Effects of iloprost on bleomycin-induced pulmonary fibrosis in rats compared with methyl-prednisolone

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Aytemur, S.S. Hacievliyagil, M. Iraz, E. Samdanci, E. Ozerol, I. Kuku, Z. Nurkabulov, K. Yildiz" "autores" => array:8 [ 0 => array:3 [ "nombre" => "Z.A." "apellidos" => "Aytemur" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:4 [ "nombre" => "S.S." "apellidos" => "Hacievliyagil" "email" => array:1 [ 0 => "suleyman.hacievliyagil@inonu.edu.tr" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "¿" "identificador" => "cor0005" ] ] ] 2 => array:3 [ "nombre" => "M." "apellidos" => "Iraz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "E." "apellidos" => "Samdanci" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "E." 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"apellidos" => "Yildiz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Department of Pulmonary Disease, Inonu University Medical Faculty, Malatya, Turkey" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Pharmacology Disease, Bezmialem University Medical Faculty, Istanbul, Turkey" "etiqueta" => "b" "identificador" => "aff0015" ] 2 => array:3 [ "entidad" => "Department of Pathology, İnonu University Medical Faculty, Malatya, Turkey" "etiqueta" => "c" "identificador" => "aff0020" ] 3 => array:3 [ "entidad" => "Department of Biochemistry, İnonu University Medical Faculty, Malatya, Turkey" "etiqueta" => "d" "identificador" => "aff0025" ] 4 => array:3 [ "entidad" => "Department of Haematology, İnonu University Medical Faculty, Malatya, Turkey" "etiqueta" => "e" "identificador" => "aff0030" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Efeitos do iloprost na fibrose pulmonar induzida por bleomicina no rato em comparação com metil-prednisolona" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 925 "Ancho" => 1540 "Tamanyo" => 56943 ] ] "descripcion" => array:1 [ "en" => "The contents of hydroxyproline in the groups of control, BLM+placebo, BLM+methyl-prednisolone, BLM+iloprost. a The content of hydroxyproline in the BLM+placebo was significantly higher than the control group (p<0.05). b The hydroxyproline contents in the BLM+methyl-prednisolone and BLM+iloprost groups were significantly lower than the BLM+placebo groups (p<0.05)." ] ] ] "textoCompleto" => "IntroductionIdiopathic pulmonary fibrosis (IPF) is a chronic, progressively fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling. Unfortunately, despite intensive investigations, the current pharmacologic therapy of IPF is limited and the results of therapy have been unsuccessful.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> Lung transplantation is considered as the only solution that has been shown to prolong survival; however, it can be applied to limited patient groups.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Animal models play an important role in the investigation of IPF. Chronic diseases, such as IPF are more difficult to apply to a model because, etiology and natural history of IPF are unclear and there is no known single trigger able to induce “IPF” in animals.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> There are different models for inducing the pulmonary fibrosis. One of the models is intratracheal bleomycin (BLM) instillation. BLM is a chemotherapeutic antibiotic, and pulmonary fibrosis is one of the major adverse effects of this agent in human cancer therapy. Nowadays, the standard agent for inducing the experimental pulmonary fibrosis is BLM. BLM-induced pulmonary damage of animal lungs reflects histological and biochemical characteristics of fibrosis well. Meanwhile, there is an evidence that bioactive metabolites of arachidonic acid may regulate the fibroproliferative response in lung fibrosis.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5</a> Deletion of 5-lypoxygenase (5-LO) leading to a deficiency in sulphidopeptide-leukotriene production ameliorated bleomycin-induced fibrosis in mice.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> Furthermore, antagonizing leukotriene (LT) B4 receptor (LT B4 is a metabolite synthesized by 5-LO) attenuated the lung fibrosis induced by BLM in mice by suppressing the production of inflammatory and fibrotic cytokines and by promoting the antifibrotic cytokine.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> In contrast to LTB4, prostanoids, which are metabolites of arachidonic acid are important regulators of pulmonary homeostasis. Prostacyclin inhibits fibroblast proliferation and collagen synthesis.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>PGI2, known as prostacyclin, is produced by the action of cyclooxygenase (COX)-2, as an antiproliferative molecule in the setting of BLM-induced pulmonary fibrosis.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Lovgren et al. reported that mice lacking COX-2 derived PGI2 were susceptible to developing severe pulmonary fibrosis in response to BLM.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> In that case, it can be said that PGI2 may inhibit the development of pulmonary fibrosis. Therefore, Zhu et al. demonstrated that iloprost, a stable PGI2, prevents BLM-induced pulmonary fibrosis in a mouse model and these authors reported that prostacyclin may represent a novel pharmacological agent for treating pulmonary fibrosis.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> However, Dactor et al. reported that prostanoids protected against lung fibrosis when prostanoid was administered before bleomycin challenge but had no therapeutic effect when administered after bleomycin challenge.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>Corticosteroids suppress neutrophil and lymphocyte migration into the lung, decrease the level of immune complexes, and alter alveolar macrophages function but it is unclear that there is any survival advantage or prevention of fibrosis in patients treated with corticosteroids alone or in combination with other agents.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>This study aimed to investigate the effects of PGI2 by using iloprost on lung fibrosis induced by BLM exposure in a rat model and to compare the effects of iloprost with methyl-prednisolone, a traditional therapy.Material and methodsExperimental animalsIn this study, 27 male Wistar albino rats, 12-week old, weighing 200–250g were purchased from Inonu University Experiment Animals Production and Research Center. All experiments were approved by the institutional committee of animal care. The rats were randomly allocated into 4 groups. 1. Saline alone (control group) (n=6); 2. BLM+placebo (n=7); 3. BLM+methyl-prednisolone (n=7); 4. BLM+iloprost (n=7).BLM-induced lung fibrosisThe rats were anesthetized with 50mg/kg ketamin and 5mg/kg xyalazine intraperitoneally, followed by a single intratracheal injection of BLM hydrochloride (2.5mg/kg body weight in 0.25ml phosphate buffered saline (PBS), Nippon Kayaku, Japan) in 50ml of sterile saline. Control rats were injected the same volume of intratracheal saline instead of BLM. All the rats were killed 14 days after the intratracheal injection of bleomycin or PBS.Experimental groupsIn control and placebo groups, injection of 0.1ml PBS started intraperitoneally two days before the intratracheal injection of PBS or BLM. This solution was administered intraperitoneally for 16 days in two groups. Steroid treated rats were injected 5mg/kg/day methyl-prednisolone (Mustafa Nevzat Ltd., Istanbul, Turkey) intraperitoneally two days before the BLM injection and drug was administered in the same dose for 16 days. In the iloprost group, iloprost (200μg/kg Schering, Berlimed, Spain) was dissolved in 500μl of PBS. The dose levels were based on a previous study in the literature.