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Objective:To explore the preventive and therapeutic effect of pirfenidone (PFD) on radiation-induced lung fibrosis (RILF) and its mechanism.Methods:40 female C57/BL6 mice were randomly divided into 4 groups: negative control group (NC), PFD treatment group (PFD), radiation treatment group (RT) and radiation plus PFD treatment group (RT+ PFD). Mice in RT and RT+ PFD groups received a single whole lung X-ray consisting of a 50 Gy dose of radiation, delivered by small animal radiation research platform (SARRP). PFD at a dose of 300 mg/kg was administered orally 2 h before irradiation for 150 d. HE and Masson staining were used to detect the infiltration of inflammatory cells and the degree of pulmonary fibrosis. Quantitative real-time PCR (qPCR) and Western blotting (WB) were adopted to detect the expression levels of M1/M2 macrophage phenotypic markers. The expression levels of arginase-1(ARG-1), chitinase 3-like protein 3(YM-1) and interferon regulatory factor-4(IRF4) of macrophages stimulated with IL-4 and IL-13 were detected by WB. In addition, immunofluorescence staining was used to detect the expression and translocation of IRF4 in macrophages among different treatment groups.Results:HE and Masson staining showed that PFD could significantly inhibit radiation-induced infiltration of inflammatory cells and fibrosis in lung tissues. The M2 macrophages and expression levels of ARG-1 and YM-1 were down-regulated in the RT+ PFD group. Cell experiments further confirmed that PFD could significantly inhibit the polarization of macrophages to M2 induced by IL-4+ IL-13, which was mainly related to the down-regulation of IRF4.Conclusion:PFD has a preventive and therapeutic effect on RILF by inhibiting IRF4 and reducing the polarization of macrophages to M2.
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Objective:To compare the efficacy of stereotactic body radiotherapy(SBRT) and surgery in treating intrapulmonary recurrence of non-small cell lung cancer (NSCLC) after radical surgery.Methods:A retrospective analysis was conducted on NSCLC patients, who underwent radical surgery at the Cancer Hospital Affiliated to University of Chinese Academy of Sciences from November 2012 to December 2018 and then received SBRT or secondary surgery because of postoperative intrapulmonary recurrence. The survival rates of these patients were calculated using the Kaplan-Meier method. The comparison between the two groups was made using the Log-rank method, and the univariate and multivariate analysis was made using the Cox regression method.Results:Among 62 eligible patients, 33 received SBRT and 29 received secondary surgery, and they were divided into the SBRT group and the surgery group accordingly. For the SBRT and surgery groups, the median follow-up time was 45.8 months and 37.4 months, the 3-year locoregional control rate (LRCR) 79.8% and 90.2%, respectively ( P > 0.05), the progression-free-survival (PFS) 58.5% and 42.3%, respectively ( P >0.05), and the overall survival (OS) 78.0% and 85.5%, respectively ( P >0.05). The multivariate analysis suggested that treatment method, Charlson comorbidity index (CCI), and adjuvant drug therapy were independent prognostic factors for PFS ( P = 0.027, 0.013, 0.001). Conclusions:The efficacy of SBRT and surgery is comparable for patients with intrapulmonary recurrence of NSCLC after radical surgery.
