A Combination of Podophyllotoxin and Rutin Alleviates Radiation-Induced Pneumonitis and Fibrosis through Modulation of Lung Inflammation in Mice

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.

Phycocyanin attenuates X-ray-induced pulmonary inflammation via the TLR2-MyD88-NF-κB signaling pathway

“…Radiation-induced lung injury has been described as a continuous multicellular process involving the immediate release of cytokines from specifi c cells, rather than their sequential release during the incubation period, pneumonia, and later stages of injury (Verma et al, 2017). The oxidative stress induced by radiation is closely associated with infl ammation, causing cell damage and inducing changes in the expression of cytokines and growth factors in epithelial and endothelial cells, fi broblasts, and alveolar macrophages.…”

“…Pneumonia and fi brosis are the main consequences of lung radiation (Verma et al, 2017), and infl ammation is known to play a crucial role in the development of fi brosis. Moreover, reducing the extent of early stage radiation pneumonia eff ectively prevents the occurrence and development of pulmonary fi brosis.…”

Dendrimer-conjugated podophyllotoxin suppresses DENA-induced HCC progression by modulation of inflammatory and fibrogenic factors

“…In an earlier report, podophyllotoxin also successfully reduced interstitial edema, inflammatory cell intrusion, and congealing of the alveolar wall in irradiated lungs. 30 DPODO treatment was also reported to reduce hyperkeratosis, epidermal hyperplasia, and pearl body formation in DMBA-TPA-induced skin tumour. 22 IL-6 is synthesized primarily by macrophages, fibroblasts, endothelial cells, etc., and plays a role in the body's response towards injury or infection.…”

Advances in Molecular Mechanisms and Treatment of Radiation-Induced Pulmonary Fibrosis

“…Rutin demonstrates strong proton-donating and free radical–stabilizing properties. A formulation (G-003M) prepared by combining two molecules podophyllotoxin and rutin was reported to modulate immunity and inhibit RIPF by attenuating oxidative/nitrosative stress and downregulating the expression of inflammatory/fibrogenic cytokines [101] .…”