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> First doses of iloprost were administered intraperitoneally two days before the BLM injection. Iloprost was administered intraperitoneally for 16 days. Treatment procedures were based on previous drug studies in bleomycin-induced lung fibrosis in rats.<a class="elsevierStyleCrossRefs" href="#bib0010">2,11,13</a>Bronchoalveolar lavageOn day 14 after the BLM injection, rats were euthanized with xylazine (5mg/kg) and ketamine (50mg/kg) intraperitoneally. The trachea was cannulated by using a blunt needle attached to a syringe. Bronchoalveolar lavage (BAL) was performed four times with 0.8ml of PBS. Cell suspensions were concentrated by low speed centrifugation. The supernatant of BAL fluid was collected and kept at −70°C until used. The supernatant was used for the measurement of total cell counts. Total cells were counted on a hemocytometer and differential cell (alveolar macrophages, neutrophils, lymphocytes and eosinophils), counts were estimated from cystospine preparations by counting 300 cells stained with May-Grünwald-Giemsa.Lung histopathologyAfter BAL, the left lungs of scarificed rats were removed, fixed in a buffered 10% formalin solution for 24h, embedded in parafin and sectioned at 5μm thickness. Ten consecutive longitudinal sections of the lungs were stained with hematoxylin & eosin (HE) and were examined for pulmonary fibrosis. For histopathological scoring of pulmonary fibrosis, each successive field was assessed using the semiquantitative grading system described by Ashcroft et al.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> The entire lung section was reviewed at a magnification of 100×. Thirty to thirty five fields in each section were analyzed and a score ranging from 0 (normal lung) to 8 (total fibrosis) was assigned. The mean score of all fields was taken as the fibrosis score of that lung section. Criteria for grading pulmonary fibrosis were as follows. Grade 0=normal lung; Grade 1=minimal fibrous thickening of alveolar or bronchial walls; Grade 2–3=moderate thickening of walls without obvious damage to lung architecture; Grade 4–5=increased fibrosis with definite damage to lung architecture and formation of fibrous bands or small fibrous mass; Grade 6–7=severe distortion of structure and large fibrous areas; Grade 8=total fibrotic obliteration of the field. The grading was independently performed for each rat in a blind manner by two pathologists.Hydroxyproline assayAfter BAL, the right lungs were used for hydroxyproline content as an index of collagen accumulation. Lungs were homogenized in 1ml of PBS, and hydrolyzed by the addition of 1ml of 12N HCL at 120°C for 16h and dissolved in 2ml deionized water. Samples were incubated with Chloramine T solution for 20min at room temperature, and with Ehrlich's solution at 65°C for 15min. The absorbance of the Wnal reaction solutions at 550nm were measured and amount of hydroxyproline was obtained as microgram.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>Statistical analysisStatistics package program (SPSS 11.0 for Windows; SPSS Inc., Chicago, Illinois, USA) was used for statistical analysis. Data were expressed as mean±S.E.M. Comparison was made by one-way ANOVA followed by appropriate post hoc test including multiple comparison test (least significant difference). P value less than 0.05 was considered statistically significant.ResultsInflammatory cells in airwaysBLM+placebo administration caused a significant increase in the percentage of the neutrophils in BAL fluid (21.1±2.7, p<0.05) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The percentage of alveolar macrophages in BLM+placebo group was significantly lower (76.7±2.3, p<0.05). In rats treated with iloprost or methyl-prednisolone, the percentages of the neutrophil and alveolar macrophages remained similar to the levels of control rats. There were no significant differences in the percentages of lymphocytes and eosinophils among the four groups.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Grades of lung fibrosis and hydroxyproline contents in dried lung tissueIn the BLM+placebo, BLM administration produced a significant rise in lung tissue hyroxyproline content (5.65±0.78μg, p<0.05) as compared to those of the control group (3.37±0.51μg). The hydroxyproline content was significantly lower in BLM+methyl-prednisolone (4.72±0.25μg) and BLM+iloprost (4.90±0.39μg) groups (p<0.05) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). There was no significant difference in lung hyroxyproline content between BLM+iloprost and BLM+methyl-prednisolone groups.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Semiquantitative assessment of the lung tissue section from the control group (with no treatment) revealed a normal alveolar structure (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A). Fourteen days after BLM injection, rats administered BLM+placebo had more severe and extensive fibrosis (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B). Alveolar walls of these rats were thickened and the air spaces were collapsed. Pulmonary fibrosis was less severe in the iloprost and methyl-prednisolone groups (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C and D). Ashcroft score demonstrated that the degrees of pulmonary fibrosis in the BLM+methyl-prednisolone (2.57±0.94) and BLM+iloprost groups (2.29±0.68) were significantly lower than those of the BLM+placebo groups (4.86±0.93) (p<0.05) (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). In the rats treated with iloprost, fibrosis score was significantly lower than those of the methyl-prednisolone group (p<0.05).<elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>DiscussionWe assessed the effects of intraperitoneal administration of iloprost, a PGI2 analog, on BLM-induced pulmonary fibrosis and compared the effects of iloprost with methyl-prednisolone. Iloprost reduced BLM-induced lung fibrosis as shown by assessment of semiquantitative morphological indices of fibrosis and hydroxyproline content. Fibrosis score in iloprost group was significantly lower than in methyl-prednisolone group. Iloprost and methyl-prednisolone significantly attenuated lung infiltration by neutrophils. To the best of our knowledge, this is the second study of an intraperitoneal administration of iloprost in fibrosis induced by BLM in rats. The study of Zhu et al. is the first report of an intraperitoenal application of iloprost.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> However, our study is the first report to compare the preventive effects of iloprost with methyl-prednisolone on pulmonary fibrosis.Hallmarks of pulmonary fibrosis include subepithelial fibroblastic foci and excessive deposition of collagen and extracellular matrix. Lung fibroblasts play an important role in the development of lung fibrosis.