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1.
Chinese Medical Journal ; (24): 2175-2185, 2021.
Article in English | WPRIM | ID: wpr-921109

ABSTRACT

BACKGROUND@#Macrophages are involved in the pathogenesis of idiopathic pulmonary fibrosis, partially by activating lung fibroblasts. However, how macrophages communicate with lung fibroblasts is largely unexplored. Exosomes can mediate intercellular communication, whereas its role in lung fibrogenesis is unclear. Here we aim to investigate whether exosomes can mediate the crosstalk between macrophages and lung fibroblasts and subsequently induce fibrosis.@*METHODS@#In vivo, bleomycin (BLM)-induced lung fibrosis model was established and macrophages infiltration was examined. The effects of GW4869, an exosomes inhibitor, on lung fibrosis were assessed. Moreover, macrophage exosomes were injected into mice to observe its pro-fibrotic effects. In vitro, exosomes derived from angiotensin II (Ang II)-stimulated macrophages were collected. Then, lung fibroblasts were treated with the exosomes. Twenty-four hours later, protein levels of α-collagen I, angiotensin II type 1 receptor (AT1R), transforming growth factor-β (TGF-β), and phospho-Smad2/3 (p-Smad2/3) in lung fibroblasts were examined. The Student's t test or analysis of variance were used for statistical analysis.@*RESULTS@#In vivo, BLM-treated mice showed enhanced infiltration of macrophages, increased fibrotic alterations, and higher levels of Ang II and AT1R. GW4869 attenuated BLM-induced pulmonary fibrosis. Mice with exosomes injection showed fibrotic features with higher levels of Ang II and AT1R, which was reversed by irbesartan. In vitro, we found that macrophages secreted a great number of exosomes. The exosomes were taken by fibroblasts and resulted in higher levels of AT1R (0.22 ± 0.02 vs. 0.07 ± 0.02, t = 8.66, P = 0.001), TGF-β (0.54 ± 0.05 vs. 0.09 ± 0.06, t = 10.00, P < 0.001), p-Smad2/3 (0.58 ± 0.06 vs. 0.07 ± 0.03, t = 12.86, P < 0.001) and α-collagen I (0.27 ± 0.02 vs. 0.16 ± 0.01, t = 7.01, P = 0.002), and increased Ang II secretion (62.27 ± 7.32 vs. 9.56 ± 1.68, t = 12.16, P < 0.001). Interestingly, Ang II increased the number of macrophage exosomes, and the protein levels of Alix (1.45 ± 0.15 vs. 1.00 ± 0.10, t = 4.32, P = 0.012), AT1R (4.05 ± 0.64 vs. 1.00 ± 0.09, t = 8.17, P = 0.001), and glyceraldehyde-3-phosphate dehydrogenase (2.13 ± 0.36 vs. 1.00 ± 0.10, t = 5.28, P = 0.006) were increased in exosomes secreted by the same number of macrophages, indicating a positive loop between Ang II and exosomes production.@*CONCLUSIONS@#Exosomes mediate intercellular communication between macrophages and fibroblasts plays an important role in BLM-induced pulmonary fibrosis.


Subject(s)
Angiotensin II , Animals , Bleomycin/toxicity , Exosomes , Fibroblasts , Lung , Macrophages , Mice , Mice, Inbred C57BL , Pulmonary Fibrosis/chemically induced , Receptor, Angiotensin, Type 1
2.
Article in Chinese | WPRIM | ID: wpr-880825

ABSTRACT

OBJECTIVE@#To study the changes in mRNA and long non-coding RNA (lncRNA) expression profiles in a mouse model of bleomycin-induced lung fibrosis and identify lung fibrosis-related mRNA for coding-noncoding coexpression (CNC) bioinformatics analysis of the differential lncRNAs.@*METHODS@#Lung fibrosis was induced by intratracheal injection of bleomycin in 10 C57BL/6 mice and another 10 mice with intratracheal injection of saline served as the control group. Lung tissues were harvested from the mice at 14 days after the injections and lung fibrosis was assessed using Masson and HE staining. LncRNA chip technology was used to screen the differentially expressed mRNAs and lncRNAs in mice with lung fibrosis, and GO and KEGG pathway analyses of the differential mRNAs were performed using NCBI database and UCSC database to identify possible fibrosis-related mRNAs, which were validated by qRT-PCR to construct a coding and non-coding co- expression network with the differential lncRNAs.@*RESULTS@#Compared with the control mice, the mice with intratracheal injection of bleomycin showed obvious lung fibrosis. The results of gene chip analysis showed that 127 mRNAs were upregulated and 184 mRNAs were down-regulated in the model group as compared with the control group. GO and pathway analysis suggested that the differentially expressed genes participated mainly in immune response, cell differentiation, and cytoskeletons; the involved signal pathways were associated mainly with cytokine and cytokine receptor interaction and chemokine signal transduction. Bioinformatics analysis identified a significant coexpression network between the fibrosisrelated mRNA and the differentially expressed lncRNA.@*CONCLUSIONS@#In mice with lung fibrosis, the differential expressions of fibrosis-related mRNAs in the lung tissues are closely correlated with the co- expressions of a large number of differential lncRNAs, which points to a new direction for investigation of the pathogenesis of pulmonary fibrosis.


