2/Extracellular Matrix Cascade in Human Fibrosis Explants and Improves Radiation-Induced Intestinal Fibrosis in Rats

“…The present study is the first to report a significant improvement of the intestinal structure after pravastatin administration in a rat model of radiation enteropathy, and confirms the relevance of these findings for human pathology using human samples. These experiments in the gut confirm the results previously obtained by Williams et al In William's study, conducted on mice, the beneficial action of lovastatin on radiation-induced pulmonary fibrosis was reported to be associated with decreased collagen deposition attributed to the classic antiinflammatory action of lovastatin such as decreased macrophage and lymphocyte recruitment (31). In the present study, another explanation for decreased collagen deposition is proposed based on the direct ability of pravastatin to decrease ECM and CCN2 expression secreted by the mesenchymal compartment through alteration of the Rho pathway.…”

Gene Expression Profiling Distinguishes Radiation-Induced Fibrosing Alveolitis from Alveolitis in Mice

“…Complement signaling can influence innate and adaptive immune responses (16,17), both of which have been implicated in the development of radiation-induced lung disease (18,19). In this study, we demonstrate that a deficiency in complement component C4b does not accelerate the onset of respiratory distress nor the amount of lung disease in mice exposed to whole-thorax irradiation.…”

Simvastatin Ameliorates Radiation Enteropathy Development After Localized, Fractionated Irradiation by a Protein C-Independent Mechanism

“…The dose used in our study is higher than that used by the Rochester group (5 mg/kg/d) to ameliorate pneumonitis after whole lung irradiation (42). First, however, the 80 mg/kg/d dose was well tolerated in a pilot study with localized intestinal irradiation (43).…”