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> A number of studies have shown that prostanoids may play a role in limiting fibrotic responses in the lungs.<a class="elsevierStyleCrossRefs" href="#bib0025">5,8–11</a> Prostanoids are capable of inhibiting fibroblast migration, proliferation, and collagen synthesis. Patients with IPF, have been seen with a decrease of prostacyclin production from lung fibroblasts.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> Prostacyclin syntase expression has been demonstrated on pneumocytes, fibroblasts and endothelial cells in the healthy lungs. However, this expression did not continue to increase after induction of fibrosis with BLM.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> The treatment of rats with prostacyclin provided protection against BLM-induced fibrosis. Our data showed that fibrosis score and hyroxyproline levels decreased in rats treated with iloprost and methyl-prednisolone groups.This point implies that neutrophils were markedly augmented in lungs of rats exposed to BLM+placebo and the augmentation of neutrophils into the lung was inhibited by BLM+iloprost and BLM+methyl-prednisolone. In rats treated with iloprost and methyl-prednisolone, alveolar macrophages remained similar to the levels of control rats whereas alveolar macrophages in BLM+placebo group were significantly lower. Zhu et al. showed that the number of inflammatory cells and lymphocytes accumulated in lungs was significantly higher in the BLM (no iloprost) group than those treated with iloprost. However, there was no significant difference in the number of macrophages and neutrophils in BAL fluid between the BLM (no iloprost) and the BLM+iloprost groups.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> These divergent results may be due to differences in study protocol, since Zhu et al. only administered iloprost 10–15min prior to injection of BLM. Bleomycin increases both neutrophils and lymphocytes in the lungs. However, in our study, lymphocytes did not significantly accumulate in the lungs in the BLM+placebo group. In rats treated with iloprost and methyl-prednisolone, lymphocytes remained similar to the levels of BLM+placebo group.During the last 50 years, corticosteroid use has evolved into accepted practice in the treatment of IPF despite the fact that no prospective randomised placebo-controlled trial has ever been performed.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Transient clinical response was found in a small minority of patients with no survival benefit compared to untreated patients in some studies.<a class="elsevierStyleCrossRefs" href="#bib0085">17–21</a> There has been a small but statistically significant reduction in the overall use of corticosteroids as classic treatment since the publication of treatment guidelines in recent years.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> Richeldi et al., carried out a systematic review of the efficacy of corticosteroids in the treatment of IPF reporting that no randomized controlled trial or clinical control trials in which corticosteroid treatment was compared to placebo were available. According to this review, results did not support the efficacy of corticosteroid in the treatment of IPF.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> The development of new IPF pathogenetic paradigms has driven research into new therapeutic strategies.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> In literature, there are some human studies which have evaluated the therapeutic effects in severe pulmonary hypertension secondary to pulmonary fibrosis.<a class="elsevierStyleCrossRefs" href="#bib0120">24,25</a> However, there is no human study in English literature which compares the therapeutic effects and superiority of prostacyclin analogs with corticosteroids in patients with IPF. Animal studies show that prostacyclin may have an important protective role in fibrotic disease<a class="elsevierStyleCrossRefs" href="#bib0025">5,10,11</a> but in these studies, the effects of prostacyclin analogs were not compared with traditional therapies such as corticosteroids. In the study of Zhu et al., iloprost was given 10–15min prior to intratracheal BLM. The results of this study indicated that iloprost could be preventive, but possibly not therapeutic for fibrosis.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> The authors recommended additional studies to evaluate both the reversal effect of iloprost in a time- and dose-dependent fashion and whether long-term treatment with iloprost would be beneficial for patients with fibrotic lung diseases. In the study of Dactor et al., mice were administered a single dose of bleomycin via oropharyngeal aspiration. Prostaglandin E2 and iloprost were administered 7 days before or 14 days after bleomycin challenge. When administered 7 days before bleomycin challenge, prostaglandin E2 protected against lung fibrosis. However, this agent had no therapeutic effect on lung fibrosis when administered 14 days after bleomycin.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> In our study, first doses of iloprost were administered two days before the BLM injection and it was continued intraperitoneally at the same doses for 16 days. Intraperitoneal administration of iloprost attenuated the development of BLM-induced pulmonary fibrosis and iloprost significantly improved fibrotic process in comparison to methyl-prednisolone.In this present study, we did not compare groups according to survival and mortality which was expected up to the time of evaluation. No side-effects related to iloprost therapy were observed.In conclusion, our findings provide evidence of the beneficial effects of iloprost in decreasing pulmonary fibrosis induced by BLM, namely by decreased inflammation, lung damage and fibrogenic activity in lung tissue.Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres173940" "titulo" => array:5 [ 0 => "Abstract" 1 => "Objective" 2 => "Methods" 3 => "Results" 4 => "Conclusion" ] ] 1 => array:2 [ "identificador" => "xpalclavsec162236" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres173939" "titulo" => array:5 [ 0 => "Resumo" 1 => "Objetivo" 2 => "Métodos" 3 => "Resultados" 4 => "Conclusão" ] ] 3 => array:2 [ "identificador" => "xpalclavsec162237" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Experimental animals" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "BLM-induced lung fibrosis" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Experimental groups" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Bronchoalveolar lavage" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Lung histopathology" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Hydroxyproline assay" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0050" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Inflammatory cells in airways" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Grades of lung fibrosis and hydroxyproline contents in dried lung tissue" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-12-28" "fechaAceptado" => "2012-04-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec162236" "palabras" => array:5 [ 0 => "Pulmonary fibrosis" 1 => "Bleomycin" 2 => "Iloprost" 3 => "Methyl-prednisolone" 4 => "Rats" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec162237" "palabras" => array:5 [ 0 => "Fibrose pulmonar" 1 => "Bleomicina" 2 => "Iloprost" 3 => "Metil-prednisolona" 4 => "Ratos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "ObjectiveProstacyclin (PGI2) has been shown to inhibit the expression of pro-inflammatory and pro-fibrotic mediators in pulmonary fibrosis. In this study, we aimed to test the preventive effects of intraperitoneally administered iloprost, a stable PGI2 analog, on bleomycin-induced pulmonary fibrosis in rats and to compare the effects of iloprost with the effects of methyl-prednisolone, a traditional therapy. MethodsRats were randomly allocated into four groups: 1. Saline alone (n=6); 2. Bleomycin+placebo (n=7); 3. Bleomycin+methyl-prednisolone (n=7); 4. Bleomycin+iloprost (n=7). Fibrotic changes in the lungs were demonstrated by analyzing the cellular composition of bronchoalveolar lavage fluid, histological evaluation and lung hydroxyproline content. ResultsFibrosis was made in the lungs of rats by bleomycin experimentally. Fibrosis scores in the methyl-prednisolone and the iloprost groups were significantly lower than in the placebo group (p<0.05). Furthermore, the score of the iloprost group was significantly lower than the score of the methyl-prednisolone group. The hydroxyproline content was significantly less in the methyl-prednisolone and the iloprost groups (p<0.05). In the placebo group, the neutrophil percentage in bronchoalveolar lavage was significantly higher than in the other groups, whereas the macrophage percentage in placebo group was significantly lower (p<0.05). ConclusionIloprost has protective effect on the pulmonary fibrosis induced by bleomycin and it may be more effective in decreasing fibrotic changes than methyl-prednisolone." ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "ObjetivoA prostaciclina (PGI2) é conhecida por inibir a expressão de mediadores pró-inflamatórios e pró-fibróticos na fibrose pulmonar. Neste estudo, procurou-se testar os efeitos preventivos do iloprost administrado por via intraperitoneal, um análogo estável do PGI2, na fibrose pulmonar induzida por bleomicina em ratos e comparar os efeitos do iloprost com os efeitos da metil-prednisolona, uma terapia tradicional. MétodosOs ratos foram divididos aleatoriamente em quatro grupos: 1. Apenas soro fisiológico (n=6); 2. Bleomicina + placebo (n=7); 3. Bleomicina + metil-prednisolona (n=7); 4. Bleomicina + iloprost (n=7). Foram demonstradas alterações fibróticas nos pulmões analisando a composição celular do líquido de lavagem bronco-alveolar, avaliação histológica e conteúdo de hidroxiprolina pulmonar. ResultadosAparecimento de fibrose nos pulmões dos ratos tratados com bleomicina. Os resultados dos grupos tratados com metil-prednisolona e iloprost foram significativamente inferiores ao do grupo placebo (p<0.05). Além disso, o resultado do grupo de iloprost foi significativamente inferior ao resultado do grupo de metil-prednisolona. O teor de hidroxiprolina foi significativamente inferior nos grupos de metil-prednisolona e de iloprost (p <0.05). No grupo placebo, a percentagem de neutrófilos na lavagem bronco-alveolar foi significativamente mais elevada do que nos outros grupos, enquanto que a percentagem de macrófagos no grupo placebo foi significativamente inferior (p <0.05). ConclusãoO Iloprost tem um efeito protetor sobre a fibrose pulmonar induzida por bleomicina e pode ser mais eficaz na diminuição de alterações fibróticas que a metil-prednisolona." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 925 "Ancho" => 1540 "Tamanyo" => 56943 ] ] "descripcion" => array:1 [ "en" => "The contents of hydroxyproline in the groups of control, BLM+placebo, BLM+methyl-prednisolone, BLM+iloprost. a The content of hydroxyproline in the BLM+placebo was significantly higher than the control group (p<0.05). b The hydroxyproline contents in the BLM+methyl-prednisolone and BLM+iloprost groups were significantly lower than the BLM+placebo groups (p<0.05)." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2197 "Ancho" => 2667 "Tamanyo" => 853522 ] ] "descripcion" => array:1 [ "en" => "Histological H & E stained sections (200×) representative of control (A), BLM+placebo (B), BLM+iloprost (C), BLM+methyl-prednisolone (D)." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 863 "Ancho" => 1535 "Tamanyo" => 53601 ] ] "descripcion" => array:1 [ "en" => "Fibrosis scores of the control, BLM+placebo, BLM+methyl-prednisolone and BLM+iloprost groups. a Ashcroft score in the BLM+placebo was significantly higher than the control group (p<0.05). b Ashcroft score in the BLM+methyl-prednisolone was significantly lower than the BLM+placebo groups (p<0.05). c Ashcroft score in the BLM+iloprost group was significantly lower than the BLM+methyl-prednisolone and BLM+placebo groups (p<0.05)." ] ] 3 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Data presented as mean±SEM of groups." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Control(n=6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">BLM+placebo(n=7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">BLM+methyl-prednisolone(n=7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">BLM+iloprost(n=7) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Macrophages \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">91.6±0.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">76.7±2.3<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">91.5±1.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">91.8±2.0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutrophils \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.6±0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21.1±2.7<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.8±1.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.3±1.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lymphocytes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.6±0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.0±0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.4±0.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.8±1.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Eosinophils \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.0±0.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.1±0.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.1±0.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.0±0.0 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab266859.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "The percentages of macrophages and neutrophils BAL fluid were significantly low in BLM+placebo group (p<0.05)." ] ] ] "descripcion" => array:1 [ "en" => "Effects of iloprost and methyl-prednisolone on bleomycin-induced changes in inflammatory cells in BAL fluid." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:25 [ 0 => array:3 [ "identificador" => "bib0005" 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Effects of iloprost on bleomycin-induced pulmonary fibrosis in rats compared with methyl-prednisolone

