Rupatadine Protects against Pulmonary Fibrosis by Attenuating PAF-Mediated Senescence in Rodents
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{"title"=>"Rupatadine Protects against Pulmonary Fibrosis by Attenuating PAF-Mediated Senescence in Rodents", "type"=>"journal", "authors"=>[{"first_name"=>"Xiao xi", "last_name"=>"Lv", "scopus_author_id"=>"34977047900"}, {"first_name"=>"Xiao xing", "last_name"=>"Wang", "scopus_author_id"=>"36624760500"}, {"first_name"=>"Ke", "last_name"=>"Li", "scopus_author_id"=>"57045029800"}, {"first_name"=>"Zi yan", "last_name"=>"Wang", "scopus_author_id"=>"36188954400"}, {"first_name"=>"Zhe", "last_name"=>"Li", "scopus_author_id"=>"55682807600"}, {"first_name"=>"Qi", "last_name"=>"Lv", "scopus_author_id"=>"36901025600"}, {"first_name"=>"Xiao ming", "last_name"=>"Fu", "scopus_author_id"=>"53063445100"}, {"first_name"=>"Zhuo Wei", "last_name"=>"Hu", "scopus_author_id"=>"35306932400"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84880300767", "doi"=>"10.1371/journal.pone.0068631", "pui"=>"369345748", "pmid"=>"23869224", "scopus"=>"2-s2.0-84880300767", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"b82325fa-5adb-3a29-80bc-cf64e00ffc02", "abstract"=>"A similar immune response is implicated in the pathogenesis of pulmonary fibrosis and allergic disorders. We investigated the potential therapeutic efficacy and mechanism of rupatadine, a dual antagonist of histamine and platelet-activation factor (PAF), in bleomycin- (BLM-) and silica-induced pulmonary fibrosis. The indicated dosages of rupatadine were administered in rodents with bleomycin or silica-induced pulmonary fibrosis. The tissue injury, fibrosis, inflammatory cells and cytokines, and lung function were examined to evaluate the therapeutic efficacy of rupatadine. The anti-fibrosis effect of rupatadine was compared with an H1 or PAF receptor antagonist, and efforts were made to reveal rupatadine's anti-fibrotic mechanism. Rupatadine promoted the resolution of pulmonary inflammation and fibrosis in a dose-dependent manner, as indicated by the reductions in inflammation score, collagen deposition and epithelial-mesenchymal transformation, and infiltration or expression of inflammatory cells or cytokines in the fibrotic lung tissue. Thus, rupatadine treatment improved the declined lung function and significantly decreased animal death. Moreover, rupatadine was able not only to attenuate silica-induced silicosis but also to produce a superior therapeutic efficacy compared to pirfenidone, histamine H1 antagonist loratadine, or PAF antagonist CV-3988. The anti-fibrotic action of rupatadine might relate to its attenuation of BLM- or PAF-induced premature senescence because rupatadine treatment protected against the in vivo and in vitro activation of the p53/p21-dependent senescence pathway. Our studies indicate that rupatadine promotes the resolution of pulmonary inflammation and fibrosis by attenuating the PAF-mediated senescence response. Rupatadine holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.", "link"=>"http://www.mendeley.com/research/rupatadine-protects-against-pulmonary-fibrosis-attenuating-pafmediated-senescence-rodents", "reader_count"=>20, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Student > Doctoral Student"=>3, "Researcher"=>4, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Other"=>4, "Student > Bachelor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Student > Doctoral Student"=>3, "Researcher"=>4, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Other"=>4, "Student > Bachelor"=>2}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>9, "Medicine and Dentistry"=>7, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1119162"], "description"=>"<p>(<b>A</b>–<b>C</b>) Rupatadine treatment reduced the BLM-induced lung density shown by micro-CT. Representative micro-CT of main pulmonary lesions of Sham- (A, left), BLM instilled- (A, middle) and rupatadine-treated mice (6.0 mg/kg per day) (A, right) were shown at different slices. Quantification of lung parenchyma density was measured in upper, central and lower pulmonary regions excluding