Dose-response Effects of Bleomycin on Inflammation and Pulmonary Fibrosis in Mice

Kim, Soo Nam; Lee, Jin Soo; Yang, Hyo-Seon; Cho, Jae-Woo; Kwon, Soonjin; Kim, Young‐Beom; Her, Jeong-Doo; Cho, Kyu-Hyuk; Song, Chang-Woo; Lee, Kyuhong

doi:10.5487/tr.2010.26.3.217

Cited by 42 publications

(27 citation statements)

References 23 publications

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“…These observations are consistent with results of previous studies that utilized bleomycin in the high-dose range. Although these doses are much lower than those used in some previous studies [10,15], we achieved similar levels of disease severity.…”

Section: Discussionsupporting

confidence: 56%

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Bleomycin mouse model with active-phase pulmonary fibrosis and no acute mortality

Kadam¹,

Faix²,

Schnitzer³

2020

Preprint

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Background The bleomycin mouse model is the most prevalent animal model used to study idiopathic pulmonary fibrosis (IPF), ranging from basic pathophysiological mechanisms to therapeutic modalities. High mortality rates, inconsistencies in disease induction, and great severity of the disease phenotype have limited its utility and clinical relevance. In this study, we identify conditions in the mouse bleomycin model that maintain the desired IPF phenotype found in patients while avoiding the usual, associated rapid mouse mortality. Methods In two independent studies, we analyzed the effects of incremental intratracheal (IT) high (1-3 U/kg) and low (0.05-0.5 U/kg) bleomycin doses on pulmonary fibrosis in mice. We observed dose effects on weight loss, morbidity and mortality, inflammation, lung collagen content, presence of various biomarkers in bronchoalveolar lavage fluid (BALf), and histology 14 days post-treatment, when the animals were in the active phase of fibrosis. Results We characterize the fibrotic effects of various bleomycin doses in mice on pulmonary inflammation, myofibroblast activation, vascular leakiness, angiogenesis, and extracellular tissue remodeling. Higher bleomycin doses induced acute disease with severe and saturated responses, extreme and progressive weight loss, and high morbidity and mortality rates. In contrast, lower doses of bleomycin induced a milder and chronic response, featuring robust, active-phase fibrosis with mild weight loss and no mortality. Conclusion Here we demonstrate that the bleomycin mouse model can be used to reproduce symptoms of IPF patients in an animal by using low doses of bleomycin. Low concentrations of bleomycin induce chronic and progressive fibrosis with no mortality.

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Section: Discussionsupporting

confidence: 56%

“…In reading past reports, we found difficulties in comparing various studies. Inconsistencies in the source and quality (research-grade or pharmaceutical-grade) of bleomycin greatly impacts outcomes [4,10,11]. Furthermore, doses of bleomycin are reported with differing units (U/kg or mg/kg) without traceable, stoichiometric conversions.…”

Section: Discussionmentioning

confidence: 99%

Bleomycin mouse model with active-phase pulmonary fibrosis and no acute mortality

Kadam¹,

Faix²,

Schnitzer³

2020

Preprint

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“…Intratracheal instillation of PHMG-P (1.5 mg/kg, SK Chemicals, Seoul, Republic of Korea) into mice was performed as described previously 21 . Mice were euthanized with excessive anesthesia 7, 14 or 28 days after instillation, and lung tissues were collected for further analysis ( Fig.…”

Section: Methodsmentioning

confidence: 99%

Establishment of a mouse model for pulmonary inflammation and fibrosis by intratracheal instillation of polyhexamethyleneguanidine phosphate

et al. 2016

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Although several animal models have been developed to study human pulmonary fibrosis, lack of a perfect model has raised the need for various animal models of pulmonary fibrosis. In this study, we evaluated the pulmonary effect of polyhexamethyleneguanidine phosphate instillation into the lungs of mice to determine the potential of these mice as a murine model of pulmonary fibrosis. Intratracheal instillation of polyhexamethyleneguanidine phosphate induced severe lung inflammation manifested by the infiltration of mononuclear cells and neutrophils and increased production of IL-6, TNF-α, CCL2 and CXCL1. The lung inflammation gradually increased until 28 days after polyhexamethyleneguanidine phosphate exposure, and increases of collagen deposition and TGF-β production, which are indicators of pulmonary fibrosis, were seen. Our study showed that intratracheal instillation of polyhexamethyleneguanidine phosphate induces pulmonary inflammation and fibrosis in mice.

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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).…”

Section: Discussionmentioning

confidence: 99%

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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Dose-response Effects of Bleomycin on Inflammation and Pulmonary Fibrosis in Mice

Cited by 42 publications

References 23 publications

Bleomycin mouse model with active-phase pulmonary fibrosis and no acute mortality

Bleomycin mouse model with active-phase pulmonary fibrosis and no acute mortality

Establishment of a mouse model for pulmonary inflammation and fibrosis by intratracheal instillation of polyhexamethyleneguanidine phosphate

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

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