2.Simvastatin attenuates bleomycin-induced pulmonary fibrosis in mice.
Xue-mei OU ; Yu-lin FENG ; Fu-qiang WEN ; Xiang-yang HUANG ; Jun XIAO ; Ke WANG ; Tao WANG
Chinese Medical Journal 2008;121(18):1821-1829
BACKGROUNDBleomycin-induced fibrosis is extensively used to model aspects of the pathogenesis of interstitial pulmonary fibrosis. This study aimed to determine the benefic effects and mechanisms of simvastatin on bleomycin-induced pulmonary fibrosis in mice.
METHODSBleomycin-induced pulmonary fibrosis mice were administered with simvastatin in different doses for 28 days. We measured inflammatory response, fibrogenic cytokines and profibrogenic markers in both bleomycin-stimulated and control lungs, and correlated these parameters with pulmonary fibrosis.
RESULTSSimvastatin attenuated the histopathological change of bleomycin-induced pulmonary fibrosis and prevented the increase of lung hydroxyproline content and collagen (I and III) mRNA expression induced by bleomycin. Moreover, simvastatin down-regulated the increased expression of transforming growth factor-beta1 (TGF-beta1) and connective tissue growth factor (CTGF) induced by bleomycin at both gene and protein levels. Simultaneously, the accumulation of neutrophils and lymphocytes and the increased production of tumor necrosis factor-alpha (TNF-alpha) in bronchial alveolar lavage fluid were inhibited by simvastatin in early inflammatory phase after bleomycin infusion. The higher dose of simvastatin was associated with a more significant reduction in these inflammatory and fibrotic parameters. Furthermore, the inactivation of p38, RhoA and Smad2/3 signaling pathways was observed during simvastatin administration.
CONCLUSIONSSimvastatin attenuated bleomycin-induced pulmonary fibrosis, as indicated by decreases in Ashcroft score and lung collagen accumulation. The inhibitory effect of simvastatin on the progression of pulmonary fibrosis may be demonstrated by reducing inflammatory response and production of TGF-beta1 and CTGF. These findings indicate that simvastatin may be used in the treatment of pulmonary fibrosis.
Animals ; Antibiotics, Antineoplastic ; Bleomycin ; Mice ; Mice, Inbred C57BL ; Pulmonary Fibrosis ; chemically induced ; metabolism ; pathology ; Simvastatin ; pharmacology
3.Isoniazid and pulmonary fibrosis.
Chae Uk CHUNG ; Dong Il PARK ; Choong Sik LEE ; Sung Soo JUNG
Chinese Medical Journal 2015;128(5):702-703
4.Effects of the water channel aquaporin 4 deficiency on bleomycin-induced lung fibrosis in mice.
Xu-yun LI ; Xiao-fang XU ; Jing HANG ; Zhi-xian LIU ; Shu-ying YU ; San-Hua FANG ; Wei-ping ZHANG ; Er-qing WEI ; Yun-bi LU
Journal of Zhejiang University. Medical sciences 2014;43(3):281-286
OBJECTIVETo evaluate the effect of water channel aquaporin 4 (AQP4) on bleomycin-induced lung fibrosis in mice.
METHODSIn wild type and AQP4 gene knockout (AQP4-/-) mice, lung fibrosis was induced by injection of bleomycin (3 mg/kg) into the trachea and saline injection was used as a control. At d3, 7, 14, 28 after bleomycin-treatment, mice were randomly sacrificed in batch and the lung coefficient was determined. Serum levels of TGF-β1 and TNF-α were measured by ELISA and hydroxyproline contents in lung tissue were determined by Alkaline hydrolysis method. H-E staining and Masson's staining were performed to examine the pathological changes of lung tissues after bleomycin-treatment.
RESULTSOn d14 after bleomycin-treatment, the lung coefficients in wild type mice and AQP4-/- mice were 1.9-fold (12.69 ± 6.05 vs 6.80 ± 0.82, q=4.204, P<0.05) and 2.3-fold (14.05 ± 5.82 vs 6.05± 0.58, q=5.172, P<0.01) of that in control, respectively, but no significant difference was found between wild type and AQP4-/- mice in the lung coefficient value (P>0.05). The hydroxyproline contents in the lung increased after bleomycin-treatment; on d28, the lung hydroxyproline contents in wild type and in AQP4-/- mice were 1.55-fold (0.85 ± 0.22 g/mg vs 0.55 ± 0.14 μg/mg, q=4.313, P<0.05) and 1.4-fold (0.84 ± 0.13 μg/mg vs 0.60 ± 0.14μg/mg, q=4.595,P<0.05) of that in control, respectively, but no significant difference was noticed between wild type and AQP4-/- mice in lung hydroxyproline contents. There was a tendency that serum TGF-β1 and TNF-α levels increased in bleomycin-treated mice, but no significant difference was found between wild type and AQP4-/- mice. AQP4-knockout showed no effects on pathological changes of lung tissues with H-E staining and Masson's staining in mice with bleomycin-induced lung fibrosis.