Efeitos do iloprost na fibrose pulmonar induzida por bleomicina no rato em comparação com metil-prednisolona

Z.A. Aytemura, S.S. Hacievliyagila,

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suleyman.hacievliyagil@inonu.edu.tr

Corresponding author.

, M. Irazb, E. Samdancic, E. Ozerold, I. Kukue, Z. Nurkabulovc, K. Yildizc

a Department of Pulmonary Disease, Inonu University Medical Faculty, Malatya, Turkey

b Department of Pharmacology Disease, Bezmialem University Medical Faculty, Istanbul, Turkey

c Department of Pathology, İnonu University Medical Faculty, Malatya, Turkey

d Department of Biochemistry, İnonu University Medical Faculty, Malatya, Turkey

e Department of Haematology, İnonu University Medical Faculty, Malatya, Turkey

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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">The contents of hydroxyproline in the groups of control&#44; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo&#44; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone&#44; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost&#46; <span class="elsevierStyleSup">a</span> The content of hydroxyproline in the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo was significantly higher than the control group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <span class="elsevierStyleSup">b</span> The hydroxyproline contents in the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone and BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost groups were significantly lower than the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p>"
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Chronic diseases&#44; such as IPF are more difficult to apply to a model because&#44; etiology and natural history of IPF are unclear and there is no known single trigger able to induce &#8220;IPF&#8221; in animals&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> There are different models for inducing the pulmonary fibrosis&#46; One of the models is intratracheal bleomycin &#40;BLM&#41; instillation&#46; BLM is a chemotherapeutic antibiotic&#44; and pulmonary fibrosis is one of the major adverse effects of this agent in human cancer therapy&#46; Nowadays&#44; the standard agent for inducing the experimental pulmonary fibrosis is BLM&#46; BLM-induced pulmonary damage of animal lungs reflects histological and biochemical characteristics of fibrosis well&#46; Meanwhile&#44; there is an evidence that bioactive metabolites of arachidonic acid may regulate the fibroproliferative response in lung fibrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> Deletion of 5-lypoxygenase &#40;5-LO&#41; leading to a deficiency in sulphidopeptide-leukotriene production ameliorated bleomycin-induced fibrosis in mice&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Furthermore&#44; antagonizing leukotriene &#40;LT&#41; B4 receptor &#40;LT B4 is a metabolite synthesized by 5-LO&#41; attenuated the lung fibrosis induced by BLM in mice by suppressing the production of inflammatory and fibrotic cytokines and by promoting the antifibrotic cytokine&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In contrast to LTB4&#44; prostanoids&#44; which are metabolites of arachidonic acid are important regulators of pulmonary homeostasis&#46; Prostacyclin inhibits fibroblast proliferation and collagen synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">PGI2&#44; known as prostacyclin&#44; is produced by the action of cyclooxygenase &#40;COX&#41;-2&#44; as an antiproliferative molecule in the setting of BLM-induced pulmonary fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Lovgren et al&#46; reported that mice lacking COX-2 derived PGI2 were susceptible to developing severe pulmonary fibrosis in response to BLM&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> In that case&#44; it can be said that PGI2 may inhibit the development of pulmonary fibrosis&#46; Therefore&#44; Zhu et al&#46; demonstrated that iloprost&#44; a stable PGI2&#44; prevents BLM-induced pulmonary fibrosis in a mouse model and these authors reported that prostacyclin may represent a novel pharmacological agent for treating pulmonary fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> However&#44; Dactor et al&#46; reported that prostanoids protected against lung fibrosis when prostanoid was administered before bleomycin challenge but had no therapeutic effect when administered after bleomycin challenge&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Corticosteroids suppress neutrophil and lymphocyte migration into the lung&#44; decrease the level of immune complexes&#44; and alter alveolar macrophages function but it is unclear that there is any survival advantage or prevention of fibrosis in patients treated with corticosteroids alone or in combination with other agents&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">This study aimed to investigate the effects of PGI2 by using iloprost on lung fibrosis induced by BLM exposure in a rat model and to compare the effects of iloprost with methyl-prednisolone&#44; a traditional therapy&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Experimental animals</span><p id="par0030" class="elsevierStylePara elsevierViewall">In this study&#44; 27 male Wistar albino rats&#44; 12-week old&#44; weighing 200&#8211;250<span class="elsevierStyleHsp" style=""></span>g were purchased from Inonu University Experiment Animals Production and Research Center&#46; All experiments were approved by the institutional committee of animal care&#46; The rats were randomly allocated into 4 groups&#46; 1&#46; Saline alone &#40;control group&#41; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41;&#59; 2&#46; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41;&#59; 3&#46; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41;&#59; 4&#46; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">BLM-induced lung fibrosis</span><p id="par0035" class="elsevierStylePara elsevierViewall">The rats were anesthetized with 50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg ketamin and 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg xyalazine intraperitoneally&#44; followed by a single intratracheal injection of BLM hydrochloride &#40;2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg body weight in 0&#46;25<span class="elsevierStyleHsp" style=""></span>ml phosphate buffered saline &#40;PBS&#41;&#44; Nippon Kayaku&#44; Japan&#41; in 50<span class="elsevierStyleHsp" style=""></span>ml of sterile saline&#46; Control rats were injected the same volume of intratracheal saline instead of BLM&#46; All the rats were killed 14 days after the intratracheal injection of bleomycin or PBS&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Experimental groups</span><p id="par0040" class="elsevierStylePara elsevierViewall">In control and placebo groups&#44; injection of 0&#46;1<span class="elsevierStyleHsp" style=""></span>ml PBS started intraperitoneally two days before the intratracheal injection of PBS or BLM&#46; This solution was administered intraperitoneally for 16 days in two groups&#46; Steroid treated rats were injected 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day methyl-prednisolone &#40;Mustafa Nevzat Ltd&#46;&#44; Istanbul&#44; Turkey&#41; intraperitoneally two days before the BLM injection and drug was administered in the same dose for 16 days&#46; In the iloprost group&#44; iloprost &#40;200<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg Schering&#44; Berlimed&#44; Spain&#41; was dissolved in 500<span class="elsevierStyleHsp" style=""></span>&#956;l of PBS&#46; The dose levels were based on a previous study in the literature&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> First doses of iloprost were administered intraperitoneally two days before the BLM injection&#46; Iloprost was administered intraperitoneally for 16 days&#46; Treatment procedures were based on previous drug studies in bleomycin-induced lung fibrosis in rats&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;11&#44;13</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Bronchoalveolar lavage</span><p id="par0045" class="elsevierStylePara elsevierViewall">On day 14 after the BLM injection&#44; rats were euthanized with xylazine &#40;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; and ketamine &#40;50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; intraperitoneally&#46; The trachea was cannulated by using a blunt needle attached to a syringe&#46; Bronchoalveolar lavage &#40;BAL&#41; was performed four times with 0&#46;8<span class="elsevierStyleHsp" style=""></span>ml of PBS&#46; Cell suspensions were concentrated by low speed centrifugation&#46; The supernatant of BAL fluid was collected and kept at &#8722;70<span class="elsevierStyleHsp" style=""></span>&#176;C until used&#46; The supernatant was used for the measurement of total cell counts&#46; Total cells were counted on a hemocytometer and differential cell &#40;alveolar macrophages&#44; neutrophils&#44; lymphocytes and eosinophils&#41;&#44; counts were estimated from cystospine preparations by counting 300 cells stained with May-Gr&#252;nwald-Giemsa&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Lung histopathology</span><p id="par0050" class="elsevierStylePara elsevierViewall">After BAL&#44; the left lungs of scarificed rats were removed&#44; fixed in a buffered 10&#37; formalin solution for 24<span class="elsevierStyleHsp" style=""></span>h&#44; embedded in parafin and sectioned at 5<span class="elsevierStyleHsp" style=""></span>&#956;m thickness&#46; Ten consecutive longitudinal sections of the lungs were stained with hematoxylin &#38; eosin &#40;HE&#41; and were examined for pulmonary fibrosis&#46; For histopathological scoring of pulmonary fibrosis&#44; each