Bleomycin delivery by osmotic minipump: similarity to human scleroderma interstitial lung disease

Lee, Rebecca; Reese, Charles; Bonner, Michael; Tourkina, Elena; Hajdu, Zoltán; Riemer, Ellen C.; Silver, Richard M.; Visconti, Richard P.; Hoffman, Stanley

doi:10.1152/ajplung.00210.2013

Cited by 58 publications

(81 citation statements)

References 25 publications

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“…In agreement with previous reports that a murine model of lung fibrosis induced by implanting an osmotic minipump containing BLM, 19,20 we confirmed this finding based on our observation of the pathological changes in the lung. Compared with the lung changes induced by intratracheal administration or multiple sc injections of BLM, BLM given by osmotic minipump led to a greater increase in lung hydroxyproline and much extensive pleural surface involvement.…”

Section: Discussionsupporting

confidence: 93%

“…22 A very recent study also mentioned the thickening of skin following the implantation of osmotic minipumps with BLM. 19 We here further described the time course of changes in skin morphology, cutaneous infiltrates, and pro-inflammatory cytokine expression following the treatment of minipumps with BLM in detail. Thus, this modified murine model of SSc could be helpful to understand the underlying mechanisms of SSc and search for new therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

“…Compared with the lung changes induced by intratracheal administration or multiple sc injections of BLM, BLM given by osmotic minipump led to a greater increase in lung hydroxyproline and much extensive pleural surface involvement. 19,20 As the skin and lung exhibit the low activity of BLM hydrolase, a cytosolic aminopeptidase, 21 they are more sensitive to BLM than other organs. Therefore, systemic BLM given via osmotic minipump leads to skin and lung infiltration of activated inflammatory cells that secrete cytokines and chemokines, leading to impaired healing process, thereby promoting fibrosis ultimately.…”

Section: Discussionmentioning

confidence: 99%

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A modified murine model of systemic sclerosis: bleomycin given by pump infusion induced skin and pulmonary inflammation and fibrosis

Liang

Zou

et al. 2015

Laboratory Investigation

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Daily subcutaneous (sc) injection of bleomycin (BLM) causes dermal fibrosis but rarely causes lung changes in mice. There are also significant disadvantages to this traditional model for systemic sclerosis, including a variable distribution of lesions and a requirement for repetitive procedures. The present study was undertaken to develop a convenient method of BLM administration that yields stable dermal inflammation and fibrosis with extensive and reproducible interstitial lung disease (ILD) in mice. Osmotic minipumps containing BLM (150 mg/kg) or saline were implanted sc in C57BL/6 mice and the drug was delivered as a continuous infusion over 1B4 weeks. The time course of morphological features, collagen content, and pro-inflammatory cytokine expression in the skin and the lungs were analyzed. Pathological examination demonstrated dominant inflammatory infiltrates at week 1 and significant fibrosis at week 4. Decreased microvessel density and increased myofibroblast counts were observed in the skin of BLM-treated mice at week 4. In addition, there were obvious increases in dermal infiltration of CD45 þ leukocytes, including F4/80 þ macrophages, Gr-1 þ neutrophils, and CD3 þ T lymphocytes in BLM-treated mice. IL-1b, IL-4, and CXCL2 transcripts were continually upregulated by BLM in the skin and lung tissues. In addition, lungs from BLM-treated mice showed significant inflammatory infiltrates and confluent subpleural fibrosis at week 4. In conclusion, this modified murine model for drug-induced systemic inflammation and fibrosis uses a single procedure and provides reproducible skin and lung lesions, mimicking human systemic sclerosis (SSc) with ILD-like manifestation.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A modified murine model of systemic sclerosis: bleomycin given by pump infusion induced skin and pulmonary inflammation and fibrosis

Liang

Zou

et al. 2015

Laboratory Investigation

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“…Although bleomycin has been claimed to have minimal immunosuppressive activity and low hematopoietic toxicity, chemotherapy using bleomycin is often complicated by interstitial pulmonary fibrosis (Kawai and Akaza, 2003;Kim et al, 2010). Thus, bleomycin has been widely used in making pulmonary fibrosis animal models (Lee et al, 2014). Repetitive administrations of bleomycin by intraperitoneal or intravenous injection induce pleural and subpleural fibrosis, which is similar to what is seen in human IPF (Mouratis and Aidinis, 2011).…”

Section: Discussionmentioning

confidence: 96%

Bleomycin induced epithelial–mesenchymal transition (EMT) in pleural mesothelial cells

