Transgenically-expressed secretoglobin 3A2 accelerates resolution of bleomycin-induced pulmonary fibrosis in mice

BMC Pulmonary Medicine

Shioko Kimura¹  Arjun Guha⁷  Wayne Mitzner³  Hiroyuki Abe⁶  Taketomo Kido⁸  Minoru Okamoto⁵  Reiko Kurotani⁶  Takeshi Tomita⁴  Mitsuhiro Yoneda¹  Yan Cai² 

[1] Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda 20892, MD, USA;Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda 20892, MD, USA;Bloomberg School of Public Health, Johns Hopkins University, Baltimore 21205, MD, USA;Department of Pharmacology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan;Department of Veterinary Immunopathology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Hokkaido, Japan;Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University, Yonezawa 992-8510, Yamagata, Japan;Department of Medicine, Pulmonary Center, Boston University School of Medicine, Boston 02118, MA, USA;Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan

关键词: Transgenic mouse;    Spontaneous resolution of bleomycin-induced pulmonary fibrosis;    Bleomycin-induced pulmonary fibrosis model;    SCGB3A2;    SCGB;    Secretoglobin;   

Others  :  1219947
DOI  :  10.1186/s12890-015-0065-4

 received in 2014-11-20, accepted in 2015-06-28,  发布年份 2015

【 摘 要 】

Background

Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, is predominantly expressed in airway epithelial cells. While SCGB3A2 is known to have anti-inflammatory, growth factor, and anti-fibrotic activities, whether SCGB3A2 has any other roles, particularly in lung homeostasis and disease has not been demonstrated in vivo. The aim of this study was to address these questions in mice.

Methods

A transgenic mouse line that expresses SCGB3A2 in the lung using the human surfactant protein-C promoter was established. Detailed histological, immunohistochemical, physiological, and molecular characterization of the Scgb3a2-transgenic mouse lungs were carried out. Scgb3a2-transgenic and wild-type mice were subjected to bleomycin-induced pulmonary fibrosis model, and their lungs and bronchoalveolar lavage fluids were collected at various time points during 9 weeks post-bleomycin treatment for further analysis.

Results

Adult Scgb3a2-transgenic mouse lungs expressed approximately five-fold higher levels of SCGB3A2 protein in comparison to wild-type mice as determined by western blotting of lung tissues. Immunohistochemistry showed that expression was localized to alveolar type II cells in addition to airway epithelial cells, thus accurately reflecting the site of surfactant protein-C expression. Scgb3a2-transgenic mice showed normal lung development and histology, and no overt gross phenotypes. However, when subjected to a bleomycin-induced pulmonary fibrosis model, they initially exhibited exacerbated fibrosis at 3 weeks post-bleomycin administration that was more rapidly resolved by 6 weeks as compared with wild-type mice, as determined by lung histology, Masson Trichrome staining and hydroxyproline content, inflammatory cell numbers, expression of collagen genes, and proinflammatory cytokine levels. The decrease of fibrosis coincided with the increased expression of SCGB3A2 in Scgb3a2-transgenic lungs.

Conclusions

These results demonstrate that SCGB3A2 is an anti-fibrotic agent, and suggest a possible therapeutic use of recombinant SCGB3A2 in the treatment of pulmonary fibrosis.

【 授权许可】

   
2015 Cai et al.

【 图 表 】

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