successive field was assessed using the semiquantitative grading system described by Ashcroft et al&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The entire lung section was reviewed at a magnification of 100&#215;&#46; Thirty to thirty five fields in each section were analyzed and a score ranging from 0 &#40;normal lung&#41; to 8 &#40;total fibrosis&#41; was assigned&#46; The mean score of all fields was taken as the fibrosis score of that lung section&#46; Criteria for grading pulmonary fibrosis were as follows&#46; Grade 0<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>normal lung&#59; Grade 1<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>minimal fibrous thickening of alveolar or bronchial walls&#59; Grade 2&#8211;3<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>moderate thickening of walls without obvious damage to lung architecture&#59; Grade 4&#8211;5<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>increased fibrosis with definite damage to lung architecture and formation of fibrous bands or small fibrous mass&#59; Grade 6&#8211;7<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>severe distortion of structure and large fibrous areas&#59; Grade 8<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>total fibrotic obliteration of the field&#46; The grading was independently performed for each rat in a blind manner by two pathologists&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Hydroxyproline assay</span><p id="par0055" class="elsevierStylePara elsevierViewall">After BAL&#44; the right lungs were used for hydroxyproline content as an index of collagen accumulation&#46; Lungs were homogenized in 1<span class="elsevierStyleHsp" style=""></span>ml of PBS&#44; and hydrolyzed by the addition of 1<span class="elsevierStyleHsp" style=""></span>ml of 12<span class="elsevierStyleHsp" style=""></span>N HCL at 120<span class="elsevierStyleHsp" style=""></span>&#176;C for 16<span class="elsevierStyleHsp" style=""></span>h and dissolved in 2<span class="elsevierStyleHsp" style=""></span>ml deionized water&#46; Samples were incubated with Chloramine T solution for 20<span class="elsevierStyleHsp" style=""></span>min at room temperature&#44; and with Ehrlich&#39;s solution at 65<span class="elsevierStyleHsp" style=""></span>&#176;C for 15<span class="elsevierStyleHsp" style=""></span>min&#46; The absorbance of the Wnal reaction solutions at 550<span class="elsevierStyleHsp" style=""></span>nm were measured and amount of hydroxyproline was obtained as microgram&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">Statistics package program &#40;SPSS 11&#46;0 for Windows&#59; SPSS Inc&#46;&#44; Chicago&#44; Illinois&#44; USA&#41; was used for statistical analysis&#46; Data were expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>S&#46;E&#46;M&#46; Comparison was made by one-way ANOVA followed by appropriate post hoc test including multiple comparison test &#40;least significant difference&#41;&#46; <span class="elsevierStyleItalic">P</span> value less than 0&#46;05 was considered statistically significant&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Inflammatory cells in airways</span><p id="par0065" class="elsevierStylePara elsevierViewall">BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo administration caused a significant increase in the percentage of the neutrophils in BAL fluid &#40;21&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;7&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The percentage of alveolar macrophages in BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo group was significantly lower &#40;76&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;3&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; In rats treated with iloprost or methyl-prednisolone&#44; the percentages of the neutrophil and alveolar macrophages remained similar to the levels of control rats&#46; There were no significant differences in the percentages of lymphocytes and eosinophils among the four groups&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Grades of lung fibrosis and hydroxyproline contents in dried lung tissue</span><p id="par0070" class="elsevierStylePara elsevierViewall">In the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo&#44; BLM administration produced a significant rise in lung tissue hyroxyproline content &#40;5&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;78<span class="elsevierStyleHsp" style=""></span>&#956;g&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; as compared to those of the control group &#40;3&#46;37<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;51<span class="elsevierStyleHsp" style=""></span>&#956;g&#41;&#46; The hydroxyproline content was significantly lower in BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone &#40;4&#46;72<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;25<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; and BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost &#40;4&#46;90<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;39<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; There was no significant difference in lung hyroxyproline content between BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost and BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone groups&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">Semiquantitative assessment of the lung tissue section from the control group &#40;with no treatment&#41; revealed a normal alveolar structure &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#46; Fourteen days after BLM injection&#44; rats administered BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo had more severe and extensive fibrosis &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#46; Alveolar walls of these rats were thickened and the air spaces were collapsed&#46; Pulmonary fibrosis was less severe in the iloprost and methyl-prednisolone groups &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>C and D&#41;&#46; Ashcroft score demonstrated that the degrees of pulmonary fibrosis in the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone &#40;2&#46;57<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;94&#41; and BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost groups &#40;2&#46;29<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;68&#41; were significantly lower than those of the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo groups &#40;4&#46;86<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;93&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; In the rats treated with iloprost&#44; fibrosis score was significantly lower than those of the methyl-prednisolone group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">We assessed the effects of intraperitoneal administration of iloprost&#44; a PGI2 analog&#44; on BLM-induced pulmonary fibrosis and compared the effects of iloprost with methyl-prednisolone&#46; Iloprost reduced BLM-induced lung fibrosis as shown by assessment of semiquantitative morphological indices of fibrosis and hydroxyproline content&#46; Fibrosis score in iloprost group was significantly lower than in methyl-prednisolone group&#46; Iloprost and methyl-prednisolone significantly attenuated lung infiltration by neutrophils&#46; To the best of our knowledge&#44; this is the second study of an intraperitoneal administration of iloprost in fibrosis induced by BLM in rats&#46; The study of Zhu et al&#46; is the first report of an intraperitoenal application of iloprost&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> However&#44; our study is the first report to compare the preventive effects of iloprost with methyl-prednisolone on pulmonary fibrosis&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Hallmarks of pulmonary fibrosis include subepithelial fibroblastic foci and excessive deposition of collagen and extracellular matrix&#46; Lung fibroblasts play an important role in the development of lung fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> A number of studies have shown that prostanoids may play a role in limiting fibrotic responses in the lungs&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;8&#8211;11</span></a> Prostanoids are capable of inhibiting fibroblast migration&#44; proliferation&#44; and collagen synthesis&#46; Patients with IPF&#44; have been seen with a decrease of prostacyclin production from lung fibroblasts&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Prostacyclin syntase expression has been demonstrated on pneumocytes&#44; fibroblasts and endothelial cells in the healthy lungs&#46; However&#44; this expression did not continue to increase after induction of fibrosis with BLM&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The treatment of rats with prostacyclin provided protection against BLM-induced fibrosis&#46; Our data showed that fibrosis score and hyroxyproline levels decreased in rats treated with iloprost and methyl-prednisolone groups&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">This point implies that neutrophils were markedly augmented in lungs of rats exposed to BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo and the augmentation of neutrophils into the lung was inhibited by BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost and BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone&#46; In rats treated with iloprost and methyl-prednisolone&#44; alveolar macrophages remained similar to the levels of control rats whereas alveolar macrophages in BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo group were significantly lower&#46; Zhu et al&#46; showed that the number of inflammatory cells and lymphocytes accumulated in lungs was significantly higher in the BLM &#40;no iloprost&#41; group