Chen

Zhang

et al. 2015

Toxicology and Applied Pharmacology

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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis. Recent studies revealed that pleural mesothelial cells (PMCs) undergo epithelial-mesenchymal transition (EMT) and play a pivotal role in IPF. In animal model, bleomycin induces pulmonary fibrosis exhibiting subpleural fibrosis similar to what is seen in human IPF. It is not known yet whether bleomycin induces EMT in PMCs. In the present study, PMCs were cultured and treated with bleomycin. The protein levels of collagen-I, mesenchymal phenotypic markers (vimentin and α-smooth muscle actin), and epithelial phenotypic markers (cytokeratin-8 and E-cadherin) were measured by Western blot. PMC migration was evaluated using wound-healing assay of culture PMCs in vitro, and in vivo by monitoring the localization of PMC marker, calretinin, in the lung sections of bleomycin-induced lung fibrosis. The results showed that bleomycin induced increases in collagen-I synthesis in PMC. Bleomycin induced significant increases in mesenchymal phenotypic markers and decreases in epithelial phenotypic markers in PMC, and promoted PMC migration in vitro and in vivo. Moreover, TGF-β1-Smad2/3 signaling pathway involved in the EMT of PMC was demonstrated. Taken together, our results indicate that bleomycin induces characteristic changes of EMT in PMC and the latter contributes to subpleural fibrosis.

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“…It has been reported that administration of a high dose of bleomycin often leads to lethal lung injury and pulmonary fibrosis in human patients, as well as in rodent (Hoshino et al, 2009). Therefore, it has been widely used in making pulmonary fibrosis animal models (Lee et al, 2014). The bleomycin model has the advantage that it is quite easy to perform, widely accessible and reproducible, and therefore fulfills important criteria expected from a good animal model (Mouratis and Aidinis, 2011).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic use of fisetin, curcumin, and mesoporous carbon nanoparticle loaded fisetin in bleomycin-induced idiopathic pulmonary fibrosis

Kar¹,

Konsam²,

Hore³

et al. 2015

Biomed Res Ther

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Abstract-Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology, for which there is no curative pharmacological therapy. Bleomycin, an anti-neoplastic agent that causes lung fibrosis in human patients has been used extensively in rodent models to mimic IPF. The conventional therapy has been steroids and immunosuppressive agents. But only a minority of patients responds to such a therapy. IPF is a progressive, ultimately fatal disorder for which substantive medical therapy is desperately needed. Fisetin is a flavonol which inhibits the activity of several pro-inflammatory cytokines. The polyphenol curcumin is used to treat inflammatory diseases, abdominal disorders, and a variety of other ailments. The aim of this study was to evaluate the beneficial effect of fistine, curcumin and mesoporous carbaon nanoparticle (MCN) loaded fisetin as an anti-inflammatory agents against bleomycin-induced changes in mice with IPF. In our study, flavonoids showed their anti fibrotic action. The inflammatory cell count was greatly increased for bleo treated individuals and effectiveness of fisein was increased after addition of MCN particles with it, curcumin also showed anti-inflammatory effects. In another experiment, bleomycin effectively inhibits the cellular recruitment to the spleen and treatment with fisetin, and curcumin increases the cellular recruitment in spleen. Colony count was also increased in MCN+fisetin treated groups, and it was statistically significant. We also observed the increased level of cytokines with fisetin treatment, with curcumin treatment and with MCN +fisetin treatment as compared to the bleo treated sample. In conclusion, the present research suggests that fisetin and curcumin and MCN loaded fisetin may be a promising therapeutic agent for bleomycin-induced changes in mice with IPF. This will open up new perspectives for a potential role of these drugs as a molecular target in Idiopathic pulmonary fibrosis.

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Bleomycin delivery by osmotic minipump: similarity to human scleroderma interstitial lung disease

Abstract: Lee R, Reese C, Bonner M, Tourkina E, Hajdu Z, Riemer EC, Silver RM, Visconti RP, Hoffman S. Bleomycin delivery by osmotic minipump: similarity to human scleroderma interstitial lung disease.

Cited by 58 publications

References 25 publications

A modified murine model of systemic sclerosis: bleomycin given by pump infusion induced skin and pulmonary inflammation and fibrosis

A modified murine model of systemic sclerosis: bleomycin given by pump infusion induced skin and pulmonary inflammation and fibrosis

Bleomycin induced epithelial–mesenchymal transition (EMT) in pleural mesothelial cells

Therapeutic use of fisetin, curcumin, and mesoporous carbon nanoparticle loaded fisetin in bleomycin-induced idiopathic pulmonary fibrosis

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