the hilum and bronchi. Scale bar in images = 1 cm. The data are expressed as the mean Hounsfield units (HU) ± SEM of 8 mice per group (B). Rupatadine (6.0 mg/kg per day) reduced parenchymal loss in the fibrotic mice (C). (<b>D</b>) Rupatadine (6.0 mg/kg per day) improved lung functions in the fibrotic mice. Mice were anesthetized with 50 mg/kg i.p. pentobarbital and placed on the flexivent system at the indicated times after bleomycin administration. Mice were mechanically ventilated with a tidal volume of 10 ml/kg and a respiratory rate of 150 breaths/min. The parameters of lung function were calculated by measuring total lung capacity, Snapshot, Quickprime-3, and pressure-volume loops. All perturbations were performed until three acceptable measurements with a coefficient of determination (COD) ≥ 0.9 were recorded for each individual subject. The data are expressed as the mean ± SEM of 6 mice per group. <sup>#</sup><i>P</i><0.05, <sup># # </sup><i>P</i><0.01 vs. Sham group; <sup>*</sup><i>P</i><0.05, <sup>**</sup><i>P</i><0.01 vs. BLM treated group.</p>", "links"=>[], "tags"=>["enhanced", "improves", "functions", "fibrotic"], "article_id"=>745645, "categories"=>["Biological Sciences"], "users"=>["Xiao-Xi Lv", "Xiao-Xing Wang", "Ke Li", "Zi-Yan Wang", "Zhe Li", "Qi Lv", "Xiao-Ming Fu", "Zhuo-Wei Hu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0068631.g002", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rupatadine_reduces_enhanced_lung_density_and_improves_lung_functions_in_fibrotic_mice_/745645", "title"=>"Rupatadine reduces enhanced lung density and improves lung functions in fibrotic mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-15 02:18:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1119161"], "description"=>"<p>The mice were intragastrically administered with solvent alone (sham group) or rupatadine at 1.5, 3.0, or 6.0 mg/kg per day from day 10 to 28 after BLM administration (5 U/kg). On day 28, mice were sacrificed and a lung was obtained for histological analysis and other studies. (<b>A</b>–<b>D</b>) Rupatadine attenuated pulmonary fibrosis and inflammation. Representative H&E staining data are shown (A, top), and the expression of α-SMA in fibrotic lungs. The lung sections were stained with an anti-α-SMA antibody for immunohistochemistry analysis (A, bottom). The IOD of each section was analyzed by Image-Pro Plus image analysis software (D) (n=10 per group). Inflammatory score was evaluated by a professional pathologist who was blind to the animal groups (B) (n=15 per group). Rupatadine treatment reduced the lung index in a dose-dependent manner (C) (n=10 per group). (<b>E</b>–<b>G</b>) Rupatadine decreased collagen deposition in the lungs. The lung tissue sections were stained with Sirius Red (SR) (normal light and polarized light) to indicate the collagen deposition (E and F). Additionally, rupatadine decreased hydroxyproline contents in fibrotic mice (<b>G</b>). Scale bar in images = 200 μm. The representative images in A and E were obtained from animals treated with rupatadine of 6.0 mg/kg per day. Data are expressed as the mean ± SEM of 8 mice per group. Rupatadine treatment inhibited the fibrosis-associated molecules in the fibrotic lung tissue (<b>H</b>). Western blot analysis was performed on lung lysates and detected the expression of α-SMA, E-cadherin and collagen-I in lung tissue. Data were expressed as folds of the sham group ± SEM of 8 mice per group. Rupatadine decreased animal death in BLM-injured mice (<b>I</b>). The cumulative survival rates of mice were analyzed by the Kaplan-Meier method (n=40 per group which were at the start of the experiment). <sup>#</sup><i>P</i><0.05, <sup># # </sup><i>P</i><0.01 vs. Sham group; <sup>*</sup><i>P</i><0.05, <sup>**</sup><i>P</i><0.01 vs. BLM treated group.