than those treated with iloprost&#46; However&#44; there was no significant difference in the number of macrophages and neutrophils in BAL fluid between the BLM &#40;no iloprost&#41; and the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost groups&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> These divergent results may be due to differences in study protocol&#44; since Zhu et al&#46; only administered iloprost 10&#8211;15<span class="elsevierStyleHsp" style=""></span>min prior to injection of BLM&#46; Bleomycin increases both neutrophils and lymphocytes in the lungs&#46; However&#44; in our study&#44; lymphocytes did not significantly accumulate in the lungs in the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo group&#46; In rats treated with iloprost and methyl-prednisolone&#44; lymphocytes remained similar to the levels of BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo group&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">During the last 50 years&#44; corticosteroid use has evolved into accepted practice in the treatment of IPF despite the fact that no prospective randomised placebo-controlled trial has ever been performed&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Transient clinical response was found in a small minority of patients with no survival benefit compared to untreated patients in some studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#8211;21</span></a> There has been a small but statistically significant reduction in the overall use of corticosteroids as classic treatment since the publication of treatment guidelines in recent years&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Richeldi et al&#46;&#44; carried out a systematic review of the efficacy of corticosteroids in the treatment of IPF reporting that no randomized controlled trial or clinical control trials in which corticosteroid treatment was compared to placebo were available&#46; According to this review&#44; results did not support the efficacy of corticosteroid in the treatment of IPF&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> The development of new IPF <span class="elsevierStyleItalic">pathogenetic</span> paradigms has driven research into new therapeutic strategies&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> In literature&#44; there are some human studies which have evaluated the therapeutic effects in severe pulmonary hypertension secondary to pulmonary fibrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;25</span></a> However&#44; there is no human study in English literature which compares the therapeutic effects and superiority of prostacyclin analogs with corticosteroids in patients with IPF&#46; Animal studies show that prostacyclin may have an important protective role in fibrotic disease<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;10&#44;11</span></a> but in these studies&#44; the effects of prostacyclin analogs were not compared with traditional therapies such as corticosteroids&#46; In the study of Zhu et al&#46;&#44; iloprost was given 10&#8211;15<span class="elsevierStyleHsp" style=""></span>min prior to intratracheal BLM&#46; The results of this study indicated that iloprost could be preventive&#44; but possibly not therapeutic for fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The authors recommended additional studies to evaluate both the reversal effect of iloprost in a time- and dose-dependent fashion and whether long-term treatment with iloprost would be beneficial for patients with fibrotic lung diseases&#46; In the study of Dactor et al&#46;&#44; mice were administered a single dose of bleomycin via oropharyngeal aspiration&#46; Prostaglandin E2 and iloprost were administered 7 days before or 14 days after bleomycin challenge&#46; When administered 7 days before bleomycin challenge&#44; prostaglandin E2 protected against lung fibrosis&#46; However&#44; this agent had no therapeutic effect on lung fibrosis when administered 14 days after bleomycin&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In our study&#44; first doses of iloprost were administered two days before the BLM injection and it was continued intraperitoneally at the same doses for 16 days&#46; Intraperitoneal administration of iloprost attenuated the development of BLM-induced pulmonary fibrosis and iloprost significantly improved fibrotic process in comparison to methyl-prednisolone&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In this present study&#44; we did not compare groups according to survival and mortality which was expected up to the time of evaluation&#46; No side-effects related to iloprost therapy were observed&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">In conclusion&#44; our findings provide evidence of the beneficial effects of iloprost in decreasing pulmonary fibrosis induced by BLM&#44; namely by decreased inflammation&#44; lung damage and fibrogenic activity in lung tissue&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0110" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Palavras-chave"
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          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Material and methods"
          "secciones" => array:7 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Experimental animals"
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            1 => array:2 [
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              "titulo" => "BLM-induced lung fibrosis"
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              "titulo" => "Experimental groups"
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              "identificador" => "sec0030"
              "titulo" => "Bronchoalveolar lavage"
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              "identificador" => "sec0035"
              "titulo" => "Lung histopathology"
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              "titulo" => "Hydroxyproline assay"
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              "titulo" => "Statistical analysis"
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          "titulo" => "Results"
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              "titulo" => "Inflammatory cells in airways"
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              "identificador" => "sec0060"
              "titulo" => "Grades of lung fibrosis and hydroxyproline contents in dried lung tissue"
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          ]
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          "titulo" => "Discussion"
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          "titulo" => "Conflicts of interest"
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    "fechaRecibido" => "2011-12-28"
    "fechaAceptado" => "2012-04-29"
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          "clase" => "keyword"
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          "palabras" => array:5 [
            0 => "Pulmonary fibrosis"
            1 => "Bleomycin"
            2 => "Iloprost"
            3 => "Methyl-prednisolone"
            4 => "Rats"
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          "clase" => "keyword"
          "titulo" => "Palavras-chave"
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          "palabras" => array:5 [
            0 => "Fibrose pulmonar"
            1 => "Bleomicina"
            2 => "Iloprost"
            3 => "Metil-prednisolona"
            4 => "Ratos"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Prostacyclin &#40;PGI2&#41; has been shown to inhibit the expression of pro-inflammatory and pro-fibrotic mediators in pulmonary fibrosis&#46; In this study&#44; we aimed to test the preventive effects of intraperitoneally administered iloprost&#44; a stable PGI2 analog&#44; on bleomycin-induced pulmonary fibrosis in rats and to compare the effects of iloprost with the effects of methyl-prednisolone&#44; a traditional therapy&#46;</p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Rats were randomly allocated into four groups&#58; 1&#46; Saline alone &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41;&#59; 2&#46; Bleomycin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41;&#59; 3&#46; Bleomycin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41;&#59; 4&#46; Bleomycin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41;&#46; Fibrotic changes in the lungs were demonstrated by analyzing the cellular composition of bronchoalveolar lavage fluid&#44; histological evaluation and lung hydroxyproline content&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Fibrosis was made in the lungs of rats by bleomycin experimentally&#46; Fibrosis scores in the methyl-prednisolone and the iloprost groups were significantly lower than in the placebo group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Furthermore&#44; the score of the iloprost group was significantly lower than the score of the methyl-prednisolone group&#46; The hydroxyproline content was significantly less in the methyl-prednisolone and the iloprost groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; In the placebo group&#44; the neutrophil percentage in bronchoalveolar lavage was significantly higher than in the other groups&#44; whereas the macrophage percentage in placebo group was significantly lower &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Iloprost has protective effect on the pulmonary fibrosis induced by bleomycin and it may be more effective in decreasing fibrotic changes than methyl-prednisolone&#46;</p>"
      ]