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Objective:To study the effect of crizotinib on acute radiation-induced lung injury in mice and its possible mechanism.Methods:A total of 72 mice were randomly divided into 4 groups by the random number table method: healthy control group (NC group, n=12), crizotinib-only group (CRZ group, n=12), radiotherapy-only group (RT group, n=24), and radiotherapy pluscrizotinib group (RT+ CRZ group, n=24). The whole lungs were exposed to a single dose of 12 Gy X-rays. Lung tissue and bronchoalveolar lavage fluid (BALF) were obtained at 1, 2, 4, and 8 weeks after radiotherapy. The total number of nucleated cells was counted under a light microscope, and the total protein content of BALF was detected by bicinchoninic acid (BCA) protein assay. The pathological changes of lung tissue were observed by HE staining and MASSON staining. The expressions of TGF-β1 and ICAM-1 mRNA in lung tissue were detected by real-time quantitative polymerase chain reaction (qPCR), the locations and expressions of MPO and ICAM-1 proteins were observed by immunohistochemical staining, and the expressions of TGF-β1, Smad3, p-Smad3 and ICAM-1 proteins in lung tissue were detected by Western blot. Results:At different time points after irradiation, the pathological manifestations such as inflammation and exudation of lung tissue in the RT+ CRZ group were significantly increased, and the total number of cells and protein content in BALF was higher than that of the other three groups, compared with RT group, the difference was statistically significant at 4 week ( t=-5.031, -2.814, P<0.05). Compared with RT group, the expressions of ICAM-1 and TGF-β1 mRNA in lung tissue of the RT+ CRZ group were significantly increased, while the expression of TGF-β1 increased significantly at 1, 4 and 8 weeks after irradiation ( t=-2.687, -7.032, -5.221, P<0.05), and the expression of ICAM-1 increased significantly at 2 and 4 weeks after irradiation ( t=-4.819, -6.057, P<0.05). The expressions of these two gradually increased from 1 to 4 weeks and peaked in 4 weeks, then decreased at 8 weeks. At the same time, the trend of the expression of MPO mRNA was consistent with ICAM-1 and TGF-β1. At 4 week, there was no difference in the expression of Smad3 protein in these four groups ( P>0.05). The expressions of TGF-β1, p-Smad3, ICAM-1 and p-Smad3/Smad3 proteins of the RT+ CRZ group were all higher than those of the other three groups ( F=14.74, 10.03, 35.29, 22.94, P<0.05). Conclusions:Crizotinib combined with radiotherapy can aggravate acute radiation-induced lung injury, which may due to the increase of ICAM-1 expression by up-regulating the TGF-β1 signaling pathway.
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BACKGROUND@#Tumor microenvironment is a complex and dynamic community, which plays a crucial role in tumor progression via the co-evolution of cancer cells and tumor stroma. Among them, tumor-associated macrophages (TAMs) and tumor neo-vessels are two key components in the tumor microenvironment during cancer invasion. In addition, programmed cell death ligand 1/programmed cell death ligand 1 (PD-1/PD-L1) also plays an important role in tumorigenesis and development, and the clinical strategies to block PD-1/PD-L1 pathway could have great benefits for cancer patients. This study was aimed at analyzing the quantitative expression and prognostic significance of TAMs, tumor neo-vessels and PD-L1 in tumor microenvironment and exploring the relations between the expression of above components with the patients' prognosis of non-small cell lung cancer (NSCLC).@*METHODS@#Clinico-pathological data and surgical specimens of 92 patients with NSCLC were collected, and immunohistochemistry was used to stain the expression of TAMs, tumor neo-vessels and PD-L1 on tumor tissue and peri-tumor tissues. The inverted microscopy was used to take pictures and Image-pro Plus 6.0 software was used for quantitative analysis. The clinicopathological characteristics and overall survival (OS) were analyzed.@*RESULTS@#The median OS of 92 NSCLC cases was 22.5 month. The expression of TAMs, tumor neo-vessels and PD-L1 in tumor tissue and peri-tumor tissues were not statistically significant (P>0.05). According to the cutoff of above key three components in tumor microenvironment, all the cases could be classified into high, middle and low expression groups. The survival analysis demonstrated that the OS in high expression group of TAMs (P=0.016) and PD-L1 (P=0.002) was shorter than the other two groups, respectively, with statistical significance. The OS in high tumor neo vessels group was shorter than the other two groups. However, there was no statistical significance between these three group (P=0.626). Combined with above the three components, all the cases could be classified into low, middle and high density groups. The survival analysis demonstrated that the median OS of combined high density group was shorter than the other two groups (P=0.001). Multivariate analysis by Cox regression indicated that pathological type, TAMs and PD-L1 expression were the independent prognostic factors.@*CONCLUSIONS@#The key components of TAMs and PD-L1 in tumor microenvironment are closely related to the prognosis of NSCLC patients.