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01.12.2015 | Research article | Ausgabe 1/2015 Open Access

BMC Pulmonary Medicine 1/2015

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

Zeitschrift:
BMC Pulmonary Medicine > Ausgabe 1/2015
Autoren:
Yan Cai, Mitsuhiro Yoneda, Takeshi Tomita, Reiko Kurotani, Minoru Okamoto, Taketomo Kido, Hiroyuki Abe, Wayne Mitzner, Arjun Guha, Shioko Kimura
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12890-015-0065-4) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

YC conceived of the study, designed the experiments, characterized Scgb3a2-transgenic mouse lungs, carried out BLM study, and wrote a draft of the manuscript. TT established and characterized the Scgb3a2-transgenic mouse line. MY, RK, TK participated in characterization of the transgenic mouse lungs. MY, RK, MO carried out immunohistochemistry/immunofluorescence studies, and analyzed the data. HA carried out electron microscopy analysis. WM intellectually and technically contributed to morphometric analysis of mouse lungs, AG carried out characterization of mouse embryonic lungs, SK designed and integrated this study, wrote and revised the manuscript. All authors read and approved the final manuscript.

Abstract

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.
Zusatzmaterial
Additional file 1: Figure S1. Scanning electron microscopy of wild-type (WT) and Scgb3a2-transgenic mouse (TG) airways. Figure S2. Characterization of Scgb3a2-transgenic embryo lungs. Figure S3. Lung morphometric analysis. Figure S4. Survival curve of wild-type (WT) and Scgb3a2-transgenic mice (TG) after BLM treatment. Figure S5. SP-C expression in wild-type (WT) and Scgb3a2-transgenic mouse (TG) lungs at 6 and 9 weeks post-BLM administration.
12890_2015_65_MOESM1_ESM.pdf
Additional file 2: Table S1. Up and down-regulated genes in lungs of Scgb3a2-transgenic vs. wild-type mice.
12890_2015_65_MOESM2_ESM.xlsx
Literatur
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