</p>", "links"=>[], "tags"=>["attenuates", "blm-induced", "pulmonary"], "article_id"=>745644, "categories"=>["Biological Sciences"], "users"=>["Xiao-Xi Lv", "Xiao-Xing Wang", "Ke Li", "Zi-Yan Wang", "Zhe Li", "Qi Lv", "Xiao-Ming Fu", "Zhuo-Wei Hu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0068631.g001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rupatadine_attenuates_BLM_induced_pulmonary_fibrosis_/745644", "title"=>"Rupatadine attenuates BLM-induced pulmonary fibrosis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-15 02:18:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1119169"], "description"=>"<p>(<b>A</b>) Rupatadine inhibited the expression or phosphorylation of the BLM-induced senescence-related molecules in MLE-12 cells. The data are representative immune blots and expressed as the mean ± SEM of four independent assays. (<b>B</b>) Rupatadine inhibited the secretion of IL-6 and PAF from the BLM- and PAF-induced senescent MLE-12 cells. The content of IL-6 and PAF in supernatant solutions was detected by ELISA kits. The data are expressed as the mean ± SEM of four independent assays with triplicates. (<b>C</b>) Rupatadine inhibited the expression of SA β-gal induced by BLM and C-PAF. MLE-12 cells were planted on coverglass-bottom dishes and treated with BLM (3 μg/ml), rupatadine (25 μg/ml), histamine (10 μg/ml), or C-PAF (5 μg/ml) for 96 hours. MLE-12 cells were stained by a senescence kit and examined for SA β-gal activity (blue). Scale bar in images = 50 μm. (<b>D</b> and <b>E</b>) Recovery from BLM and C-PAF induced growth arrest by rupatadine. MLE-12 cells were cultured in the presence or absence of BLM (3 μg/ml), rupatadine (25 μg/ml), histamine (10 μg/ml), and C-PAF (5 μg/ml) for 10 days. Population doubling (D) and representative DNA profile for the treated cells at day 10 were examined by flow cytometry (E). <sup>#</sup><i>P</i><0.05, <sup># # </sup><i>P</i><0.01 vs. Untreated group; <sup>*</sup><i>P</i><0.05, <sup>**</sup><i>P</i><0.01 vs. BLM treated group; † † <i>P</i><0.01 vs. C-PAF group.</p>", "links"=>[], "tags"=>["inhibits", "blm-", "paf-induced", "epithelial", "cellular"], "article_id"=>745652, "categories"=>["Biological Sciences"], "users"=>["Xiao-Xi Lv", "Xiao-Xing Wang", "Ke Li", "Zi-Yan Wang", "Zhe Li", "Qi Lv", "Xiao-Ming Fu", "Zhuo-Wei Hu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0068631.g006", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rupatadine_inhibits_BLM_and_PAF_induced_epithelial_cellular_senescence_/745652", "title"=>"Rupatadine inhibits BLM- and PAF-induced epithelial cellular senescence.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-15 02:18:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1119166"], "description"=>"<p>(<b>A</b>) Rupatadine (6.0 mg/kg per day) attenuated the expression or activity of senescence-related molecules in fibrotic lung tissue. Lung tissue extract was prepared for western blotting. The data are representative immune blots and expressed as the mean ± SEM of 8 mice per group. (<b>B</b>) Rupatadine (6 mg/kg) reduced the number of senescent cell in fibrotic mouse lung tissue. Representative images of lung sections were acquired by confocal microscopy for DAPI (blue)/ γ-H2A.X (green) or immunohistochemistry for p21. Scale bar in images = 10 μm or 50 μm. The data are expressed as the mean ± SEM of 5 mice per group. <sup>#</sup><i>P</i><0.05, <sup># # </sup><i>P</i><0.01 vs. Sham group; <sup>*</sup><i>P</i><0.05, <sup>**</sup><i>P</i><0.01 vs. BLM treated group.</p>", "links"=>[], "tags"=>["attenuates", "cellular", "senescence", "fibrotic"], "article_id"=>745649, "categories"=>["Biological Sciences"], "users"=>["Xiao-Xi Lv", "Xiao-Xing Wang", "Ke Li", "Zi-Yan Wang", "Zhe Li", "Qi Lv", "Xiao-Ming Fu", "Zhuo-Wei Hu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0068631.g004", "stats"=>{"downloads"=>0, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rupatadine_attenuates_cellular_senescence_in_fibrotic_mice_/745649", "title"=>"Rupatadine attenuates cellular senescence in fibrotic mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-15 02:18:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1119164"], "description"=>"<p>(<b>A</b>) BALF was collected on day 28 after BLM administration, and the counts of total WBC and classified cells were evaluated by differential counting. The data are expressed as the mean ± SEM of 8 mice per group. (<i>B</i> and <i>C</i>) Rupatadine