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.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
4.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
;
therapy
5.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
;
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*
;
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
;
Steel/adverse effects*
6.Scanning electron microscopic study of capillary change in bleomycin-induced pulmonary fibrosis.
Kun Young KWON ; Kwan Kyu PARK ; Eun Sook CHANG
Journal of Korean Medical Science 1991;6(3):234-245
The architectural changes which occur in the capillaries are difficult to illustrate without a three-dimensional tool, such as scanning electron microscopy. Therefore, a scanning electron microscopic study was occasionally undertaken to show the capillary changes of lung fibrosis. Fibrosis was induced in twenty rats by an intratracheal injection of bleomycin. After 30 days the rats were sacrificed, and light microscopy and scanning electron microscopy were performed. The vascular trees of both lungs were cast with methacrylate. Light microscopically, the pulmonary fibrosis was patchy and inflammatory cell infiltration was rather sparse. Scanning electron microscopically, the intercapillary spaces became wider; and some capillaries revealed large irregular dilatation. The pleural and alveolar capillaries were variably dilated. The pleural capillary diameter was increased (P = 0.06), and the capillary plexus diameter was decreased (P = 0.00). Distance between the capillary branches of the pleural surface was increased (P = 0.06). The appearance of irregularly shaped capillaries, an increase in diameter with variable dilatation of alveolar capillary rings and a decrease in branching between the capillaries, resulting in a loss of surface area are the main scanning electron microscopic findings of the remodeling which occurs pulmonary capillaries in bleomycin-induced pulmonary fibrosis.
Animals
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*Bleomycin
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Capillaries/pathology/*ultrastructure
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Microscopy, Electron, Scanning
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Pulmonary Alveoli/*blood supply/ultrastructure
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Pulmonary Fibrosis/chemically induced/*pathology
;
Rats
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Rats, Inbred Strains
7.The expression of alpha-smooth muscle actin in primary cultural fibroblasts of rats.
Jing-ping YANG ; De-jun SU ; Shu-nan LI ; Li GAO
Chinese Journal of Applied Physiology 2009;25(3):339-343
AIMTo observe the expression of a-smooth muscle actin(a-SMA) in primary cultural fibroblasts of rats.
METHODS12 female Wistar rats were randomly assigned into two groups, the normal group and the model group. The model group was filled with bleomycin A2 (5 mg/kg) once into the trachea. The normal group was filled with equal saline into the trachea. The rats were sacrificed under drugged state at 28 days of feeding, then Hematoxylin-Eosin staining and electron microscopy were used to evaluate the foundation of the model. The isolated fibroblasts from the rats were cultured in vitro. Flow cytometry was used in the test to observe the expression of alpha-SMA in fibroblast in vitro in rats.
RESULTSThe formation of fibroblast foci was observed in the model group by optical microscope. The ultrastructure in pulmonary tissue of the model group rats were changed and proliferated myofibroblasts with filaments were found in the alveolar septa by electron microscopy. The expression of alpha-SMA was positive in the normal and model group. There was no difference between the two groups in the rates of positive cells (P > 0.05).
CONCLUSIONBoth the normal and model groups had the phenotype conversion in lung fibroblasts in vitro.
Actins ; metabolism ; Animals ; Bleomycin ; Cells, Cultured ; Female ; Fibroblasts ; metabolism ; pathology ; Lung ; pathology ; Myofibroblasts ; pathology ; Pulmonary Fibrosis ; chemically induced ; pathology ; Rats ; Rats, Wistar
8.Preliminary study on the biological effects of MiR-144 in pulmonary injury in rats induced by nanosized SiO₂.
Canshan LAO ; Yingjian ZHANG ; Wenchao LI ; Mingyue LI ; Hong YANG ; E-mail: YANGHONGR@SEU.EDU.CN.
Chinese Journal of Industrial Hygiene and Occupational Diseases 2015;33(9):641-645
OBJECTIVETo Investigate the biological effects of miR-144 in rats' pulmanory injury induced by nanosized SiO₂preliminarily.
METHOD150 healthy SD rats were divided into five groups randomly: the control group, the nanosized SiO₂groups of 6.25, 12.5, 25.0 mg/ml, and the microsized SiO₂group of 25.0 mg/ml, 30 rats each group. Six rats were sacrificed for their pathological change on the 7th, 15th, 30th, 60th and 90th day after exposure. The expression levels of mature miR-144 in lung tissue of the rats after instilled intracheally nanosized SiO₂at 90d was detected by Quantitative Reverse Transcription PCR. Target prediction for miR-144 was conducted by databases of Target-scan, microRNA.org and miRDB. Function-significant enrichment analysis and signal pathway analysis for predicted target genes were respectively conducted by the Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes, then target genes related to pulmonary fibrosis were screened out.
RESULTSThe expression of miR-144 was up-regulated in lung tissue of rats exposed to nanosized SiO₂. The result was consistent with the results of high-throughput sequencing Hiseq 2000. The target genes of miR-144 related to fibrosis or signal pathway involved in fibrosis were screened out.They are SMAD4, SMAD5, ADAMTS3, ADAMTS15 and ADAMTS19.
CONCLUSIONMiR-144 probably participate in the regulation of fibrosis, which may play an important role in pulmonary injury induced by nanosized SiO₂.
