Abstract
BackgroundSecretoglobin (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.MethodsA 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.ResultsAdult 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.ConclusionsThese results demonstrate that SCGB3A2 is an anti-fibrotic agent, and suggest a possible therapeutic use of recombinant SCGB3A2 in the treatment of pulmonary fibrosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-015-0065-4) contains supplementary material, which is available to authorized users.
Highlights
Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, is predominantly expressed in airway epithelial cells
Western blotting using a whole lung of 3-month-old mice demonstrated that the expression of SCGB3A2 protein was approximately five-fold higher in transgenic mouse lungs compared to wild-type control lungs (Fig. 1c)
Immunohistochemical staining for SCGB3A2 confirmed that in E18.5 transgenic lungs, SCGB3A2 was strongly expressed in bronchiolar epithelial cells, the normal expression site for SCGB3A2 and the precursor to type II cells, the site of surfactant protein C (SP-C) expression (Additional file 1: Figure S2E, bottom panel) [3, 26, 27]
Summary
Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, is predominantly expressed in airway epithelial cells. Secretoglobin (SCGB) 3A2, called UGRP1 (uteroglobinrelated protein 1), is a member of the SCGB gene superfamily, consisting of cytokine-like secretory proteins of small molecular weight (~10 kDa) [1,2,3]. SCGB3A2 plays a role in lung development as demonstrated using ex vivo embryonic lung organ cultures in the presence of SCGB3A2, and in vivo by administration of SCGB3A2 to pregnant female mice, followed by examination of pre-term pups [4]. Expression of SCGB3A2 appears earlier than SCGB1A1, the founding member of the SCGB gene superfamily, called Club cell secretory protein (CCSP) or Club cell 10 kDa protein (CC10). SCGB1A1 was previously thought to be the only definitive marker for Club cells [5]
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