We have demonstrated anti-inflammatory, growth factor and anti-fibrotic activities of SCGB3A2 using various mouse models with recombinant mouse SCGB3A2 protein. In order to demonstrate that SCGB3A2 intrinsically possesses anti-inflammatory, growth factor, and anti-fibrotic activities, and to demonstrate any other activities that SCGB3A2 may have in vivo, we produced Scgb3a2-knockout mouse (Scgb3a2-/-) and Scgb3a2 transgenic (Scgb3a2-Tg) mouse that overexpresses SCGB3A2 in lung specific fashion under the regulation of human surfactant protein C gene promoter. Scgb3a2-/- mice did not exhibit any overt phenotypes, suggesting that SCGB3A2 is not required for development and homeostasis of lung. When subjected to ovalbumin (OVA)-induced airway allergic inflammation model, Scgb3a2-/- mice in mixed genetic background showed a decreased OVA-induced airway inflammation, while six times C57BL/6NCr backcrossed congenic Scgb3a2-/- mice showed a slight exacerbation of OVA-induced airway inflammation as compared to wild-type littermates. These results indicate that the loss of SCGB3A2 function was influenced by a modifier gene(s) in mixed genetic background, and suggest that SCGB3A2 has anti-inflammatory property. The results further suggest the possible use of recombinant human SCGB3A2 as an anti-inflammatory agent. On the other hand, lung-specifically overexpressing Scgb3a2-Tg mice 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-Tg 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-Tg mouse lungs. These results demonstrate that SCGB3A2 is an anti-fibrotic agent. The studies on Scgb3a2-/- and Scgb3a2-Tg mice suggested a possible therapeutic use of recombinant SCGB3A2 in the treatment of inflammation and fibrosis of lung.
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