CONCLUSIONAQP4 might not be involved in bleomycin-induced lung fibrosis in mice.
Animals ; Aquaporin 4 ; genetics ; Bleomycin ; toxicity ; Male ; Mice ; Mice, Knockout ; Pulmonary Fibrosis ; chemically induced ; genetics
5.Dynamic changes of pathological morphology and ultrastructure of lung injury in rats induced by SiO₂ nanoparticles.
Yingjian ZHANG ; Wenchao LI ; Yi ZHENG ; Xuefei WANG ; Ganyun LI ; Hong YANG
Chinese Journal of Industrial Hygiene and Occupational Diseases 2014;32(7):504-510
OBJECTIVETo observe the lung injury in rats induced by SiO₂ nanoparticles.
METHODSOne hundred and fifty SD rats were divided into five groups: the control group, the nanosized SiO₂ groups of 6.25, 12.5, 25 mg/ml, and the microsized SiO₂ group of 25 mg/ml, 30 rats each group. On the 7th, 15th, 30th, 60th and 90th day after exposure, six rats were sacrificed at each time point and the lung viscera coefficient, the pathological morphology and ultrastructure of lung were observed.
RESULTSAt each time point, the rat lung viscera coefficient of 25 mg/ml microsized SiO₂ and nanosized SiO₂ group were higher than the physiological saline group (P < 0.05), 25 mg/ml microsized SiO₂ group was higher than the same dose of nanosized SiO₂ group (P < 0.05); With longer duration of dye dust, lung viscera coefficient of 25 mg/ml microsized SiO₂ group and each dose of nanosized SiO₂ group were in time-effect relationship. Under light microscope we can see microsized SiO₂ group gradually formed cellularity nodules, and fused into fibrous nodules; At the early stage 25 mg/ml nanosized SiO₂ group occured focal alveolar macrophages and fibroblast proliferation and later fibrous connective tissue proliferated. Under TEM osmium lamellar corpuscle of type II alveolar epithelial cells were abnormal, and collagen and elastic fiber proliferated in mesenchyme of microsized and nanosized SiO₂ group.
CONCLUSIONNanosized SiO₂ particles after exposure can cause lung tissue injury in rat, and at the early stage it is showed inflammation, and later mainly characterized by pulmonary interstitial fibrosis differing from nodular lung fibrosis caused by microsized SiO₂, its ability to fibrosis is weaker compared with the same concentration of microsized SiO₂.
Animals ; Lung ; drug effects ; pathology ; ultrastructure ; Lung Injury ; chemically induced ; Male ; Nanoparticles ; toxicity ; Pulmonary Fibrosis ; chemically induced ; pathology ; Rats ; Rats, Sprague-Dawley ; Silicon Dioxide ; toxicity
6.Pulmonary fibrosis in a steel mill worker.
Jong Han LEEM ; Yun Chul HONG ; Jeong Soo SONG ; Won PARK ; Hye Seung HAN
Journal of Korean Medical Science 2000;15(2):224-228
We report a case of pulmonary fibrosis in a 32-year-old man, who had worked at a steel mill and who died of respiratory failure due to interstitial fibrosis despite vigorous treatment. He showed SLE-associated symptoms, such as pleural effusion, malar rashes, discoid rashes, arthritis, leukopenia, and positive antinuclear antibody and anti-histone antibody. However, he did not present anti-DNA antibody. A thoracoscopic lung biopsy showed interstitial fibrosis, chronic inflammation and a small non-caseating granuloma in lung tissues, which could be induced by external agents such as metals. The manganese concentration in the lung tissue was 4.64 microg/g compared to 0.42-0.7 microg/g in the controls. The levels of other metals, such as iron, nickel, cobalt and zinc in patient's lung tissue were higher than those in the controls. The patient was probably exposed to Si and various metal dusts, and the lung fibrosis was related to these exposures. Exposure to Si and metal dusts should be sought in the history of any patient with SLE, especially in a male with pulmonary signs, and if present, exposure should be stopped. In the meantime, steps should be taken to ensure that workers exposure to Si and metal dusts in all environments have adequate protection.
