We have demonstrated anti-inflammatory, growth factor and anti-fibrotic activities of SCGB3A2 in lung using various mouse models and in vitro embryonic lung organ cultures, in conjunction with administration/use of recombinant mouse SCGB3A2 protein. The use of Scgb3a2- knockout mice in ovalbumin-induced airway inflammation model further confirmed anti-inflammatory activity of SCGB3A2. On the other hand, the transgenic mice overexpressing SCGB3A2 specifically in lung under the regulation of human surfactant protein C gene promoter, when subjected to bleomycin-induced pulmonary fibrosis model, exhibited less severe fibrosis as compared with wild-type mice, establishing the anti-fibrotic activity of SCGB3A2. Further, it is known that pulmonary fibrosis induced by bleomycin in mice spontaneously resolves. The resolution process was more rapidly observed in the Scgb3a2-transgenic mice as compared with wild-type mice. Using the Scgb3a2-null mice, we revisited the fundamental question whether SCGB3A2 has anti-fibrotic activity. Bleomycin treatment caused weight loss of both Scgb3a2-null and wild-type mice, however, the loss was far more pronounced in bleomycin-treated Scgb3a2-null than wild-type mice, and the weight of day 21 of bleomycin-treated Scgb3a2-null mice was about half of that of bleomycin-treated wild-type mice. Hematoxylin & Eosin, Masson Trichrome, and Sirius Red staining of lung sections, Ashcroft fibrosis scores, hydroxyproline contents, and the levels of mRNAs encoding various collagens demonstrated that bleomycin-treated Scgb3a2-null mouse lungs had more severe fibrosis than those of wild-type mouse lungs. Total and differential inflammatory cell numbers in bronchoalveolar lavage fluids, and levels of lung mRNAs including those encoding Th2 cytokines such as IL-4 and profibrotic cytokines such as TGFbeta were higher in bleomycin-treated Scgb3a2-null mouse lungs as compared to those of wild-type mouse lungs. In contrast, mRNAs encoding surfactant proteins A, B, C, and D, and SCGB1A1, another SCGB protein expressed in airway, did not differ between bleomycin-treated Scgb3a2-null and wild-type mouse lungs. In conclusion, the pulmonary fibrosis in the Scgb3a2-null mice was more severe than the wild-type controls, thus establishing that SCGB3A2 has anti-fibrotic activity in vivo. Importantly, surfactant proteins and SCGB1A1 appear not to be involved in the susceptibility of Scgb3a2-null mice to bleomycin-induced pulmonary fibrosis. Previously we found that administration of recombinant human SCGB3A2 protein to bleomycin-induced pulmonary fibrosis model mice suppressed pulmonary fibrosis at similar degree to that found with recombinant mouse SCGB3A2 protein, thus suggesting that human SCGB3A2 may be functional as anti-fibrotic agent in human as well. These results altogether suggest the possible use of recombinant human SCGB3A2 as an anti-fibrotic agent to treat or prevent pulmonary fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010449-15
Application #
9343622
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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