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        "resumen" => "<span class="elsevierStyleSectionTitle">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A prostaciclina &#40;PGI2&#41; &#233; conhecida por inibir a express&#227;o de mediadores pr&#243;-inflamat&#243;rios e pr&#243;-fibr&#243;ticos na fibrose pulmonar&#46; Neste estudo&#44; procurou-se testar os efeitos preventivos do iloprost administrado por via intraperitoneal&#44; um an&#225;logo est&#225;vel do PGI2&#44; na fibrose pulmonar induzida por bleomicina em ratos e comparar os efeitos do iloprost com os efeitos da metil-prednisolona&#44; uma terapia tradicional&#46;</p> <span class="elsevierStyleSectionTitle">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Os ratos foram divididos aleatoriamente em quatro grupos&#58; 1&#46; Apenas soro fisiol&#243;gico &#40;n&#61;6&#41;&#59; 2&#46; Bleomicina &#43; placebo &#40;n&#61;7&#41;&#59; 3&#46; Bleomicina &#43; metil-prednisolona &#40;n&#61;7&#41;&#59; 4&#46; Bleomicina &#43; iloprost &#40;n&#61;7&#41;&#46; Foram demonstradas altera&#231;&#245;es fibr&#243;ticas nos pulm&#245;es analisando a composi&#231;&#227;o celular do l&#237;quido de lavagem bronco-alveolar&#44; avalia&#231;&#227;o histol&#243;gica e conte&#250;do de hidroxiprolina pulmonar&#46;</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Aparecimento de fibrose nos pulm&#245;es dos ratos tratados com bleomicina&#46; Os resultados dos grupos tratados com metil-prednisolona e iloprost foram significativamente inferiores ao do grupo placebo &#40;p&#60;0&#46;05&#41;&#46; Al&#233;m disso&#44; o resultado do grupo de iloprost foi significativamente inferior ao resultado do grupo de metil-prednisolona&#46; O teor de hidroxiprolina foi significativamente inferior nos grupos de metil-prednisolona e de iloprost &#40;p &#60;0&#46;05&#41;&#46; No grupo placebo&#44; a percentagem de neutr&#243;filos na lavagem bronco-alveolar foi significativamente mais elevada do que nos outros grupos&#44; enquanto que a percentagem de macr&#243;fagos no grupo placebo foi significativamente inferior &#40;p &#60;0&#46;05&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Conclus&#227;o</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">O Iloprost tem um efeito protetor sobre a fibrose pulmonar induzida por bleomicina e pode ser mais eficaz na diminui&#231;&#227;o de altera&#231;&#245;es fibr&#243;ticas que a metil-prednisolona&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">The contents of hydroxyproline in the groups of control&#44; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo&#44; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone&#44; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost&#46; <span class="elsevierStyleSup">a</span> The content of hydroxyproline in the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo was significantly higher than the control group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <span class="elsevierStyleSup">b</span> The hydroxyproline contents in the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone and BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost groups were significantly lower than the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Histological H &#38; E stained sections &#40;200&#215;&#41; representative of control &#40;A&#41;&#44; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo &#40;B&#41;&#44; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost &#40;C&#41;&#44; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone &#40;D&#41;&#46;</p>"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Fibrosis scores of the control&#44; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo&#44; BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone and BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost groups&#46; <span class="elsevierStyleSup">a</span> Ashcroft score in the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo was significantly higher than the control group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <span class="elsevierStyleSup">b</span> Ashcroft score in the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone was significantly lower than the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <span class="elsevierStyleSup">c</span> Ashcroft score in the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost group was significantly lower than the BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone and BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>placebo groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p>"
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                  \t\t\t\t" style="border-bottom: 2px solid black">Control&#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methyl-prednisolone&#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">BLM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>iloprost&#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">91&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">76&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;3<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">91&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">91&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Neutrophils&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">21&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;7<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">5&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">5&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Lymphocytes&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Eosinophils&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Effects of iloprost and methyl-prednisolone on bleomycin-induced changes in inflammatory cells in BAL fluid&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:25 [
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              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "titulo" => "American Thoracic Society&#46; Idiopathic pulmonary fibrosis&#46; Diagnosis and treatment&#46; International consensus statement&#46; American Thoracic Society &#40;ATS&#41; and European Respiratory Society &#40;ERS&#41;"
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Am J Res Crit Care Med"
                        "fecha" => "2000"
                        "volumen" => "161"
                        "paginaInicial" => "646"
                        "paginaFinal" => "664"
                      ]
                    ]
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            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The bleomycin animal model&#58; a useful tool to investigate treatment options for idiopathic pulmonary fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "A&#46; Moeller"
                            1 => "K&#46; Ask"
                            2 => "D&#46; Warburton"
                            3 => "J&#46; Gauldie"
                            4 => "M&#46; Kolb"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.biocel.2007.08.011"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Biochem Cell Biol"
                        "fecha" => "2008"
                        "volumen" => "40"
                        "paginaInicial" => "362"
                        "paginaFinal" => "382"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17936056"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Current perspectives on the treatment of idiopathic pulmonary fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "N&#46; Walter"
                            1 => "H&#46;R&#46; Collard"
                            2 => "T&#46;E&#46; King"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1513/pats.200602-016TK"
                      "Revista" => array:6 [
                        "tituloSerie" => "Proc Am Thorac Soc"
                        "fecha" => "2006"
                        "volumen" => "3"
                        "paginaInicial" => "330"
                        "paginaFinal" => "338"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16738197"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Eicosanoid lipid mediators in fibrotic lung diseases&#58; ready for prime time&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46;K&#46; Huang"
                            1 => "M&#46; Peters-Golden"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1378/chest.08-0306"
                      "Revista" => array:6 [
                        "tituloSerie" => "Chest"
                        "fecha" => "2008"
                        "volumen" => "133"
                        "paginaInicial" => "1442"
                        "paginaFinal" => "1450"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18574287"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prostacyclin agonist with thromboxane synthase inhibitory activity &#40;ONO-1301&#41; attenuates bleomycin-induced pulmonary fibrosis in mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Murakami"
                            1 => "N&#46; Nagaya"
                            2 => "T&#46; Itoh"
                            3 => "M&#46; Kataoka"
                            4 => "T&#46; Iwase"
                            5 => "T&#46; Horio"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1152/ajplung.00042.2005"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Physiol Lung Cell Mol Physiol"
                        "fecha" => "2006"
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Article information

ISSN: 21735115
Original language: English

DOI:10.1016/j.rppnen.2012.10.002

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Year/Month	Html	Pdf	Total

2024 November	6	7	13
2024 October	26	49	75
2024 September	37	25	62
2024 August	48	59	107
2024 July	44	49	93
2024 June	29	34	63
2024 May	33	46	79
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2024 March	42	28	70
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2023 October	14	25	39
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