Dietary Curcumin Increases Antioxidant Defenses in Lung, Ameliorates Radiation-Induced Pulmonary Fibrosis, and Improves Survival in Mice

Abstract

The effectiveness of lung radiotherapy is limited by radiation tolerance of normal tissues and by the intrinsic radiosensitivity of lung cancer cells. The chemopreventive agent curcumin has known antioxidant and tumor cell radiosensitizing properties. Its usefulness in preventing radiation-induced pneumonopathy has not been tested previously. We evaluated dietary curcumin in radiation-induced pneumonopathy and lung tumor regression in a murine model. Mice were given 1%or 5%(w/w) dietary curcumin or control diet prior to irradiation and for the duration of the experiment. Lungs were evaluated at 3 weeks after irradiation for acute lung injury and inflammation by evaluating bronchoalveolar lavage (BAL) fluid content for proteins, neutrophils and at 4 months for pulmonary fibrosis. In a separate series of experiments, an orthotopic model of lung cancer using intravenously injected Lewis lung carcinoma (LLC) cells was used to exclude possible tumor radioprotection by dietary curcumin. In vitro, curcumin boosted antioxidant defenses by increasing heme oxygenase 1 (HO-1) levels in primary lung endothelial and fibroblast cells and blocked radiation-induced generation of reactive oxygen species (ROS). Dietary curcumin significantly increased HO-1 in lungs as early as after 1 week of feeding, coinciding with a steady-state level of curcumin in plasma. Although both 1% and 5% w/w dietary curcumin exerted physiological changes in lung tissues by significantly decreasing LPS-induced TNF-α production in lungs, only 5%dietary curcumin significantly improved survival of mice after irradiation and decreased radiation-induced lung fibrosis. Importantly, dietary curcumin did not protect LLC pulmonary metastases from radiation killing. Thus dietary curcumin ameliorates radiation-induced pulmonary fibrosis and increases mouse survival while not impairing tumor cell killing by radiation.

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

“…123 Curcumin ameliorated radiation-induced pulmonary fibrosis and enhanced the survival of mice in association with upregulation of antioxidant defenses in lungs. 124 Quercetine, a dietary flavonoid found in citrus fruits, is another potential activator of Nrf2. Using ARE-luciferase reporter gene assays, quercetin has been shown to activate Nrf2 and upregulate NQO1.…”

Plant Extracts and Plant-Derived Compounds: Promising Players in Countermeasure Strategy Against Radiological Exposure: A Review

“…Cultures were then exposed to 2 Gy of IR (Dose rate of 1.14 Gy/min). As mentioned earlier (Lee et al, 2010), ROS produced by the pulmonary endothelium was detected by H 2 DCF-DA fluorescence. It was found that a significant increase in ROS generation occurred shortly after radiation (assess by fluorescent imaging), which was diminished in a dose-dependent manner by SDG (p<0.001).…”

“…Others act against radiation exposure by inducing the expression of Mn-SOD, GSH, CAT, and GPx, the important members of antioxidant defence system (Han et al, 2005;Gottfredsen et al, 2014) or modulate the immune response against radiation exposure Qiu et al, 2008;Pragya et al, 2014;Yu et al, 2014). Additionally, some of these plant extract/plant-derived compounds have also been found to reduce ROS, suppress cytokines, TNF-α and TGF-β1, thereby reducing the OH-proline level (the fibrotic index) in radiation-induced lung tissue (Han et al, 2006;Xie et al, 2006;Lee et al, 2009;Lee et al, 2010;Flechsig et al, 2010;Qiu et al, 2011;Gorshkova et al, 2012;Cho et al, 2013;Ding et al, 2013;Horton et al, 2013). Therefore, in general, the plant extracts/plant-derived compounds might act, either by suppressing some of these radiationinduced proinflammatory cytokines and other mediators of inflammatory response such as TNF-α, which in turn can induce the antioxidant defence system, or might activate the antioxidant defence system directly, in response to radiation exposure.…”

“…It was demonstrated in systemic LPS-induced sepsis that curcumin inhibit transmigration and infiltration of neutrophils from blood vessels to the underlying liver tissue, suppressing damage to the tissue (Madan and Ghosh, 2003). Another study revealed the antioxidant potential of curcumin against radiation-induced oxidative stress (Lee et al, 2010). In this study, pulmonary microvascular endothelial cells (PMVEC) isolated from mouse lungs were pretreated with curcumin (5, 10, 25, 50, 100 μg) 4 h prior to γ-irradiation (2 Gy; dose rate of 1.7 Gy/min).…”

“…Clonogenic survival assay after treatment of murine Lewis lung carcinoma (LLC) cells or PMVEC with 10 or 25 μM curcumin or dimethyl sulfoxide (DMSO; vehicle control) 4 h prior to IR exposure (2, 4 and 6 Gy) revealed that curcumin was able to radiosensitize these cells but not normal endothelial cells (Lee et al, 2010). Curcumin treatment resulted in significant increase (p<0.05) in radiation killing of the LLC cells in a dose-dependent manner (particularly at 6 Gy) but did not increase the killing of PMVEC cells.…”