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Objective To investigate the mechanism of an inhibitor of NADPH oxidases,diphenylene iodonium (DPI),in preventing radiation-induced lung injury.Methods Totally 48 adult SD male rats were randomly classified into 4 groups:control group (C),radiation group (R),radiation plus DPI group (R + D) and DPI group (D).The radiation induced pulmonary injury model was preformed by using 6 MV X-rays to deliver 8 Gy per day for 5 consecutive days with 40 Gy in total to the thorax of each animal.Rats in R + D group were subcutaneously administered with 0.02％ DPI (1 mg/kg) at 1 h prior to radiation while rats in D group received the same dose of DPI without radiation.DPI was given from 3 d before radiation to 30 d after the first radiation.Rats in C and D groups received the same dose of saline.Animals were sacrificed at 1 month and 6 months after radiation,respectively.The lungs were removed and processed for HE and Masson staining,hydroxyproline content measurement,and TGF-β1 immunohistochemical detection.Results At 1 month post-radiation,rats in R group showed typical alveolitis,the level of hydroxyproline was (0.69 ± 0.05) μg/mg,and the positive area of TGF-β1 expression was (39.97 ± 0.90) ％,while the level of hydroxyproline in R + D group was (0.55 ± 0.03) μg/mg and the positive area of TGF-β1 expression was(33.83 ± 1.55) ％,rats in R + D group showed less severe alveolitis compared with R group(t =5.32,5.93,P ＜0.05).At 6 months post-radiation,rats in R group showed typical lung fibrosis with hydroxyproline level of (1.04 ±-0.02) μg/mg and TGF-β1 expression of (37.80 ± 0.85) ％,whereas the hydroxyproline level in R + D group was (0.85 ± 0.02) μg/ mg,the TGF-β1 expression was(23.93 ± 1.16)％,rats in R + D group showed moderate lung fibrosis(t =15.77,16.68,P ＜ 0.05),rats in C and D group had no noticeable changes.Conclusions Diphenylene iodonium could prevent radiation-induced lung injury by reducing the level of hydroxyproline and the expression of TGF-β1.
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The expression of CD(8) (+)CD(25) (+)FoxP(3) (+) regulatory T cells (CD(8) (+)Tregs) in the peripheral blood of patients with stable chronic obstructive pulmonary disease (COPD), and the effect of muscarinic cholinergic receptor antagonist tiotropium bromide on the expression of CD(8) (+)Tregs were investigated. Twenty-three patients with moderate to severe stable COPD were enrolled in this study. All patients inhaled tiotropium bromide (18 μg daily) for 3 months. Before and after inhalation of tiotropium bromide, peripheral blood samples were collected from the patients, and T cells were labeled by three-color labeled monoclonal antibodies. Flow cytometry was used to detect the quantity and percentage of CD(8) (+)T cells, CD(8) (+)CD(25) (+)T cells, CD(8) (+)Tregs, CD(4) (+)T cells, CD(4) (+)CD(25) (+)T cells and CD(4) (+)CD(25) (+)FoxP(3) (+) regulatory T cells (CD(4) (+)Tregs) respectively. The percentage of CD(4) (+)T cells was increased from (27.82±2.18)% to (35.53±1.3)% (t=3.20, P=0.004) in the peripheral blood of patients with stable COPD after inhalation of tiotropium bromide for 3 months, that of CD(4) (+)CD(25) (+)T cells was decreased from (10.03 ±1.42)% to (4.21 ±0.65)% (t=3.78, P=0.001), and that of CD(8) (+)Tregs was increased from (8.41 ±1.68)% to (21.34 ±4.20)% (t=2.72, P=0.013). At baseline, CD(8) (+)T cells, CD(8) (+)CD(25) (+)T cells and CD(4) (+)Tregs were detectable in the peripheral blood, but no significant changes were observed after treatment. Linear correlation analysis revealed that the difference before and after treatment in CD(4) (+)T cells and CD(4) (+)CD(25) (+)T cells was negatively correlated with the ratio of change in CD(8) (+)Tregs before and after treatment (r=-0.61, P=0.013; r=-0.72, P=0.001 respectively). In the peripheral blood of patients with stable COPD, there was the expression of CD(8) (+)Tregs and CD(4) (+)Tregs. Muscarinic receptor antagonist, tiotropium bromide, can promote the amplification of CD(4) (+)T cells, inhibit the expression of CD(25) (+)T cells, and enhance the expression of CD(8) (+)Tregs. CD(8) (+)Tregs and CD(4) (+)Tregs can be used as new indicators to understand the immune status of patients. They are helpful in judging the treatment efficacy and disease immunophenotype.