Adult
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Biopsy
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Case Report
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Fatal Outcome
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Human
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Male
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Occupational Diseases/radiography*
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Occupational Diseases/pathology
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Occupational Diseases/chemically induced*
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Occupational Exposure
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Pulmonary Alveoli/pathology
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Pulmonary Fibrosis/radiography*
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Pulmonary Fibrosis/pathology
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Pulmonary Fibrosis/chemically induced*
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Respiratory Insufficiency/radiography
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Respiratory Insufficiency/pathology
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Respiratory Insufficiency/chemically induced
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Steel/adverse effects*
7.Progress on pathogenesis and treatment of paraquat-induced pulmonary fibrosis.
Journal of Zhejiang University. Medical sciences 2014;43(6):717-727
Paraquat (PQ) is a highly effective herbicide with contact toxicity. PQ mainly accumulates in the lungs after absorption into the blood circulation. The respiratory function failure caused by PQ-induced lung injury, especially the irreversible pulmonary fibrosis in late phase, is the leading cause of death in patients with PQ poisoning. The mechanism of PQ poisoning is still unclear. Now it is speculated that oxidative stress and inflammation injury are the main pathogenic mechanisms, and abnormal gene expression, mitochondrial damage, loss of pulmonary surfactant, cytokine network and unbalanced matrix metalloproteinases/tissue inhibitors may be also involved in the pathogenesis. In addition to reducing poison absorption and increasing its removal, the current clinical treatment is mainly composed of antioxidant and anti-immune response, but has poor therapeutic effects. Although many novel methods of treatment have been proposed, most of them are still in the experimental stage. It is a hot spot to clarify the mechanism of PQ poisoning and to seek safe and effective treatment of pulmonary fibrosis. This article reviews the research progress on pathogenesis and treatment of PQ-induced pulmonary fibrosis.
Antioxidants
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Gene Expression
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Humans
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Inflammation
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Lung
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pathology
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Oxidative Stress
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Paraquat
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poisoning
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Pulmonary Fibrosis
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chemically induced
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pathology
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therapy
8.The pulmonary toxicity of amiodarone: six-case report.
Chinese Journal of Cardiology 2005;33(1):66-68
OBJECTIVETo report the clinical features and the prognosis, the methods of diagnosis and treatment, and the early detection of the pulmonary toxicity induced by amiodarone.
METHODThe clinical course, the findings of X-ray and CT and the results of treatment were summarized and analyzed in six patients with amiodarone-induced pulmonary toxicity.
RESULTSFive males, one female, aged 62 - 69 (66.0 +/- 2.4) years. Amiodarone was used because of paroxysmal atrial fibrillation in five patients and ventricular arrhythmia in one. The loading dose was 7 g and the maintaining dose was 0.2 g/d or less. Pulmonary toxicity was recognized at the times in 0.5 - 4.0 (2.1 +/- 1.3) years after amiodarone therapy. Dyspnea occurred, crack rales were audible in both lower parts of the lungs, and the chest X-ray showed grid-like changes in case one. No symptom was found in the others. Their diagnosis was made according to the pulmonary intestinal changes by high-resolution computerized tomography when the lung marking was increased or deranged by chest X-ray during the regular follow-up. Pulmonary function examination showed that the restrictive ventilation and the CO diffusing capacity decreased in case one, while the CO diffusing capacity was normal in the others. The decreased obstructive ventilation capacity was found in case six. Amiodarone was discontinued in all the cases after the diagnosis of induced pulmonary toxicity. One patient was treated with corticosteroid, three with azithromycin, and the another two patients were not treated with drug. During 0.1 - 5.0 year period of follow-up the symptoms were markedly attenuated in case one, and no new symptoms and radiography findings were found in the others.
CONCLUSIONSPulmonary toxicity is a serious adverse effect of amiodarone. The typical feature is pulmonary intestinal fibrosis and thick pulmonary intestine in the early stage. Corticosteroid treatment seems effective. It would be helpful for early diagnosis to take chest X-ray examination regularly and CT examination in suspicions cases during the therapy. The prognosis may be good in the early diagnosed cases.
Aged ; Amiodarone ; adverse effects ; Female ; Humans ; Male ; Middle Aged ; Prognosis ; Pulmonary Fibrosis ; chemically induced ; diagnostic imaging ; Radiography
9.Study of toxicity to rats induced by nanosized SiO2 and standard SiO2.
Xingqiu YING ; Yi-Fan ZHENG ; Hui-Juan ZHU ; Jing JIN ; Qun-Li ZENG ; Qun-Wei ZHANG ; Xin-Qiang ZHU
Chinese Journal of Industrial Hygiene and Occupational Diseases 2007;25(1):26-29
OBJECTIVETo study the pulmonary toxicity to rats induced by the nanosized SiO(2) or the standard SiO(2).
