Abstract
Pneumonitis and pulmonary fibrosis are predominant consequences of radiation exposure, whether planned or accidental. The present study, demonstrates radioprotective potential of a formulation, prepared by combining podophyllotoxin and rutin (G-003M), in mice exposed to 11 Gy thoracic gamma radiation (TGR). Treated mice were observed for survival and other symptomatic features. Formation of reactive oxygen species (ROS)/nitric oxide (NO) was measured in bronchoalveolar lavage cells. DNA damage and cell death were assessed in alveolar cells by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Total protein (TP), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) were measured in bronchoalveolar lavage fluid (BALF)/serum of mice to assess lung vascular permeability. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), cluster of differentiation 45, inducible nitric oxide synthase (iNOS), and nitrotyrosine were also estimated in lungs/BALF of differentially treated mice. Our observations revealed 100% survival in G-003M-pretreated mice against 66.50% in 11 Gy TGR exposed. Other symptoms like reduction in graying of hair, weight loss, and breathing rate were also observed in pretreated groups. Significant decline in ROS/NO and cell death in formulation pretreated mice were also observed. Decreased level of TP, LDH, and ALP in BALF/serum samples revealed G-003M-induced inhibition in lung permeability. Level of IL-6, TNF-α, and TGF-β1 in the lungs of these mice was found corresponding to control group at 8 weeks posttreatment. On the contrary, these cytokines raised significantly in 11 Gy TGR-exposed mice. Lung pneumonitis and fibrosis were found significantly countered in these mice. The observations revealed that G-003M could regulate immune system by curtailing radiation-induced oxidative and inflammatory stress, which has helped in minimizing radiation-inflicted pneumonitis and fibrosis.
Highlights
Radiation-induced complications to the respiratory system are among one of the common causes of fatality
Polyclonal anti-transforming growth factor-β1 (TGF-β1) (AV 37894), antiiNOS (N7782), 2′,7′-dichlorofluorescein diacetate (DCF-DA), diaminofluorescein diacetate (DAF-2), dimethyl sulfoxide (DMSO), trichloroacetic acid (TCA), chloramine-T, sodium acetate, isopropanol, p-dimethylaminobenzaldehyde, perchloric acid, trans-4-hydroxy-l-proline standard, and all other required chemicals were obtained from Sigma Aldrich
Since reactive oxygen species (ROS)/reactive nitrogen species (RNS) are prevalent in radiation-induced lung injuries, use of antioxidant molecules/enzymes has been frequented to reduce the formation of these species in the related organ [10]
Summary
Radiation-induced complications to the respiratory system are among one of the common causes of fatality. Radiation-induced pneumonitis and fibrosis in humans as well as in experimental animals have been repeatedly documented [2,3,4,5]. The early phase of an inflammatory response, mediates the release of certain pro-fibrotic cytokines such as fibroblast growth factor, transforming growth factor-β1 (TGF-β1), platelet derived growth factor (PDGF), etc. Owing to high oxygen content, production of radiation-induced reactive oxygen species (ROS)/ reactive nitrogen species (RNS) is excessive in lungs. Increased ROS/nitric oxide (NO) perturbs alveolar epithelium and vascular endothelium, which may lead to recruitment of certain inflammatory cells in the lung parenchyma [5, 8]. Cytokines [tumor necrosis factor-α (TNF-α), IL-1, interleukin-6 (IL-6), PDGF, fibroblast growth factor, and TGF-β1] released by inflammatory cells, consequentially lead to lung pathogenesis and subsequent loss in functional integrity of the organ [9]. TGF-β1, secreted by numerous inflammatory, mesenchymal, and epithelial cells converts fibroblasts and other cell types into matrix-producing myofibroblasts leading to fibrosis [6, 9]
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