Subject(s)
Animals , Bleomycin/toxicity , Gene Expression Profiling , Gene Regulatory Networks , Mice , Mice, Inbred C57BL , Pulmonary Fibrosis/genetics , RNA, Long Noncoding/genetics , RNA, Messenger/genetics
3.
Yonsei Medical Journal ; : 68-77, 2009.
Article in English | WPRIM | ID: wpr-83529

ABSTRACT

PURPOSE: Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of pulmonary fibrosis. To understand the role of MMP-2 and MMP-9 in pulmonary fibrosis, we evaluated the sequential dynamic change and different cellular sources of the 2 MMPs along the time course and their differential expression in the bronchoalveolar lavage (BAL) fluid and in the lung parenchyma of the bleomycin-induced pulmonary fibrosis models in rats. MATERIALS AND METHODS: The level of MMPs in BAL fluid of 54 bleomycin-treated rats was assessed by zymography from 1 to 28 days after intratracheal bleomycin instillation. The level of MMPs in lung parenchyma was evaluated by immunohistochemistry. RESULTS: MMP-2 and MMP-9 were markedly increased in both the BAL fluid and in the lung parenchyma of the bleomycin-treated rats, especially in the early phase with the peak on the 4th day. The levels of both MMPs in the BAL fluid correlated generally well to those in lung parenchyma, although the level of MMP-9 in BAL fluid was higher than MMP-2. In the lung parenchyma, the 2 MMPs, in early stage, were predominantly expressed in the inflammatory cells. In late stage, type II pneumocytes and alveolar epithelial cells at the periphery of the fibrotic foci retained MMP expression, which was more prominent in the cells showing features of cellular injury and/or repair. CONCLUSION: In bleomycin-induced pulmonary fibrosis, MMP-2 and MMP-9 may play important roles, especially in the early phase. In the late stage, the MMP-2 and MMP-9 may play a role in the process of repair.


Subject(s)
Animals , Antibiotics, Antineoplastic/toxicity , Bleomycin/toxicity , Bronchioles/enzymology , Bronchoalveolar Lavage Fluid/cytology , Disease Models, Animal , Enzyme Activation , Gelatin , Immunohistochemistry , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Neutrophils/pathology , Pulmonary Fibrosis/chemically induced , Rats , Rats, Sprague-Dawley
4.
New Egyptian Journal of Medicine [The]. 2000; 23 (Supp. 5): 49-59
in English | IMEMR | ID: emr-54917

ABSTRACT

The current study aimed to investigate the effect of oral supplementation with the nitric oxide [NO] precursor; namely, L- arginine [ARG] and the NO synthesis inhibitor; namely, NG-nitro-L- arginine methyl ester [L-NAME] on bleomycin [BLM]-induced pulmonary toxicity. BLM was administered i.p. at a dose of 15 mg/kg, three times a week, for a total period of four weeks to male Wistar rats. Treatment with either ARG [500 mg/kg/day] or L-NAME [100 mg/kg/day] was commenced with BLM and continued up to the end of the experiment. Appropriate controls were performed. The results of the study indicated that the lung toxicity exerted by chronic administration of BLM is alleviated by ARG, while exacerbated by L-NAME supplementation and could address a possible protective role of NO


Subject(s)
Animals, Laboratory , Bleomycin/toxicity , Arginine , Antibiotics, Antineoplastic , Nitric Oxide , Rats, Wistar , Oxidants , Collagen
5.
Indian J Exp Biol ; 1995 Oct; 33(10): 734-8
Article in English | IMSEAR | ID: sea-56879

ABSTRACT

Fibrosis of organs and tissues are major causes of morbidity and mortality in human. The currently available pharmacologically based treatments are unsatisfactory. As an experimental animal model antitumor antibiotic drug bleomycin (BLM) is widely used to produce lung fibrosis. The present study has been undertaken to investigate the possible role of a potent immunomodulator Staphylococcus protein-A (SpA) in the modulation of lung lesions caused by treatment of BLM. In mice BLM, 0.5 mg in 200 microliters of normal saline and SpA, 6 micrograms in 200 microliters of normal saline was administered singly or in combination twice a week for 4 weeks. The fibrotic lesions in the lungs were observed after 4 weeks of BLM treatment. After 4 weeks treatment of SpA, the hyperreactive changes in bronchi and bronchioles were observed. In the co-treatment group of BLM and SpA, the effects observed were in the form of enhanced lesions in the lung parenchyma. Moreover, the pleural lesions were also observed in co-treatment group (BLM + SpA). Opposite to the assumption, SpA being a potent immunomodulator was not able to reduce the lung lesions produced by BLM.


Subject(s)
Animals , Antibiotics, Antineoplastic/toxicity , Bleomycin/toxicity , Drug Synergism , Male , Mice , Pulmonary Fibrosis/chemically induced , Staphylococcal Protein A/toxicity
6.
Rev. chil. urol ; 52(1): 65-9, 1989. tab, ilus
Article in Spanish | LILACS | ID: lil-87515

ABSTRACT

Se presentan 19 pacientes con Ca. testicular en etapas B1, B2, B3, y C sometidos a quimioterapia con PVB entre 1981-1987 en nuestro Servicio. Se analizan los signos de toxicidad con este esquema quimioterápico. Hubo R.C. (respuesta completa) en 14 pacientes y R.P. (respuesta parcial) en 3 enfermos en etapa B3 (que se convirtieron en R.C. con cirugía y más quimioterapia) y en 2 pacientes en etapa C (1 paciente muerto de su enfermedad y 1 paciente vivo con enfermedad). De 19 pacientes tratados con el esquema PVB solo o en combinación con cirugía tenemos 17 enfermos vivos y sin evidencia de enfermedad


Subject(s)
Adolescent , Adult , Humans , Male , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bleomycin/administration & dosage , Cisplatin/administration & dosage , Testicular Neoplasms/drug therapy , Vinblastine/administration & dosage , Bleomycin/toxicity , Cisplatin/toxicity , Vinblastine/toxicity
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