title: A modified murine model of systemic sclerosis: bleomycin given by pump infusion induced skin and pulmonary inflammation and fibrosis.
abstract: 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 1∼4 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(+) leukocytes, including F4/80(+) macrophages, Gr-1(+) neutrophils, and CD3(+) T lymphocytes in BLM-treated mice. IL-1β, 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.
authors.affiliation: 1] Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China [2] Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China.
authors.forename: Minrui
authors.initials: M
authors.lastname: Liang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Jiaoyan
authors.initials: J
authors.lastname: Lv
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zou
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Yingluo
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: 1] Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China [2] Division of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Chen
authors.affiliation: 1] Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China [2] Department of Clinical Laboratory, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Guan
authors.affiliation: 1] Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China [2] Biotherapy Research Center, Fudan University, Shanghai, China.
authors.forename: Rui
authors.initials: R
authors.lastname: He
authors.affiliation: 1] Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China [2] Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China.
authors.forename: Hejian
authors.initials: H
authors.lastname: Zou
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity; D001761:Bleomycin / Q000008:administration & dosage* / Q000633:toxicity; D054426:Chemokine CXCL2 / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D015918:Infusion Pumps, Implantable; D053583:Interleukin-1beta / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D054426:Chemokine CXCL2; D053583:Interleukin-1beta; D001761:Bleomycin; D015847:Interleukin-4