METHODSSeventy-two male SD rats were divided into three groups: the nanosized SiO(2) group, the standard SiO(2) group and the control group. 24 rats each group. The nanosized SiO(2) group and the standard SiO(2) group were instilled intratracheally with 0.5 ml suspension of 0.6 mg/ml nanosized SiO(2) or standard SiO(2) respectively while the control group was instilled with 0.5 ml physiological saline. On the 3rd, 7th, 14th, and 28th day after exposure, six rats were sacrificed at each time point and the total white cells counts and total protein in BALF and the histopathological changes were observed. The pulmonary toxicities of the two SiO(2) dusts were compared.
RESULTSNanosized SiO(2) caused significant increase at 3rd, 7th, 14th day after the exposure [(16.0 +/- 6.0) x 10(6), (11.1 +/- 4.0) x 10(6), (12.2 +/- 4.6) x 10(6)] compared with saline (P < 0.05 or P < 0.01) in the total numbers of white cells and on the 3rd after the exposure compared with standard SiO(2) [(5.7 +/- 3.7) x 10(6), P < 0.01]. Meanwhile, Nanosized SiO(2) significantly increased the total protein on the 14th, 28th day after the exposure (0.41 +/- 0.14, 0.41 +/- 0.19 g/L) compared with saline or standard SiO(2) and nanosized SiO(2) on the 3rd, 7th day after the exposure (P < 0.05 or P < 0.01). Nanosized SiO(2)-treated rats showed marked white cell infiltration in alveolar space or around brondum the blood vessel. Standard SiO(2) caused similar but less severe responses compared with nanosized SiO(2). Van Gieson's-stained sections showed no significant fibrosis in these dust-exposed rats at 28th day after the exposure.
CONCLUSIONNanosized SiO(2) can cause severer and longer pulmonary toxicity in rats than standard SiO(2). The pulmonary particle load threshold of nanosized SiO(2) may be lower than that of standard SiO(2).
Animals ; Male ; Nanoparticles ; toxicity ; Particle Size ; Pulmonary Fibrosis ; chemically induced ; Rats ; Rats, Sprague-Dawley ; Silicon Dioxide ; toxicity
10.Effect of amygdalin on serum proteinic biomarker in pulmonary fibrosis of bleomycin-induced rat.
Hai-Ke DU ; Fu-Cheng SONG ; Xin ZHOU ; He LI ; Jian-Peng ZHANG
Chinese Journal of Industrial Hygiene and Occupational Diseases 2010;28(4):260-263
OBJECTIVETo evaluate effect of amygdalin on expression of four biomarkers in the animal model of pulmonary fibrosis induced by bleomycin.
METHODSRats were given one dose (5 mg/kg) of bleomycin in bleomycin-treated groups, amygdalin-treated groups and saline in controls by intratracheal instillation exposed surgically. The amygdalin-treated groups rats were treated with intraperitoneal injection of amygdalin (15 mg x kg(-1) x day(-1)). The rats were sacrificed 7, 14 and 28 days after bleomycin administration. Polarized light microscopy and Image-Pro Plus detected I and III collagen expressed in Paraffin-embedded lung sections stained with Sirius red. Surface-enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF MS) with weak cationic proteinchip (CM10) detected differentially expressed proteins in the pooled serum samples of all groups.
RESULTSConsistent fibrotic responses were found in all bleomycin and amygdalin-tread groups. On the 7th, 14th and 28th day after bleomycin or saline instillation, four differentially expressed proteins were detected in the pooled serum of all groups rats, consisting of 4 proteins with mass/charge ratio of 3530.7, 7043.5, 8332.6 and 9068.0, respectively. Compared with control groups, protein peaks intensity ratio with mass/charge ratio of 3530.7 on 7, 28 d and 7043.5, 8332.6 and 9068.0 on 7, 14 and 28 d was > 2 in bleomycin-treated groups. Compared with amygdalin-treated groups, protein peaks intensity with mass/charge ratio of 3530.7 at 7, 14, 28 d had no change almost, but protein peaks intensity ratio with mass/charge ratio of 7043.5 at 7 d, 8332.6 on 28 d and 9068.0 on 14 d was > 2 in bleomycin-tread groups. All the four protein peaks intensity had no change almost at other point.
CONCLUSIONAmygdalin may reduce the bleomycin-induced increase of differentially expressed protein peak intensities in rat serum.
Amygdalin ; pharmacology ; Animals ; Biomarkers ; blood ; Bleomycin ; adverse effects ; Blood Proteins ; metabolism ; Male ; Pulmonary Fibrosis ; blood ; chemically induced ; Rats ; Rats, Wistar