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Objective To study the expression and significance of indoleamine-2,3-dioxygenase(IDO)in non-small-cell lung cancer(NSCLC).Methods Thirty-eight cases of lung cancer tissues and 10 cases of paracancerous normal lung tissue were collected.The semiquantitative immunohistochemistry was used to detect the positive rate of IDO and fluorescent quantitative PCR to detect the level of IDO mRNA in the lung tissues respectively.Results The positive rate of IDO and the level of IDO mRNA in NSCLC group were significantly higher than in paracancerous normal lung tissues(P＜0.05).There was no significant difference in the positive rate of IDO and the level of IDO mRNA between the adenocarcinoma group and the squamous cell carcinoma group(P＞0.05).Statistically,there was significant difference in positive rate of IDO and the level of IDO mRNA among low,middle and high differentiation groups(P＜0.05).There was significant difference in positive rate of IDO and the level of IDO mRNA between the lymph node metastasis and non-metastasis groups(P＜0.05).Conclusion The high expression of IDO in NSCLC is correlated with the degree of differentiation and the metastasis of lymph nodes,but not with the pathological types.
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Objective To evaluate the efficacy of Budesonide/formoterol to control asthma under real-life conditions.Methods A muhi-center, open label, non-interventional study was conducted.Asthma control after 12 week therapy with Budesonide/formoterol was assessed by Asthma Control Questionnaire (ACQ) and modified Asthma Control Questionnaire (ACQ5).Results A total of 360 asthma patients were recruited,including 228 adult patients and 132 child patients.After 12 weeks' therapy,all the patients' medium value of ACQ was decreased significantly from 2.03 (adults 2.20, children 1.74) at baseline to 0.60 (adults 0.78, children 0.29) (P < 0.0001), and the medium value of ACQ5 was also decreased significantly from 2.4 (adults 2.24, children 1.76) at baseline to 0.47 (adults 0.62, children 0.20) (P < 0.0001).Conclusion Budesonide/formoterol is effective in asthma treatment, by which most asthma patients obtain and maintain clineal control.
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Objective To test the reliability and validity of ICF Core Sets for Chinese COPD patients.Methods Fifty-two COPD patients were measured with ICF Core Sets for COPD patients and SF-36. For reliability test, the internal consistency was analyzed and expressed by Cronbach α coefficients and split-half reliability. For va-lidity test, the content validity and criterion validity were analyzed and expressed with Spearman rank correlation coef-ficients. Results For body function, body structure and activity and participation, there were good internal consis-tency (Cronbach α coefficients 0. 698～0.957). For environmental factors Crnnbach α coefficient and split-half reli-ability did not exist. Most items of body function, activity and participation and body structure possessed good content validity. There was concurrent validity for ICF components of body function, body structure and activity and participa-tion with SF-36, FEV1/FVC, COPD grade and health self-assessment. The environmental factors demonstrated poor reliability and validity. Conclusion The ICF Core Sets for COPD patients showed good reliability and validity. It is a good comprehensive functional measurement scale for COPD patients, but it is necessary to test the generality of this result, and some items need to be adjusted.