Animals ; Lung ; pathology ; Lung Injury ; chemically induced ; metabolism ; pathology ; MicroRNAs ; metabolism ; Nanoparticles ; adverse effects ; Pulmonary Fibrosis ; metabolism ; pathology ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Silicon Dioxide ; toxicity
9.Effects of curcumin on bleomycin-induced damages in pulmonary functions in rats.
Cheng-jiang ZHAO ; Jian-zhao NIU ; Ji-feng WANG ; Gang ZHOU ; Bing-hua TANG
China Journal of Chinese Materia Medica 2008;33(12):1434-1438
OBJECTIVETo determine the effects of curcumin on bleomycin (BLM)-induced pulmonary fibrosis in rats.
METHODOne hundred and forty-four male Sprague-Dawley rats were randomized into 6 groups (24 rats in each group, model group, sham group, prednisone group (0.56 mg x kg(-1) x d(-1)), curcumin with low dose 5 mg group, curcumin with middle dose group 10 mg and curcumin with high dose group 20 mg per 100 g of body weight). Rats in all groups except in sham group were injected with BLM intratracheally. Curcumin with different doses were given by gavage one time everyday for 7, 14 and 28 days. Prednisone were given to rats in prednisone group, po, serving as the positive treatment group. On the 7th, 14th, 28th day, the lung functions (inspiratory resistance, maximal volutary ventilation, forced vital capacity, Fev 0.2/FVC, peak expiratory flow) were determinated in experimental rats, respectively, and the concentrations of hydroxyproline in lung homogenates of each rat were assayed.
RESULTAdministration of curcumin in different doses improved lung functions of BLM-induced fibrotic rats in the all experimental days; and it decreased the concentration of hydroxyproline in lung homogenates compared with those levels in model control group; and it also lessened the hyperplasia of BLM-induced pulmonary fibrosis in rats.
CONCLUSIONAdministration of curcumin can suppress BLM induced pulmonary fibrosis indicated by improved respiratory function, as well as companied with low content of hydroxyproline in lung tissue of rats.
Animals ; Bleomycin ; adverse effects ; Curcumin ; pharmacology ; Hydroxyproline ; metabolism ; Lung ; drug effects ; metabolism ; pathology ; physiopathology ; Male ; Pulmonary Fibrosis ; chemically induced ; metabolism ; pathology ; physiopathology ; Rats ; Time Factors
10.The comparative study of quartz dust and bleomycin-induced pulmonary fibrosis in rats.
Wei-Wei LIU ; Juan CHEN ; Yi-Min LIU ; Su-Mei LI ; Wei YU ; Jia-Yu CHEN ; Cheng ZHANG ; Li-Juan TANG ; Chen-Li LIN ; Xue-Yun ZHONG
Chinese Journal of Industrial Hygiene and Occupational Diseases 2011;29(7):496-501
OBJECTIVETo compare the pulmonary alveolitis and the early fibrosis of pulmonary fibrosis induced by quartz dust and bleomycin in rats, and investigate their mechanism.
METHODSThe female rats were divided into three groups: control group exposed to normal saline by the trachea; SiO2 group exposed to SiO2 by the trachea; BLM group exposed to BLM A5 by the trachea. Each half of the animals were sacrificed on the 7th and 14th day after exposure. The lungs of rats were collected to observe pulmonary alveolitis by HE staining and to observe fibrosis by saturated picric acid sirius red staining. The expression of tumor necrosis factor-alpha (TNF-alpha) and CD68 in pulmonary tissues were analyzed quantitatively by immunohistochemistry and image analysis system.
RESULTS(1) The alveolitis and pulmonary fibrosis of rats in both SiO2 group and BLM group were became more serious gradually over time, HE staining under light microscope showed that BLM group on the 7th day had the most obvious alveolitis (2.814 +/- 0.832), the saturated picric acid sirius red staining under polarized light showed that BLM group on the 14th day had the worst pulmonary fibrosis (1284.57 +/- 554.72), which were significantly higher than those (103.69 +/- 18.29 and 111.78 +/- 37.45) in control group and SiO2 group on the 7th day (P < 0.05). (2) The results of immunohistochemistry examination indicated that the expression (17.100 +/- 1.831) of TNF-alpha in the BLM group on the 7th day was significantly higher than those (0.451 +/- 0.441, 7.909 +/- 1.275 and 13.506 +/- 1.454) in control group, SiO2 group on 7th day and BLM group on 14th day (P < 0.05). The expression (22.778 +/- 2.512) of TNF-alpha in the SiO2 group on the 14th day was significantly higher than those in control group, SiO2 group on 7th day and BLM group on 14th day (P < 0.05). The expression (134.941 +/- 35.951) of CD68 in the SiO2 group on the 14th day was significantly higher than those in control group, SiO2 group on 7th day and BLM group on 14th day (P < 0.05).
CONCLUSIONThe early alveolitis of BLM-induced lung injury model was more serious than that of SiO2-induced lung injury model, and the fibrosis process of BLM-induced lung injury model was earlier than that of SiO2-induced lung injury model. TNF-alpha plays an important role in the course of both models, but macrophages is involved in SiO2-induced pulmonary in a more continuous way than in BLM-induced pulmonary fibrosis.
Animals ; Bleomycin ; adverse effects ; Disease Models, Animal ; Dust ; Female ; Lung ; pathology ; Pulmonary Fibrosis ; chemically induced ; pathology ; Quartz ; adverse effects ; Rats ; Rats, Wistar