Radiation therapy is widely used for thoracic cancers. However, it occasionally causes radiation-induced lung injuries, including pneumonitis and fibrosis. Chung-Sang-Bo-Ha-Tang (CSBHT) has been traditionally used to treat chronic pulmonary disease in Korea. PM014, a modified herbal formula derived from CSBHT, contains medicinal herbs of seven species. In our previous studies, PM014 exhibited anti-inflammatory effects in a chronic obstructive pulmonary disease model. In this study, we have evaluated the effects of PM014 on radiation-induced lung inflammation. Mice in the treatment group were orally administered PM014 six times for 2 weeks. Effects of PM014 on radiation pneumonitis were evaluated based on histological findings and differential cell count in bronchoalveolar lavage fluid. PM014 treatment significantly inhibited immune cell recruitment and collagen deposition in lung tissue. Normal lung volume, evaluated by radiological analysis, in PM014-treated mice was higher compared to that in irradiated control mice. PM014-treated mice exhibited significant changes in inspiratory capacity, compliance and tissue damping and elastance. Additionally, PM014 treatment resulted in the downregulation of inflammatory cytokines, chemokines, and fibrosis-related genes and a reduction in the transforming growth factor-β1-positive cell population in lung tissue. Thus, PM014 is a potent therapeutic agent for radiation-induced lung fibrosis and inflammation.
Background/Aims: Radiation-induced skin fibrosis is a common side effect of clinical radiotherapy. Our previous next-generation sequencing (NGS) study demonstrated the reduced expression of the regulatory α subunit of phosphatidylinositol 3-kinase (PIK3r1) in irradiated murine skin. Metformin has been reported to target the PIK3-FOXO3 pathway. In this study, we investigated the effects of metformin on radiation-induced skin fibrosis. Methods: Metformin was orally administered to irradiated mice. Skin fibrosis was analyzed by staining with H&E and Masson’s trichrome stain. The levels of cytokines and chemokines associated with fibrosis were analyzed by immunohistochemistry and quantitative RT-PCR. The roles of PIK3rl and FOXO3 in radiation-induced skin fibrosis were studied by overexpressing PIK3rl and transfecting FOXO3 siRNA in NIH3T3 cells and mouse-derived dermal fibroblasts (MDF). Results: The oral administration of metformin significantly reduced radiation-induced skin thickening and collagen accumulation and significantly reduced the radiation-induced expression of FOXO3 in murine skin. Additionally, the overexpression of PIK3r1 reduced the radiation-induced expression of FOXO3, while FOXO3 silencing decreased the radiation-induced expression of TGFβ in vitro. Conclusions: The results indicated that metformin suppresses radiation-induced skin injuries by modulating the expression of FOXO3 through PIK3r1. Collectively, the data obtained in this study suggested that metformin could be a potent therapeutic agent for alleviating radiation-induced skin fibrosis.
Radiation therapy is an important modality in the treatment of lung cancer, but it can lead to radiation pneumonitis, and eventually radiation fibrosis. To date, only few available drugs can effectively manage radiation-induced pulmonary fibrosis. Lipoxins are endogenous molecules exhibit anti-inflammatory and pro-resolving effects. These molecules play a vital role in reducing excessive tissue injury and chronic inflammation; however, their effects on radiation-induced lung injury (RILI) are unknown. In this study, we investigated the effects of lipoxin A 4 (LXA 4) on RILI using our specialized small-animal model of RILI following focal-ablative lung irradiation (IR). LXA 4 significantly inhibited immune-cell recruitment and reduced IR-induced expression of pro-inflammatory cytokines and fibrotic proteins in the lung lesion sites. In addition, micro-CT revealed that LXA 4 reduced IR-induced increases in lung consolidation volume. The flexiVent TM assays showed that LXA4 significantly reversed IR-induced lung function damage. Moreover, LXA4 downregulated the activities of NF-κB and the Smad-binding element promoters. The expression of FPR2, an LXA 4 receptor, increased during the development of IR-induced pulmonary fibrosis, whereas silencing of endogenous LXA 4 using an antagonist (WRW4) or FPR2 siRNA resulted in impaired development of pulmonary fibrosis in response to IR. Collectively, these data suggest that LXA 4 could serve as a potent therapeutic agent for alleviating RILI.