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To compare the difference in tumor immunity and autoimmunity elicited by adenovirus (Ad) encoding human or murine tyrosinase-related protein 2 (AdhTRP2 or AdmTRP2), and to find the most effective way to induce immunity by AdhTRP2 or AdmTRP2, C57BL/6 mice were immunized with AdhTRP2 or AdmTRP2 intramuscularly at different doses of 10(5), 10(6), 10(7) and 10(8) separately (10 mice for each dose). Two weeks after the immunization, in vivo CTL assay and intracellular staining (ICS) of IFN-gamma were carried out to analyze the dose-effect relationship. Tumor growth and vitiligo (as an sign of autoimmunity) were observed until 3 months after challenge with 10(5) B16F10 tumor cells. The results showed that Ad encoding AdmTrp2 induced weak tumor immune response. Similar immunization with AdhTrp-2 elicited stronger protective immunity. CTL activity and IFN-gamma-produced CD8+T cells were directly proportional to dose of AdhTrp2 or AdmTrp2. Moreover, AdhTrp2 group showed tumor rejection in 100% of challenged mice till the end of 3rd month while 60% of mice immunized with AdmTrp2 were protected against tumor. In the whole process of this experiment, no vitiligo was observed in mice immunized either with AdhTrp2 or AdmTrp2. It is concluded that anti-melanoma responses induced by genetic vaccination expressing xenoantigens breaks immune tolerance effectively and is able to elicit strong antigen-specific cytotoxic T cell response without vitiligo.
Subject(s)
Adenoviridae/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cytokines/metabolism , Immune System , Immune Tolerance , Interferon-gamma/metabolism , Intramolecular Oxidoreductases/biosynthesis , Intramolecular Oxidoreductases/genetics , Mice, Inbred C57BL , T-Lymphocytes, Cytotoxic/metabolism , Vitiligo/metabolismABSTRACT
The up-regulation mechanism of membrane type I matrix metalloproteinase (MT1-MMP) in macrophages stimulated by silica in vitro and the contribution of early growth response 1 (Egr-1) transcription factor in the gene expression pathway were investigated. Macrophages stimulated by silica were treated with Egr-1 antibody or Egr-1 decoy oligodeoxynucleotides (ODN). The levels of MT1-MMP proteins were determined by Western blot and the expression of MT1-MMP mRNAs was detected by RT-PCR. The results showed as compared with control macrophages, silica-stimulated group showed up-regulated gene expression of MT1-MMP via Egr-1 (P<0.01). Compared with silica-stimulated macrophages untreated with antibody, the cells treated with 5 microg/mL Egr-1 antibody were associated with reduced expression of MT1-MMP protein (P<0.01) and mRNA (P<0.01). Compared with silica-stimulated untransfected group, the Egr-1 "decoy" ODN group was associated with reduction in the expression of MT1-MMP protein and mRNA (P<0.01). It was concluded gene expression of MT1-MMP which may play a critical role in silicosis was up-regulated by silica in macrophages. Egr-1 participated in the expression of MT1-MMP and positively regulated the expression. Both Egr-1 antibody and Egr-1 decoy ODN suppressed the expression of MT1-MMP through the Egr-1 pathway and may become a potential therapeutic tool in the management of silicosis in the future.
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The up-regulation mechanism of membrane type Ⅰ matrix metalloproteinase (MT1-MMP) in macrophages stimulated by silica in vitro and the contribution of early growth response 1 (Egr-1) transcription factor in the gene expression pathway were investigated. Macrophages stimulated by silica were treated with Egr-1 antibody or Egr-1 decoy oligodeoxynucleotides (ODN). The levels of MT1-MMP proteins were determined by Western blot and the expression of MT1-MMP mRNAs was detected by RT-PCR. The results showed as compared with control macrophages, silica-stimulated group showed up-regulated gene expression of MT1-MMP via Egr-1 (P＜0.01). Compared with silica-stimulated macrophages untreated with antibody, the cells treated with 5 μg/mL Egr-1 antibody were associated with reduced expression of MTI-MMP protein (P＜0.01) and mRNA (P＜0.01). Compared with silica-stimulated untransfected group, the Egr-1 "decoy" ODN group was associated with reduction in the expression of MT1-MMP protein and mRNA (P＜0.01). It was concluded gene expression of MT1-MMP which may play a critical role in silicosis was up-regulated by silica in macrophages. Egr-1 participated in the expression of MT1-MMP and positively regulated the expression. Both Egr-1 antibody and Egr-1 decoy ODN suppressed the expression of MT1-MMP through the Egr-1 pathway and may become a potential therapeutic tool in the management of silicosis in the future.