decreased the population of lung-infiltrating mast cells and stabilized their activity in the fibrotic lung tissue. The density of mast cells in examined lung sections was detected by staining with 0.05% (w/v) toluidine blue (shown by arrows). The data are representative images of 3 assays with similar results. The mast cells (shown by arrow) were counted in 15 fields at 400x of each mouse. The data are representative images and are summarized as the mean ± SEM of 8 mice per group. Scale bar in images = 200 μm(B). The expression of MCP-7, a specific protease secreted by mast cell degranulation, was detected by Western blotting (C). The data are representative immune blots and summarized as the mean ± SEM of 8 mice per group. (<b>D</b> and <b>E</b>) Rupatadine (6.0 mg/kg per day) regulated the infiltration and polarization of macrophages in BALF in the fibrotic mice. Images of BALF cells on glass coverslips were acquired by confocal microscopy for MAC-3 (red) iNOS (green in top) and Arg-1 (green in bottom). The data are representative images of 3 assays. Scale bar in images = 10 μm(D). M1 and M2 cells on the sections were analyzed by Image-Pro Plus software and expressed as the mean ± SEM of 6 mice per group (E). <sup>#</sup><i>P</i><0.05, <sup># # </sup><i>P</i><0.01 vs. Sham group; <sup>*</sup><i>P</i><0.05, <sup>**</sup><i>P</i><0.01 vs. BLM treated group.</p>", "links"=>[], "tags"=>["inflammatory"], "article_id"=>745647, "categories"=>["Biological Sciences"], "users"=>["Xiao-Xi Lv", "Xiao-Xing Wang", "Ke Li", "Zi-Yan Wang", "Zhe Li", "Qi Lv", "Xiao-Ming Fu", "Zhuo-Wei Hu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0068631.g003", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rupatadine_promotes_the_resolution_of_inflammatory_responses_/745647", "title"=>"Rupatadine promotes the resolution of inflammatory responses.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-15 02:18:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1119177", "https://ndownloader.figshare.com/files/1119179", "https://ndownloader.figshare.com/files/1119180"], "description"=>"<div><p>A similar immune response is implicated in the pathogenesis of pulmonary fibrosis and allergic disorders. We investigated the potential therapeutic efficacy and mechanism of rupatadine, a dual antagonist of histamine and platelet-activation factor (PAF), in bleomycin- (BLM-) and silica-induced pulmonary fibrosis. The indicated dosages of rupatadine were administered in rodents with bleomycin or silica-induced pulmonary fibrosis. The tissue injury, fibrosis, inflammatory cells and cytokines, and lung function were examined to evaluate the therapeutic efficacy of rupatadine. The anti-fibrosis effect of rupatadine was compared with an H1 or PAF receptor antagonist, and efforts were made to reveal rupatadine’s anti-fibrotic mechanism. Rupatadine promoted the resolution of pulmonary inflammation and fibrosis in a dose-dependent manner, as indicated by the reductions in inflammation score, collagen deposition and epithelial-mesenchymal transformation, and infiltration or expression of inflammatory cells or cytokines in the fibrotic lung tissue. Thus, rupatadine treatment improved the declined lung function and significantly decreased animal death. Moreover, rupatadine was able not only to attenuate silica-induced silicosis but also to produce a superior therapeutic efficacy compared to pirfenidone, histamine H1 antagonist loratadine, or PAF antagonist CV-3988. The anti-fibrotic action of rupatadine might relate to its attenuation of BLM- or PAF-induced premature senescence because rupatadine treatment protected against the <i>in vivo</i> and <i>in vitro</i> activation of the p53/p21-dependent senescence pathway. Our studies indicate that rupatadine promotes the resolution of pulmonary inflammation and fibrosis by attenuating the PAF-mediated senescence response. Rupatadine holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.