Radiation therapy has been used to treat over 70% of thoracic cancer; however, the method usually causes radiation pneumonitis. In the current study, we investigated the radioprotective effects of HSP27 inhibitor (J2) on radiation-induced lung inflammation in comparison to amifostine. In gross and histological findings, J2 treatment significantly inhibited immune cell infiltration in lung tissue, revealing anti-inflammatory potential of J2. Normal lung volume, evaluated by micro-CT analysis, in J2-treated mice was higher compared to that in irradiated mice. J2-treated mice reversed radiation-induced respiratory distress. However, amifostine did not show significant radioprotective effects in comparison to that of J2. In HSP27 transgenic mice, we observed increased immune cells recruitment and decreased volume of normal lung compared to wild type mice. Increased ROS production and oxidative stress after IR were down-regulated by J2 treatment, demonstrating antioxidant property of J2. The entire data of this study collectively showed that J2 may be an effective therapeutic agent for radiation-induced lung injury.
Radiation therapy is the mainstay in the treatment of lung cancer, and lung fibrosis is a radiotherapy-related major side effect that can seriously reduce patient’s quality of life. Nevertheless, effective strategies for protecting against radiation therapy-induced fibrosis have not been developed. Hence, we investigated the radioprotective effects and the underlying mechanism of the standardized herbal extract PM014 on radiation-induced lung fibrosis. Ablative radiation dose of 75 Gy was focally delivered to the left lung of mice. We evaluated the effects of PM014 on radiation-induced lung fibrosis in vivo and in an in vitro model. Lung volume and functional changes were evaluated using the micro-CT and flexiVent system. Fibrosis-related molecules were evaluated by immunohistochemistry, western blot, and real-time PCR. A orthotopic lung tumour mouse model was established using LLC1 cells. Irradiated mice treated with PM014 showed a significant improvement in collagen deposition, normal lung volume, and functional lung parameters, and these therapeutic effects were better than those of amifostine. PM104 attenuated radiation-induced increases in NF-κB activity and inhibited radiation-induced p65 translocation, ROS production, DNA damage, and epithelial-mesenchymal transition. PM104 effectively alleviated fibrosis in an irradiated orthotopic mouse lung tumour model while not attenuating the efficacy of the radiation therapy by reduction of the tumour. Standardized herbal extract PM014 may be a potential therapeutic agent that is able to increase the efficacy of radiotherapy by alleviating radiation-induced lung fibrosis.
Although lung injury including fibrosis is a well‐documented side effect of lung irradiation, the mechanisms underlying its pathology are poorly understood. X‐rays are known to cause apoptosis in the alveolar epithelial cells of irradiated lungs, which results in fibrosis due to the proliferation and differentiation of fibroblasts and the deposition of collagen. Apoptosis and BH3‐only pro‐apoptotic proteins have been implicated in the pathogenesis of pulmonary fibrosis. Recently, we have established a clinically analogous experimental model that reflects focal high‐dose irradiation of the ipsilateral lung. The goal of this study was to elucidate the mechanism underlying radiation‐induced lung injury based on this model. A radiation dose of 90 Gy was focally delivered to the left lung of C57BL/6 mice for 14 days. About 9 days after irradiation, the mice began to show increased levels of the pro‐apoptotic protein Noxa in the irradiated lung alongside increased apoptosis and fibrosis. Suppression of Noxa expression by small interfering RNA protected cells from radiation‐induced cell death and decreased expression of fibrogenic markers. Furthermore, we showed that reactive oxygen species participate in Noxa‐mediated, radiation‐induced cell death. Taken together, our results show that Noxa is involved in X‐ray‐induced lung injury.
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