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In order to investigate the immunity of unloaded dendritic cells (DCs) derived from murine bone marrow to preexisting lung melanoma metastases of mice, MO5 were intravenously injected to induce lung metastases in syngeneic C57BL/6 mice. Unloaded GM-CSF DCs, PBS and DCs+SIINFEKEL were subcutaneously injected into the mice, which were divided as experimental group, negative control group and positive control group respectively. Monoclonal antibody was used to deplete NK or T cells separately. The immunity-inhibitory effects on the lung melanoma were observed and the corresponding effector cells were examined. It was found that in the experimental and positive groups, the regression was induced in metastatic nodules in the lungs of tumor-bearing mice,but abrogated by treatment with anti-asialo-GM1 but not anti-CD8. It was concluded that the unloaded DCs could suppress the lung melanoma metastases to some extent, which was mediated by NK cells, and could be used as a potent therapeutic agents for lung tumor.
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Objective To study the expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the lung tissues of smoking cessation rat model. Methods Fifty Wistar rats were randomly divided into the normal control rats which were exposed to room air for 4 and 6 months respectively(groups A and C), the smoking rats which were exposed to cigarette smoke for 4 and 6 month respectively(groups B and D), and the smoking cessation group which was exposed to room air for 2 months after 4 months' smoke exposure.The expressions of mRNA and proteins of MMP-9 and TIMP-1 in the lung tissues were detected by in situ hybridization and immunohistochemistry respectively. The collagen Ⅳ expression in the lung tissues was assessed by immunohistochemistry. Results Compared with groups A and C, the expression levels of MMP-9 and TIMP-1 in the lung tissues of groups B and D significantly elevated(P
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Objective To study the role of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in extracellular matrix remodeling in rat model of chronic obstructive pulmonary emphysema .Methods Seventy Wistar rats were randomly subdivided into the control group and the smoking groups which were randomly subdivided into one month to six month smoking group again.The smoking groups were exposed to cigarette smoke for one to six months, The expressions of MMP-9 and TIMP-1 mRNA and proteins in lung tissue were detected by in situ hybridization and immunohistochemistry respectively.In lung tissue the expression of collagen Ⅳ was assessed by method of immunohistochemistry.Results Compared with the control group,the expressions of MMP-9 and TIMP-1 mRNA and proteins in lung tissue from the smoking groups were remarkable elevated(P
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AIM: To investigate the effect of hypoxia on the expression of MMP-2 and TIMP-1 in pulmonary artery fibroblasts. METHODS: MMP-2 activity was measured by using gelatin zymography. TIMP-1 protein level was determined by immunocytochemistry and Western blotting. mRNA expression was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: The production of MMP-2 mRNA and protein was down-regulated in pulmonary artery fibroblasts exposed to hypoxia for 24 h. Gelatin zymography also demonstrated that lower level of MMP-2 activity was induced after hypoxia. Meanwhile, hypoxia induced the up-regulation of TIMP-1 mRNA and protein in pulmonary artery fibroblasts. CONCLUSION: Hypoxia induces unbalance of MMP-2/TIMP-1 in pulmonary artery fibroblasts, which may contribute to the mechanism of hypoxic pulmonary vascular remodeling.