</p> </div>", "links"=>[], "tags"=>["protects", "pulmonary", "fibrosis", "attenuating", "paf-mediated", "senescence"], "article_id"=>745657, "categories"=>["Biological Sciences"], "users"=>["Xiao-Xi Lv", "Xiao-Xing Wang", "Ke Li", "Zi-Yan Wang", "Zhe Li", "Qi Lv", "Xiao-Ming Fu", "Zhuo-Wei Hu"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0068631.s001", "https://dx.doi.org/10.1371/journal.pone.0068631.s002", "https://dx.doi.org/10.1371/journal.pone.0068631.s003"], "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rupatadine_Protects_against_Pulmonary_Fibrosis_by_Attenuating_PAF_Mediated_Senescence_in_Rodents_/745657", "title"=>"Rupatadine Protects against Pulmonary Fibrosis by Attenuating PAF-Mediated Senescence in Rodents", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-07-15 02:18:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1119172"], "description"=>"<p>(<b>A</b>) C-PAF (5 μg/ml), but not histamine (10 μg/ml), induces the expression or phosphorylation of the senescent-related signal molecules in lung epithelial cells. The data are representative immune blots and are expressed as the mean ± SEM of four independent assays. (<b>B</b>) The lower concentration of C-PAF but not histamine induces the growth arrest of lung epithelial cells. MLE cells were treated with BLM (3 μg/ml) for 48 h followed by the withdrawal of BLM and further incubation for 10 days with or without histamine (1 μg/ml), C-PAF (0.5 μg/ml) or rupatadine (25 μg/ml). (<b>C</b>) C-PAF sustained the cell cycle arrest of senescent cells. Bar graphs show the percentage of MLE-12 cells in G0/G1, S and G2/M phase. (<b>D</b>) Schematic diagram illustrating the mechanism of rupatadine in the treatment of pulmonary fibrosis. The BLM-induced acute inflammation may convert to chronic inflammation leading to pulmonary fibrosis progression via 1) Immunosuppressive cells and soluble factors that interfere with the resolution of inflammation. 2) The injured lung tissue expresses the SASP to secret soluble factors that sustain senescence and inflammation. Rupatadine can antagonize the activation of inflammatory cells, such as mast cells, and partly inhibits the BLM- and PAF-mediated senescence response both <i>in vivo</i> and <i>in vitro</i>.</p>", "links"=>[], "tags"=>["sustains", "p53-dependent"], "article_id"=>745655, "categories"=>["Biological Sciences"], "users"=>["Xiao-Xi Lv", "Xiao-Xing Wang", "Ke Li", "Zi-Yan Wang", "Zhe Li", "Qi Lv", "Xiao-Ming Fu", "Zhuo-Wei Hu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0068631.g007", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PAF_induces_and_sustains_p53_dependent_senescence_/745655", "title"=>"PAF induces and sustains p53-dependent senescence.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-15 02:18:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1119167"], "description"=>"<p>(<b>A</b>) Rupatadine (6.0 mg/kg per day) regulated the expression or activity of autophagy-related molecules in the fibrotic lung tissue. Lung tissue extract was prepared for western blotting. The data are representative immune blots and expressed as the mean ± SEM of 6 mice per group. (<b>B</b>) Rupatadine (6.0 mg/kg per day) maintained the autophagic flux in the fibrotic lung tissue. Representative images of lung sections were acquired by confocal microscopy for LC3-II (green)/ LAMP1 (red). Scale bar in images = 200 μm. The data are representative images of 3 assays with identical results. <sup>#</sup><i>P</i><0.05, <sup># # </sup><i>P</i><0.01 vs. Sham group; <sup>*</sup><i>P</i><0.05, <sup>**</sup><i>P</i><0.01 vs. BLM treated group.</p>", "links"=>[], "tags"=>["maintains", "autophagic", "flux", "fibrotic"], "article_id"=>745650, "categories"=>["Biological Sciences"], "users"=>["Xiao-Xi Lv", "Xiao-Xing Wang", "Ke Li", "Zi-Yan Wang", "Zhe Li", "Qi Lv", "Xiao-Ming Fu", "Zhuo-Wei Hu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0068631.g005", "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rupatadine_maintains_autophagic_flux_in_fibrotic_lung_tissue_/745650", "title"=>"Rupatadine maintains autophagic flux in fibrotic lung tissue.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-15 02:18:16"}

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Relative Metric

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